ENTITYA TYPEA IDA DATABASEA ENTITYB TYPEB IDB DATABASEB EFFECT MECHANISM RESIDUE SEQUENCE TAX_ID CELL_DATA TISSUE_DATA MODULATOR_COMPLEX TARGET_COMPLEX MODIFICATIONA MODASEQ MODIFICATIONB MODBSEQ PMID DIRECT NOTES ANNOTATOR SENTENCE SIGNOR_ID SCORE MAFA protein Q8NHW3 UNIPROT NKX6-1 protein P78426 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254564 0.437 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser301 SSSPNNLsPTGWSQP 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249443 0.622 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser168 YREPLCLsPASSGSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252319 0.641 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261750 0.367 MAOB protein P27338 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264002 0.8 PTPRG protein P23470 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr413 TAPESLAyNKFSIKS -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254691 0.345 PKA proteinfamily SIGNOR-PF17 SIGNOR DNM1L protein O00429 UNIPROT down-regulates activity phosphorylation Ser637 VPVARKLsAREQRDC -1 31063459 t lperfetto For example, protein kinase A (PKA) phosphorylation of Drp1S600 has been reported to decrease Drp1 GTPase activity in vitro (23, 24), whereas phosphorylation of the same conserved serine residue by Ca2+-calmodulin–dependent protein kinase Iα (CaMKIα) in Drp1 isoform 3 has been reported to cause a significant increase in mitochondrial fission SIGNOR-262551 0.2 MECP2 protein P51608 UNIPROT DEAF1 protein O75398 UNIPROT up-regulates activity binding 10090 BTO:0000142 29636529 t Gianni We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue.To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. SIGNOR-269063 0.2 ACSS2 protein Q9NR19 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271827 0.8 ACTB protein P60709 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270619 0.496 IRF4 protein Q15306 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249559 0.7 RBPJ protein Q06330 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 12361602 t apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk SIGNOR-255379 0.949 EPAS1 protein Q99814 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271584 0.2 MKNK1 protein Q9BUB5 UNIPROT SPRY2 protein O43597 UNIPROT down-regulates phosphorylation Ser121 VSSGSRSsTRTSTSS 9606 19864419 t llicata The spry2/nedd4 association involves the ww domains of nedd4 and requires phosphorylation of the mnk2 kinase sites, ser(112) and ser(121), on spry2. mnk2 silencing decreased spry2-nedd4 interactions and also augmented the ability of spry2 to inhibit fibroblast growth factor signaling. endogenous and overexpressed nedd4 polyubiquitinate spry2 via lys(48) on ubiquitin and decrease its stability. SIGNOR-188893 0.518 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC1 protein Q96A08 UNIPROT down-regulates activity monoubiquitination Lys36 KKRKRTRkESYSIYI 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271992 0.2 GABRD protein O14764 UNIPROT GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263746 0.398 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000007 25081058 t lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. SIGNOR-262595 0.663 CSNK1D protein P48730 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 t miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). SIGNOR-268000 0.866 GRK3 protein P35626 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Thr182 VKALDFRtPRNAKII 8355 BTO:0000512 11060299 t gcesareni These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors SIGNOR-247915 0.2 ATF2 protein P15336 UNIPROT SIRT4 protein Q9Y6E7 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0002572 33861966 t miannu Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). SIGNOR-267831 0.2 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1363 TFFTDNSy 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104092 0.2 ULK2 protein Q8IYT8 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274040 0.2 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys594 GNWRGMLKTSKAEEL 9606 BTO:0000007 19638400 t Barakat Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. SIGNOR-274128 0.544 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser463 SPHNPISsVS 9606 9136927 t fspada Here, we report that bmp receptors phosphorylate and activate smad1 directly. Phosphorylation of smad1 in vivo involves serines in the carboxy-terminal motif ssxs. These residues are phosphorylated directly by a bmp type i receptor in vitro SIGNOR-210084 0.725 PPARGC1A protein Q9UBK2 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 17476214 t miannu Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state. SIGNOR-268030 0.511 CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity transcriptional regulation 9606 26652733 t inferred from family member miannu Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-267788 0.281 DGC complex SIGNOR-C217 SIGNOR GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265432 0.2 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252568 0.758 AR protein P10275 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 11916967 f lperfetto Transcription assays demonstrated that liganded ar repressed beta-catenin/t cell factor-responsive reporter gene activity SIGNOR-116260 0.723 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176370 0.82 MAP3K7 protein O43318 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 11460167 t lperfetto The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination SIGNOR-109497 0.757 MARK2 protein Q7KZI7 UNIPROT KIF13B protein Q9NQT8 UNIPROT down-regulates activity phosphorylation Ser1381 KLSRRSIsSPNVNRL 9534 BTO:0000298 20194617 t miannu We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410. SIGNOR-262955 0.421 PCCB protein P05166 UNIPROT PCC complex SIGNOR-C414 SIGNOR form complex binding 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267183 0.889 FN1/SDC4 complex SIGNOR-C210 SIGNOR WNT7A protein O00755 UNIPROT up-regulates 23290138 t apalma We found that binding of ECM glycoprotein Fibronectin (FN) to Sdc4 stimulates the ability of Wnt7a to induce the symmetric expansion of satellite stem cells SIGNOR-255287 0.316 PIN1 protein Q13526 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization binding 9606 16699525 t lperfetto Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication. SIGNOR-252256 0.633 CDC34 protein P49427 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR up-regulates activity binding 9606 25425648 t miannu The ubiquitin-conjugating enzyme Cdc34 and ubiquitin ligase SCF are capable of building polyubiquitin chains onto protein substrates both rapidly and processively; this may be explained at least in part by the atypically fast rate of Cdc34 and SCF association.Here, we use protein cross-linking to demonstrate that the Cdc34-SCF interaction occurs in multiple conformations, where several residues from the Cdc34 acidic tail are capable of contacting a broad region of the SCF basic canyon. Similar patterns of cross-linking are also observed between Cdc34 and the Cul1 paralog Cul2, implicating the same mechanism for the Cdc34-SCF interaction in other members of the cullin-RING ubiquitin ligases. SIGNOR-277334 0.764 MAPK14 protein Q16539 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates phosphorylation Ser211 PGKETNEsPWRSDLL 10090 20660302 t We demonstrate here that AMPK differentially modulates glucocorticoid action by phosphorylating the human GR at serine 211 indirectly through the activation of p38 MAPK SIGNOR-255952 0.498 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr128 DGEDDGDyESPNEEE 9606 BTO:0000782 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102511 0.801 DAB2IP protein Q5VWQ8 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 27858941 f miannu DAB2IP inactivation promotes tumor growth and survival, development, and proliferation of CSC, and resistance to chemo- and radiotherapy. It induces EMT, increases cell migration and invasion, and counteracts pro-apoptotic signaling. SIGNOR-254779 0.7 FGFR2 protein P21802 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17543283 f lperfetto Furthermore, in cultures receiving FGF-2 before adipogenic induction, mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a key transcription factor in adipogenesis, was upregulated. SIGNOR-236220 0.285 TGFBR1 protein P36897 UNIPROT SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 28520219 f miannu The transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. SIGNOR-260590 0.44 FBXW11 protein Q9UKB1 UNIPROT PER1 protein O15534 UNIPROT down-regulates ubiquitination 9606 15917223 t miannu We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1 SIGNOR-137758 0.486 HPS1 protein Q92902 UNIPROT BLOC-3 complex SIGNOR-C253 SIGNOR form complex binding 9606 20048159 t lperfetto Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. SIGNOR-260691 0.748 ADORA2B protein P29275 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257414 0.277 Olopatadine chemical CHEBI:7769 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257782 0.8 SMARCE1 protein Q969G3 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270720 0.74 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates relocalization 10116 8645147 t Activated hyperphosphorylated Akt-1 bound to Ptd Ins(3,4,5)P3 -containing vesicles in a similar manner to the inactive dephosphorylated enzyme SIGNOR-254982 0.8 UTS2R protein Q9UKP6 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257319 0.251 BMPR1A protein P36894 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR up-regulates activity phosphorylation 9606 9442019 t ggiuliani In this study, we isolated human Smad5 and found that Smad5 was involved in BMP-2 signaling cascades, which mediate the bone-inducing effects of BMP-2. Smad5 was directly serine-phosphorylated by BMPIR through a physical interaction. The activated Smad5 subsequently formed a complex with DPC4, and this complex was then translocated to the nucleus. SIGNOR-255779 0.684 SB 203580 chemical CHEBI:90705 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates chemical inhibition 9606 BTO:0000222 15208625 t fstefani Pharmacological blockade of p38?/? Kinases by sb203580 inhibits the myogenic program3_5 by repressing the transcription of early (myogenin;myog) and late (muscle-creatine kinase;ckm) muscle genes in myoblasts induced to differentiate SIGNOR-126052 0.8 CDK2 protein P24941 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 SIGNOR-C83 24173284 t lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A SIGNOR-119379 0.869 CREB1 protein P16220 UNIPROT BDNF protein P23560 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000142 32603820 t miannu Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF. SIGNOR-265062 0.499 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser373 RASSRASsRPRPDDL 9606 16474210 t lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. SIGNOR-144473 0.446 MECP2 protein P51608 UNIPROT CRH protein P06850 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000142 17108082 t Luana Collectively, these results point to a specific association between WT MeCP2 and the methylated promoter region of Crh in vivo. In contrast, the MeCP2308 protein was not detected at the Crh promoter. | Thus, the results of seqChIP indicate that MeCP2 preferentially associates with a transcriptionally inactive, dimethyl-histone H3 Lys-9-rich form of the Crh promoter in mice. SIGNOR-264548 0.476 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna SIGNOR-171034 0.436 JAK1 protein P23458 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr327 NSKPKKSyIATQGCL 9534 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236274 0.762 PRKD1 protein Q15139 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Thr120 QFDAAHPtNVQRLAE 9606 BTO:0001130 19141652 t lperfetto This study provides evidence that pkd1 interacts with and phosphorylates beta-catenin at thr(112) and thr(120) we postulate that pkd1 phosphorylation is required to maintain _-catenin transcription activity. SIGNOR-183388 0.394 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT up-regulates activity phosphorylation Ser72 PPRKRLKsKGSDKDF 9606 20663873 t miannu We found that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser(64) and Ser(72), we have identified Thr(417) as a unique Pim-1 phosphorylation target. Phosphorylation of Thr(417) controls the stability of Skp2 and its ability to degrade p27. SIGNOR-259819 0.344 PRKCD protein Q05655 UNIPROT NR2F6 protein P10588 UNIPROT down-regulates phosphorylation Ser83 CKSFFKRsIRRNLSY 9606 BTO:0000782 18701084 t esanto Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6. SIGNOR-180017 0.2 MEN1 protein O00255 UNIPROT CDKN2C protein P42773 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15640349 f irozzo Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. SIGNOR-255888 0.496 GP9 protein P14770 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 16293600 t lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbalpha, disulfide-linked to GPIbbeta, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. SIGNOR-261848 0.688 EP300 protein Q09472 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates acetylation Lys57 TIVRRRAkGAMGLEH 9606 BTO:0000801 20626350 t gcesareni A recent report shows that mkp1 may also be regulated by acetylation. When raw macrophages are stimulated with lps, mkp1 becomes acetylated on lys57 by p300 SIGNOR-166581 0.313 SYNJ1 protein O43426 UNIPROT MYO1E protein Q12965 UNIPROT up-regulates activity binding 10116 BTO:0000142 17257598 t miannu We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta. SIGNOR-265423 0.433 KCNQ3 protein O43525 UNIPROT KCNQ2 protein O43526 UNIPROT up-regulates activity binding 10116 BTO:0000938 9836639 t The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current. SIGNOR-268832 0.504 MRPL27 protein Q9P0M9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262368 0.698 arginine smallmolecule CHEBI:29016 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 27126896 f Luana  Importantly, asparagine/glutamine pre-load only results in mTOR activation following amino acid stimulation (Fig. 5a), indicating that it is their exchange factor roles that elicit mTORC1 activation. SIGNOR-268013 0.8 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT up-regulates activity post translational modification Lys83 YNNVEAGkYTVGLGQ 9606 BTO:0000007 24315375 t desuccinylation lperfetto We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5 SIGNOR-267641 0.348 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t gcesareni In ad-dition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r-/co-smad complex and further pro-moting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner SIGNOR-195687 0.332 ERBB2 protein P04626 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 8816440 t gcesareni Most breast, skin, lung, ovary, and gastrointestinal tract tumors express erbb-4, and heterodimerization of this receptor with erbb-2, may be involved in some cancer SIGNOR-43844 0.517 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 9606 10884684 t lperfetto Calmodulin is the best studied and prototypical example of the e-f-hand family of ca2+-sensing proteins. In the event of a transient rise in Ca2+, the Ca2+ ion is coordinated in each Ca2+-binding loop of Ca2+–CaM by seven, primarily carboxylate, ligands. The binding of Ca2+ leads to substantial alterations in the interhelical angles within the E–F hands in each domain and dramatically changes the two domains of CaM to produce more ‘openÂ’ conformations SIGNOR-78915 0.8 PTPRE protein P23469 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1185 FGMTRDIyETDYYRK 10116 BTO:0000575 15738637 t In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163| These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver. SIGNOR-248444 0.288 RET protein P07949 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates binding 9606 8631863 t gcesareni Grb7 and grb10, likely relay signals emanating from ret to other, as yet, unidentified targets within the cell SIGNOR-41699 0.53 clozapine chemical CHEBI:3766 ChEBI HTR1F protein P30939 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258518 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250556 0.2 ECM stimulus SIGNOR-ST20 SIGNOR AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259055 0.7 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000567 11672426 f lperfetto Conversely, only activation of the TNFR1 could stimulate mitogen-activated protein kinase (MAPK) or p38 MAPK activities in a time-dependent manner. SIGNOR-226637 0.379 MYO9A protein B2RTY4 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260508 0.553 PTGFR protein P43088 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257193 0.419 CSNK2A1 protein P68400 UNIPROT TCOF1 protein Q13428 UNIPROT up-regulates activity phosphorylation Thr210 TSSSSDEtDVEGKPS 9606 BTO:0000567 25064736 t lperfetto Phosphorylated Thr 210 in Treacle is the major interaction site for NBS1|A purified GST fragment of this region was efficiently phosphorylated by CK2 in vitro (Supplementary Fig. 4; T-2) and this fragment pulled down the MRN complex from Hela nuclear extracts only when previously phosphorylated by CK2 SIGNOR-265086 0.308 POU5F1 protein Q01860 UNIPROT TBX18 protein O95935 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254945 0.327 LPAR1 protein Q92633 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256975 0.419 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser44 ESEESQDsSDSIGSS 9606 20730097 t lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf4 SIGNOR-167572 0.2 POLR1G protein O15446 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266155 0.2 DLG1 protein Q12959 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 34960191 t Barakat Immunoblot analysis showed that phosphorylation of the activating ZAP70 kinase domain residue Tyr 493 was decreased in the DLG1 KD cells. Similarly, the Tyr 319 residue of ZAP70 and Tyr 83 residue of TCR- ζ also showed reduced phosphorylation. SIGNOR-274142 0.52 CDKN1A protein P38936 UNIPROT Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR up-regulates 10090 BTO:0000222 9388774 f gcesareni The upregulation of the cyclin-dependent kinase inhibitor p21 and the dephosphorylation of retinoblastoma protein (pRb) appear to be critical regulatory events for the establishment ,,, the postmitotic ... states [in myoblasts differentiating into mature myotubes] SIGNOR-241956 0.7 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 SIGNOR-112483 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263784 0.8 PTPN1 protein P18031 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF -1 8621392 t We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis. SIGNOR-248407 0.755 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 9606 18567737 t gcesareni Interestingly, resveratrol increased the activity of protein tyrosine phosphatase ptp1b, which dephosphorylates pdgf-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on pdgfr with concomitant reduction in akt and erk1/2 kinase activity. these results for the first time provide evidence that the stilbene resveratrol targets ptp1b to inhibit pdgfr mitogenic signaling. SIGNOR-179068 0.684 HNRNPU protein Q00839 UNIPROT HOXA2 protein O43364 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262284 0.2 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-266830 0.7 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr327 NSKPKKSyIATQGCL 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236270 0.789 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 t inferred from 70% family members gcesareni We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac. SIGNOR-269964 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CDKN2B protein P42772 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11013220 f irozzo Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15Ink4B gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-β. SIGNOR-256286 0.595 INCENP protein Q9NQS7 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 7227 16824953 t lperfetto INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop SIGNOR-252048 0.706 COX7C protein P15954 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267754 0.774 ERBB2 protein P04626 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21743488 f gcesareni We demonstrate that her2 overexpression in this cellular model of dcis drives transcriptional upregulation of multiple components of the notch survival pathway. Importantly, luminal filling required upregulation of a signaling pathway comprising notch3, its cleaved intracellular domain and the transcriptional regulator hes1. SIGNOR-174747 0.409 glucocorticoid smallmolecule CHEBI:24261 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity binding 9606 18049904 t miannu Glucocorticoid action in cells is mediated by a specific receptor protein, the glucocorticoid receptor (GR). GR is a member of a superfamily of ligand-inducible transcription factors that control a variety of physiological functions; such as, metabolism, development, and reproduction. SIGNOR-268048 0.8 AMER1 protein Q5JTC6 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000007 21304492 t lperfetto Knockdown of Amer1 reduces Wnt-induced LRP6 phosphorylation, Axin translocation to the plasma membrane and formation of LRP6 signalosomesThe generation of PtdIns(4,5)P2 in regions of receptor activity triggers the recruitment of Amer1 proteins, which in turn promote LRP6 phosphorylation by recruiting Axin/GSK3_ and CK1gamma to LRP6. SIGNOR-24265 0.464 SEMA3A protein Q14563 UNIPROT PLXNA4 protein Q9HCM2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261811 0.759 S100A9 protein P06702 UNIPROT AGER protein Q15109 UNIPROT up-regulates activity binding 9606 BTO:0001545 28137827 t miannu RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33 SIGNOR-261920 0.352 PRKCB protein P05771 UNIPROT CASR protein P41180 UNIPROT down-regulates activity phosphorylation Thr888 FKVAARAtLRRSNVS 9606 BTO:0000007 12356761 t lperfetto Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor. SIGNOR-249176 0.321 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser54 ELQPMPTsPGVDLQS 9606 BTO:0000567 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-217348 0.692 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176373 0.619 oxytocin smallmolecule CHEBI:7872 ChEBI OXTR protein P30559 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257556 0.8 PRKCA protein P17252 UNIPROT F3 protein P13726 UNIPROT up-regulates phosphorylation Ser285 RKAGVGQsWKENSPL 9606 23195225 t lperfetto We previously showed that the phosphorylation of ser253 within the cytoplasmic domain of human tissue factor (tf) initiates the incorporation and release of this protein into cell-derived microparticles. Furthermore, subsequent phosphorylation of ser258 terminates this process. The phosphorylation of ser253 is known to be mediated by protein kinase c_ SIGNOR-199872 0.2 MRGPRX1 protein Q96LB2 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257326 0.2 trichostatin A chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257942 0.8 CDK1 protein P06493 UNIPROT MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop SIGNOR-249653 0.5 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Interferons have antiviral, antigrowth and immunomodulatory effects. The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260331 0.2 PDGFA protein P04085 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252286 0.7 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0002181 22012064 t irozzo Similar to CBFβ, we show that MLL binds to AML1 abrogating its proteasome-dependent degradation.Furthermore, we demonstrate that MLL binds to a region of AML1 (that is conserved in AML2 and AML3) and increases AML1 (AML2 and AML3) protein levels SIGNOR-255707 0.556 SP1 protein P08047 UNIPROT ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARalpha but, unexpectedly, not by wild-type RARalpha/RXR. Our data support a model in which the PML-RARalpha fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein. SIGNOR-255748 0.2 SP1 protein P08047 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8921911 f miannu Studies using two mutant versions of this promoter, in which the Sp1 and C/EBP-related factor binding sites were deleted, respectively, revealed that Sp1 and C/EBP-related factors activate the transcription of SOD1 gene. the binding of Sp1 to the proximal upstream region of the Cu/Zn SOD might explain the expression of Cu/Zn SOD in a wide variety of cells. SIGNOR-253899 0.296 CLIP2 protein Q9UDT6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 15631994 f lperfetto CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability. SIGNOR-265095 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Ser615 SYKIRFNsISCSDPL 9606 BTO:0001853 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251628 0.2 INO80B protein Q9C086 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270846 0.642 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser149 RRGASDLsSEEGWRL -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-251035 0.327 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t llicata Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo SIGNOR-135696 0.673 FLNA protein P21333 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity binding 9606 20156194 t miannu We used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation. The present study provides evidence that Filamin A is one of the ‘binder’ molecules presumed to directly and closely connect MKK4 and MKK7 so that they can mediate this tyrosine/threonine phosphorylation. We showed that Filamin A (as well as Filamin B and C) associate with MKK7 and MKK4, but not with JNK1 itself SIGNOR-260628 0.261 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 11278991 t lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. SIGNOR-216674 0.411 PPP1R3B protein Q86XI6 UNIPROT GYS2 protein P54840 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 t miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) SIGNOR-271732 0.77 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 19115199 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-182988 0.742 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258459 0.8 GABA-B receptor complex SIGNOR-C336 SIGNOR GNB5 protein O14775 UNIPROT up-regulates activity binding 9606 30541966 t miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. SIGNOR-265064 0.466 RPS6KA3 protein P51812 UNIPROT ATF4 protein P18848 UNIPROT up-regulates phosphorylation Ser245 TRGSPNRsLPSPGVL 9606 15109498 t lperfetto Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression SIGNOR-124436 0.628 NFIX protein Q14938 UNIPROT ANOS1 protein P23352 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268884 0.2 ZNF804A protein Q7Z570 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity binding 9606 BTO:0005397 34364876 t miannu Together these results indicate the formation of ZNF804A:STAT2 protein complex and its translocation from the cytoplasm into the nucleus upon IFN stimulation, suggesting that it may function as a signal transducer that activates IFN-mediated gene expression programs. SIGNOR-269460 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding 23729744 t apalma The released NICD translocates directly to the nucleus, where it forms a transcriptional complex with the DNA-binding protein CSL (CBF1, Suppressor of Hairless, Lag1), Mastermind (Mam) and transcriptional co-activators to drive the expression of Notch target genes SIGNOR-255377 0.95 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249464 0.624 DPF2 protein Q92785 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 f miannu Here, DPF2 appears to be another important regulator of myeloid differentiation that can cooperate with PRMT4 to maintain the “stemness” of HSPCs. SIGNOR-261969 0.7 YWHAH protein Q04917 UNIPROT KCNK18 protein Q7Z418 UNIPROT down-regulates activity binding -1 18397886 t miannu Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. In the present study, we report that 14-3-3 proteins directly bind to the intracellular loop of TRESK and control the kinetics of the calcium-dependent regulation of the channel. Coexpression of 14-3-3η with TRESK blocked, whereas the coexpression of a dominant negative form of 14-3-3η accelerated the return of the K+ current to the resting state after the activation mediated by calcineurin in Xenopus oocytes. SIGNOR-263155 0.312 AP1B1 protein Q10567 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260685 0.816 ALDH9A1 protein P49189 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.‘X’). Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). SIGNOR-269692 0.8 INPPL1 protein O15357 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates binding 9606 BTO:0000567 15668240 t gcesareni This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor. SIGNOR-133388 0.2 SPI1 protein P17947 UNIPROT Lymphopoiesis phenotype SIGNOR-PH111 SIGNOR up-regulates activity 10090 BTO:0000725 8079170 f Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor. SIGNOR-259956 0.7 CSNK2A2 protein P19784 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 t llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. SIGNOR-250984 0.311 ADRA1A protein P35348 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256955 0.28 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser435 TLASERSsPQRKSQR -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414. An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262747 0.288 CEBPB protein P17676 UNIPROT HSD11B1 protein P28845 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19088256 t lperfetto In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. SIGNOR-268972 0.287 PLK1 protein P53350 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser260 SLDSEDYsLSEEGQE 9606 12383858 t gcesareni Here we show that the oncogenic and cell cycle-regulatory protein kinase, polo-like kinase-1 (plk1), phosphorylates mdm2 at one of these residues, ser260, and stimulates mdm2-mediated turnover of p53. These data are consistent with the idea that deregulation of plk1 during tumourigenesis may help suppress p53 function. SIGNOR-94272 0.473 PIK3CB protein P42338 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242652 0.7 HRH3 protein Q9Y5N1 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256968 0.262 CTSG protein P08311 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. SIGNOR-256312 0.633 UHRF1 protein Q96T88 UNIPROT RIF1 protein Q5UIP0 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0002181 26727879 t miannu UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation.  SIGNOR-277193 0.2 THRA protein P10827 UNIPROT GATA2 protein P23769 UNIPROT down-regulates activity binding 9606 BTO:0001073 29407449 t scontino We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2. SIGNOR-267257 0.2 FGF11 protein Q92914 UNIPROT SCN10A protein Q9Y5Y9 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253442 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK9 protein P50750 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262217 0.8 ITGB1BP1 protein O14713 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257655 0.281 Caspase 3 complex complex SIGNOR-C221 SIGNOR SPTAN1 protein Q13813 UNIPROT down-regulates cleavage 9606 BTO:0000150;BTO:0000567 9624143 t amattioni Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis. SIGNOR-256450 0.667 CDK1 protein P06493 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates activity phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 t lperfetto We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly SIGNOR-264421 0.426 quinpirole chemical CHEBI:75401 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. SIGNOR-258441 0.8 SUPT7L protein O94864 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269585 0.66 MAPK12 protein P53778 UNIPROT CARM1 protein Q86X55 UNIPROT down-regulates activity phosphorylation Ser595 GPAISMAsPMSIPTN 10090 29681515 t apalma Here, we identify a role for the mitogen-activated protein kinase (MAPK) p38g/MAPK12 as a critical regulator of satellite stem cell fate through phosphorylation of Carm1. SIGNOR-255897 0.353 CDS1 protein Q92903 UNIPROT CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI up-regulates chemical modification 9606 25375833 t lperfetto CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). SIGNOR-267017 0.8 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18377662 t Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 SIGNOR-248474 0.66 Ethylketocyclazocine chemical CHEBI:4901 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258780 0.8 mTORC1 complex SIGNOR-C3 SIGNOR ATP6V1A protein P38606 UNIPROT up-regulates quantity by expression 10090 21804531 f Giorgia These data suggested that V-ATPase mRNA levels were upregulated by mTORC1 through a transcriptional mechanism. Tfeb is required for mTORC1-induced V-ATPase expression. SIGNOR-260636 0.261 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000876 BTO:0001103 19436055 t apalma The GM-CSF receptor does not have intrinsic tyrosine kinase activity, but associates with the tyrosine kinase Jak2 that is required for Œ≤c transphosphorylation and the initiation of signaling and biological activity SIGNOR-255584 0.575 RELA protein Q04206 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 17350185 t Luana Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells  SIGNOR-266087 0.2 CAPN1 protein P07384 UNIPROT GSK3A protein P49840 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase SIGNOR-251585 0.2 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 t gcesareni Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. SIGNOR-88208 0.883 PTEN protein P60484 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260055 0.2 (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin chemical CHEBI:272 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258784 0.8 thiocyanate smallmolecule CHEBI:18022 ChEBI Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates 9606 BTO:0000133 9922160 f lperfetto Myeloperoxidase plays a fundamental role in oxidant production by neutrophils. The enzyme uses hydrogen peroxide to oxidize chloride (Cl-), bromide (Br-), iodide (I-), and the pseudohalide thiocyanate (SCN-) to their respective hypohalous acids.| Our results show that thiocyanate is an important substrate of myeloperoxidase in most environments and that hypothiocyanate is likely to contribute to leukocyte antimicrobial activity. SIGNOR-270592 0.7 2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]-4-quinazolinyl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide chemical CHEBI:91367 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258181 0.8 FER protein P16591 UNIPROT JUP protein P14923 UNIPROT down-regulates activity phosphorylation Tyr550 AAGTQQPyTDGVRME 10116 BTO:0004604 14517306 t The tyrosine kinase Fer, which modifies beta-catenin Tyr142, lessening its association with alpha-catenin, phosphorylates plakoglobin Tyr549 and exerts the contrary effect: it raises the binding of plakoglobin to alpha-catenin. Fer stimulation, through modification of Tyr549, causes diminished binding of plakoglobin to components of desmosomes (desmoplakin) and increased interaction with adherens junction proteins (α-catenin) SIGNOR-251135 0.512 LRRK2 protein Q5S007 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000007 22012985 f gcesareni We report that LRRK2 activates a calcium-dependent protein kinase kinase-² (CaMKK-²)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway which is followed by a persistent increase in autophagosome formation. SIGNOR-237005 0.7 PIK3CG protein P48736 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242658 0.7 EFNA1 protein P20827 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity SIGNOR-56904 0.814 CDCA8 protein Q53HL2 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 t miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). SIGNOR-275423 0.853 MTA1 protein Q13330 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000812 18719363 f miannu MTA1 overexpression resulted in downregulation of E-cadherin and MTA3 expression and enhanced expression of the transcriptional repressors SNAIL and SLUG. SIGNOR-254594 0.421 RAB6A protein P20340 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues SIGNOR-269203 0.378 CDC5L protein Q99459 UNIPROT HNRNPM protein P52272 UNIPROT up-regulates activity binding 9606 BTO:0000567 20467437 t 1 miannu hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay. SIGNOR-239410 0.624 SIAH2 protein O43255 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272748 0.439 HARS1 protein P12081 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270803 0.8 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser21 LEAGDLEsPLSEEFL 9606 BTO:0000599 10187842 t lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-249434 0.566 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249440 0.622 CDK1 protein P06493 UNIPROT CGAS protein Q8N884 UNIPROT down-regulates activity phosphorylation Ser305 MKRKRGGsPAVTLLI 32351706 t lperfetto The major mitotic kinase CDK1-cyclin B complex phosphorylates human cGAS at S305 or mouse cGAS at S291, which inhibits its ability to synthesize cGAMP upon mitotic entry. SIGNOR-276526 0.2 HRH2 protein P25021 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257424 0.251 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10931950 t inferred from 70% family members gcesareni These data suggest that increased signaling by erbb receptors up-regulates mapk activity, which, in turn, phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression. SIGNOR-270087 0.2 CDK5 protein Q00535 UNIPROT CLOCK protein O15516 UNIPROT up-regulates phosphorylation Thr451 AVSDPSStPTKIPTD 9606 24235147 t lperfetto Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock. SIGNOR-203227 0.332 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263778 0.7 UBAP2L protein Q14157 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 BTO:0000007 25185265 t Sara UBAP2L associates with BMI1 and RNF2. UBAP2L, BMI1, RNF2, and PHC1 define a novel Polycomb subcomplex SIGNOR-261316 0.368 SRP72 protein O76094 UNIPROT SRP68 protein Q9UHB9 UNIPROT up-regulates activity binding -1 30649417 t miannu Taken together our data show that binding of the SRP68/72 heterodimer follows an ultrasensitive response dependent on the SRP72 C-terminus. Although the large solenoids of SRP68/72 have not been structurally characterized due to intrinsic flexibility, they serve as important contact sites in ribosome interaction. SIGNOR-261164 0.99 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Thr2153 LDIPLQThrPHKLVD -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259117 0.46 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT up-regulates activity phosphorylation Ser1392 SRCTSVSsLDSFESR 9606 BTO:0000038 11487578 t lperfetto Apc can be phosphorylated by ck1epsilon at ser1279 and ser1392. Mutation of conserved serine residues in the beta-catenin regulatory motifs of APC interfered with both axin-dependent phosphorylation and phosphorylation by CKIepsilon and impaired the ability of APC to regulate beta-catenin. SIGNOR-109664 0.603 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107688 0.31 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 BTO:0000567 10669763 t lperfetto In endothelial cells, tumor necrosis factor alpha (tnf-alpha) induces dephosphorylation and subsequent ubiquitin-dependent degradation of the antiapoptotic protein bcl-2. Here, we investigate the role of different putative phosphorylation sites to facilitate bcl-2 degradation SIGNOR-74927 0.54 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr869 LGAEEKEyHAEGGKV 9606 BTO:0000452 11983694 t lperfetto In summary, this study describes a novel mechanism for metal-induced egfr transactivation, which is likely to be mediated by src through the phosphorylation site of tyr-845 on egfr. emanating from a variety of growth factor receptors, including egfry845 (e-e-k-e-y845-h-a-e) SIGNOR-235921 0.615 HIF-1 complex complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity transcriptional regulation 9606 BTO:0000889 17785433 t Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration SIGNOR-267494 0.36 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation 10090 8387505 t lperfetto The pp90rsk phosphothreonine content paralleled the ERK1 activity more closely than the phosphoserine level. These results provide compelling evidence that in fibroblasts and PC12 cells ERK1 plays a direct role in the phosphorylation of pp90rsk and that pp90rsk represents a physiologically relevant substrate of extracellular-regulated kinases SIGNOR-38999 0.71 UDP(3-) smallmolecule CHEBI:58223 ChEBI P2RY6 protein Q15077 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257565 0.8 IMPDH2 protein P12268 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30518405 f miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. SIGNOR-260959 0.2 WNT6 protein Q9Y6F9 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131894 0.579 JNJ-28312141 free base chemical CID:11676971 PUBCHEM CSF1R protein P07333 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258228 0.8 BCS1L protein Q9Y276 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains. SIGNOR-262544 0.7 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser718 KEAEEESsEDD 9606 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250990 0.374 SOX2 protein P48431 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. SIGNOR-242064 0.7 CD40 protein P25942 UNIPROT BIK protein Q13323 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 f gcesareni Bik expression was weakly but significantly down-regulated by cd27 but up-regulated by cd40. SIGNOR-93390 0.2 PDE4DIP protein Q5VU43 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates binding 9606 21569246 t miannu This study ascribes a novel function to mmgl isoform 4: it meets all criteria for classification as an akap, and we show that is involved in the phosphorylation of cmybpc as well as ctni, hence mmgl is an important regulator of cardiac contractility. SIGNOR-173766 0.313 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251460 0.2 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser286 TSGGVSEsPSGFSKH 9606 21765472 t lperfetto Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency SIGNOR-175079 0.542 CDK1 protein P06493 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Ser103 RQDKKDKsRAPISAK 31253668 t lperfetto CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103|In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation SIGNOR-265728 0.256 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 10090 21145499 t milica Because we found that multiple domains of taz/yap interacted with multiple components of the crumbs complex, which include pals1, lin7c, patj, and the crumbs regulator amot, we propose that this multifactoral interaction serves to ensure that assembly of the hippo pathway and efficient phosphorylation of taz/yap is coupled only by the assembly of the crumbs complex, rather than by any single component. SIGNOR-170364 0.36 ITCH protein Q96J02 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001045 11828324 t miannu Itch promotes Ub conjugation to JunB Molecularly, Itch associated with and induced ubiquitination of JunB, a transcription factor that is involved in TH2 differentiation. However, in Itch−/− T cells under the same conditions, degradation of JunB was markedly delayed. SIGNOR-272619 0.413 ATG4B protein Q9Y4P1 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates cleavage 9606 BTO:0000007;BTO:0000567 15187094 t gcesareni Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16. SIGNOR-125449 0.799 PCSK5 protein Q92824 UNIPROT OXT protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270327 0.25 RET/PTC2 protein Q15300 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 12637586 t Manara In addition, RET/PTC-mediated cellular transformation and proliferation of transformed cells require tyrosine 705 phosphorylation of STAT3 in NIH3T3 cells. We conclude that STAT3 activation by the RET/PTC tyrosine kinase is one of the critical signaling pathways for the regulation of specific genes, such as cyclin D1, vascular endothelial growth factor, and intercellular adhesion molecule 1, and for cellular transformation. SIGNOR-260917 0.2 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 19118012 t gcesareni Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation. SIGNOR-183013 0.451 SNRPF protein P62306 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270631 0.794 CCT137690 chemical CID:25154041 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190895 0.8 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr405 VGGSGIGtPPSVLKR BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250737 0.714 TACR2 protein P21452 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257015 0.448 ITGAV protein P06756 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253209 0.866 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Ala657 MVGGVVIaTVIVITL -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261738 0.497 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 15950189 t lperfetto It has been shown previously that ribosomal protein s3 (rps3) SIGNOR-137967 0.2 olanzapine chemical CHEBI:7735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258509 0.8 NDEL1 protein Q9GZM8 UNIPROT DYNC1H1 protein Q14204 UNIPROT up-regulates activity binding 10090 BTO:0000938 11163259 t miannu LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex SIGNOR-252159 0.713 CDK1 protein P06493 UNIPROT IREB2 protein P48200 UNIPROT down-regulates phosphorylation Ser157 LQKAGKLsPVKVQPK 9606 SIGNOR-C17 18574241 t lperfetto Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity SIGNOR-179171 0.358 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT down-regulates activity phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 t lperfetto Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. SIGNOR-275530 0.255 HOXD12 protein P35452 UNIPROT MAF protein O75444 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221887 0.371 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Thr731 FEPSPYPtTSSLEDF 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276665 0.252 NFKB1 protein P19838 UNIPROT IEX-1L protein O75353 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9703517 f gcesareni Transcription factors of the nuclear factor-kappab/rel (nf-kappab) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by fas or tumor necrosis factor type alpha (tnf), iex-1l, is described here. Its transcription induced by tnf was decreased in cells with defective nf-kappab activation, rendering them sensitive to tnf-induced apoptosis, which was abolished by transfection with iex-1l. SIGNOR-59539 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 16287866 t lperfetto Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-216876 0.427 DUSP1 protein P28562 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 t gcesareni Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2. SIGNOR-46079 0.784 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding -1 10713164 t llicata SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. SIGNOR-237617 0.591 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269336 0.721 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 15209375 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-126076 0.6 FYN protein P06241 UNIPROT KIRREL1 protein Q96J84 UNIPROT up-regulates activity phosphorylation Tyr606 KDPTNGYyNVRAHED 9606 BTO:0000007 18258597 t miannu Here we have characterized Neph1, another SD component, as a novel substrate of SFK. Fyn interacts with and phosphorylates the cytoplasmic domain of Neph1 in vitro and in intact cells. Both tyrosine 637 and 638 of Neph1 are crucial for Neph1-Grb2 binding. SIGNOR-262746 0.2 RIMBP3B protein A6NNM3 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264369 0.363 UBE2E2 protein Q96LR5 UNIPROT RNF19B protein Q6ZMZ0 UNIPROT up-regulates activity binding 9606 BTO:0000914 16709802 t miannu We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM.  We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and SIGNOR-271592 0.493 CDK2 protein P24941 UNIPROT LIG3 protein P49916 UNIPROT down-regulates phosphorylation Ser210 TTTGQVTsPVKGASF 9606 17040896 t llicata Dna ligase iii_ is specifically phosphorylated in replicating cells by the cell cycle kinase cdk2. However, in response to oxidative dna damage, dna ligase iii_ is dephosphorylated in a pathway that is dependent upon the dna damage-activated, phosphatidylinositol 3-phosphate (pi3)1-related kinase atm. SIGNOR-150121 0.425 SAG protein P10523 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 25216516 t miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  SIGNOR-272844 0.417 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252849 0.909 PPM1D protein O15297 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Ser140 GKKATQAsQEY 9606 20118229 t gcesareni Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-h2ax and suppresses dna double strand break repair. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (wip1) also dephosphorylates gamma-h2ax at serine 139 in vitro and in vivo. SIGNOR-163693 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269376 0.721 SNRPA1 protein P09661 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270655 0.77 SMAD2 protein Q15796 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates activity binding 9606 phosphorylation:Ser465;Ser467 SPSVRCSsMS;SVRCSSMs 11274206 t gcesareni the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4 SIGNOR-235183 0.713 SOSTDC1 protein Q6X4U4 UNIPROT BMP4 protein P12644 UNIPROT down-regulates activity 10090 18032587 f lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 SIGNOR-242749 0.689 SRC protein P12931 UNIPROT CTTN protein Q14247 UNIPROT down-regulates activity phosphorylation Tyr421 RLPSSPVyEDAASFK -1 15169891 t lperfetto Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y-->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP. SIGNOR-246513 0.798 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 19910923 t gcesareni Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.Wnt5a Internalized fz2 probably with ror1 or ror2 through the clathrin-mediated route, whereas wnt5a competed with wnt3a for binding to fz2 to inhibit the beta-catenin pathway. SIGNOR-189120 0.761 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002552 23479728 t lperfetto Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists| SIGNOR-267668 0.382 2-[(9S)-7-(4-Chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[8-[[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxyacetyl]amino]octyl]acetamide chemical CID:121427831 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates quantity chemical inhibition 9606 29764999 t Monia DBET6 induces efficient degradation of BET proteins and inhibits the proliferation of GBM cells SIGNOR-261095 0.8 BCOR protein Q6W2J9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 10090 BTO:0004850 26847029 f irozzo Our results strongly suggest that BCOR plays an indispensable role in hematopoiesis by inhibiting myeloid cell proliferation and differentiation and offer a mechanistic explanation for how BCOR regulates gene expression such as Hox genes. SIGNOR-256011 0.7 PRKACA protein P17612 UNIPROT CLDN3 protein O15551 UNIPROT unknown phosphorylation Thr192 PPREKKYtATKVVYS 9606 15905176 t llicata Our results suggest that claudin-3 phosphorylation by pka, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of tjs in this cancer. SIGNOR-137291 0.309 HDAC2 protein Q92769 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268836 0.763 LRFN5 protein Q96NI6 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength. SIGNOR-264085 0.7 CIITA protein P33076 UNIPROT HLA-DPB1 protein P04440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11889043 f Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation|We compared four genes co-regulated by RFX and CIITA (HLA-DRA, HLA-DPB, HLA-DMB and Ii) and found that the enhanceosome and CIITA make variable, promoter-dependent contributions to histone acetylation and transcription apparatus recruitment. SIGNOR-254006 0.497 ZW10 protein O43264 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 20462495 t lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. SIGNOR-265012 0.834 SRC protein P12931 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates phosphorylation Tyr125 PIPLQETyDVCEQPP 9606 16317717 t lperfetto The wave/scar proteins regulate actin polymerisation at the leading edge of motile cells via activation of the arp2/3 complex in response to extracellular cues.Src-dependent phosphorylation of scar1 promotes its association with the arp2/3 complex SIGNOR-142724 0.414 TNF protein P01375 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20509143 f miannu we show that TNFα treatment of human breast cancer cells up-regulates SLUG with a dependency on canonical NF-κB/HIF1α signaling, which is strongly enhanced by p53 inactivation. SIGNOR-255152 0.311 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT up-regulates activity binding -1 8683730 t lperfetto Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production. SIGNOR-270548 0.428 Complement C1 complex complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT up-regulates activity cleavage Ser20 LYPGLADsAPSCPQN 31331124 t lperfetto C1s subsequently activate serum proteins C4 and C2. C4 is cleaved to fragment C4a, which is an anaphylatoxin, and to fragment C4b, which is deposited on the adjacent surfaces. C2 is cleaved to a fragment C2b, and larger fragment C2a, which binds noncovalently to C4b on the target cell membrane. This forms the C4b2a complex SIGNOR-263421 0.486 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 10747897 t miannu We demonstrate that anisomycin- and tumor necrosis factor--induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase SIGNOR-250114 0.768 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser235 SPQDSPPsKASPAQD 9606 21215781 t lperfetto Cdk5 regulates app (amyloid precursor protein) processing and tau hyperphosphorylationtau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules SIGNOR-171018 0.758 KDM5B protein Q9UGL1 UNIPROT FOXG1 protein P55316 UNIPROT up-regulates activity binding 9606 BTO:0000007 12657635 t miannu Human PLU-1 Has transcriptional repression properties and interacts with the developmental transcription factors BF-1 and PAX9. In a reporter assay system, PLU-1 has potent transcriptional repression activity. BF-1 and PAX9 also represses transcription in the same assay, but co-expression of PLU-1 with BF-1 or PAX9 significantly enhances this repression SIGNOR-223878 0.408 MAP3K5 protein Q99683 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 8974401 t lperfetto A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) SIGNOR-45373 0.622 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT down-regulates activity phosphorylation Ser81 EPVVRRLsTQFTAAN 10090 BTO:0000944 11751901 t miannu PKA increased lipolysis in cells expressing Peri A because it abrogated the inhibitory actions of Peri A on lipolysis.  amino-terminal PKA sites (Ser-81, Ser-222, and Ser-276) SIGNOR-250492 0.49 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr210 SMAIHEVyQELIQDV -1 12923183 t In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck SIGNOR-251372 0.509 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser315 AHSIHQRsRKRLSQD 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89264 0.399 MAPK9 protein P45984 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser605 LFVQLLYsPIENIQR 9606 18423204 t amattioni Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt. SIGNOR-178262 0.663 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser558 GSSQGRNsPAPAVTA 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268340 0.26 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr811 ADDSSSStSSDSLGG -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-250910 0.343 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity phosphorylation Thr66 CERSGQRtASVLWPW 9534 BTO:0001538 12138165 t T66E mutations interfered with the ability of IRAK to autophosphorylate. Thr-66 mutations abolished the capacity of IRAK to dimerize. SIGNOR-251327 0.2 3-(dibutylamino)-1-[1,3-dichloro-6-(trifluoromethyl)-9-phenanthrenyl]-1-propanol chemical CHEBI:94392 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition -1 19222165 t Luana 4 inhibited cloned hERG potassium ion channel repolarization with an IC50 comparable to other antimalarial agents in this class (Table 6). SIGNOR-257816 0.8 RPEL1 protein Q2QD12 UNIPROT D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI down-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267066 0.8 IL1B protein P01584 UNIPROT GDF5 protein P43026 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003742 19818765 f Regulation miannu GDF-5 is suppressed by IL-1beta and enhances TGF-beta3-mediated chondrogenic differentiation in human rheumatoid fibroblast-like synoviocytes. SIGNOR-251864 0.266 AKT1 protein P31749 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by destabilization phosphorylation Thr128 FIGEFAYtYAAMYDK 9606 BTO:0000007 31358653 t miannu Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.  SIGNOR-276869 0.375 NME1 protein P15531 UNIPROT KSR1 protein Q8IVT5 UNIPROT unknown phosphorylation Ser406 TRLRRTEsVPSDINN -1 12105213 t miannu Mutation of Ser392 to alanine consistently reduced Nm23-H1 phosphorylation, confirming it as a site of Nm23-H1 kinase activity The unique phosphorylation pattern of KSR by Nm23-H1 will be the subject of further investigation to determine its effects on KSR protein binding, subcellular localization, response to various signals, etc. SIGNOR-250299 0.553 PRKACA protein P17612 UNIPROT WT1 protein P19544 UNIPROT down-regulates phosphorylation Ser393 KTCQRKFsRSDHLKT 9606 9366517 t llicata Pka phosphorylated wt1 at ser-365 and ser-393 in vitro, as well as at additional sites, and this phosphorylation abolished the dna-binding activity of wt1 in vitro. Using wt1 mutants in which ser-365 and ser-393 were mutated to ala individually and in combination, we showed that phosphorylation of these sites was critical for inhibition of dna binding in vivo. SIGNOR-53176 0.344 DAAM1 protein Q9Y4D1 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 9606 19365405 t gcesareni B-catenin-independent wnt signaling can activate rho family gtpases through at least two mechanisms: (1) direct activation of rac1 by dvl;and (2) activation of rhoa via dvl-associated activator of morphogenesis-1 (daam1), possibly through the weak-similarity guaninenucleotide exchange factor (wgef)1. SIGNOR-185268 0.818 NOTCH2 protein Q04721 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 BTO:0003960 31699119 t miannu  NOTCH2 attenuated the TRAF6-AKT signaling axis via an interaction between the NOTCH2 intracellular domain (N2ICD) and TRAF6, which inhibited epithelial-mesenchymal transition (EMT) and eventually suppressed NPC metastasis. SIGNOR-265562 0.314 KMT2E protein Q8IZD2 UNIPROT RARA protein P10276 UNIPROT up-regulates activity binding 9606 21205756 t miannu MLL5 binds to retinoic acid receptor α (RARα) and induces transcriptional activation of RARα target genes by methylation of lysine residues of histone H3. SIGNOR-260041 0.339 ESRRB protein O95718 UNIPROT NR0B1 protein P51843 UNIPROT down-regulates 9606 12482977 f lperfetto When dax-1 was cotransfected, it exerted efficient repression on transcription of the reporter gene activated by gal4-ad4bp-lbd, gal4-lrh-1-lbd, gal4-err2-lbd SIGNOR-96533 0.348 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr382 DHYRYSDtTDSDPEN 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-161122 0.616 POLR3A protein O14802 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266133 0.865 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 18455992 t gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. SIGNOR-178607 0.412 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1011 DVFPCSVyVPDEWEV -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-233564 0.2 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 7529876 t llicata We found that maximal kinase activity of fak immune complexes requires phosphorylation of both tyrosines 576 and 577. Our results indicate that phosphorylation of fak by src (or other src family kinases) is an important step in the formation of an active signaling complex. SIGNOR-27879 0.2 F2R protein P25116 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257127 0.433 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7322 RAGSRAGsRASSRRG 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264433 0.442 UV stress stimulus SIGNOR-ST7 SIGNOR RRM2B protein Q7LG56 UNIPROT up-regulates 9606 BTO:0001061 14583450 f miannu Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3. SIGNOR-259362 0.7 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134624 0.2 GSK3B protein P49841 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity by destabilization phosphorylation 7227 11955435 t lperfetto We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog. SIGNOR-219231 0.525 belinostat chemical CHEBI:61076 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257953 0.8 CHRNA7 protein P36544 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity binding 27167578 t Here, we demonstrate a role for α7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the α7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. SIGNOR-253985 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Arg) smallmolecule CHEBI:29171 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270363 0.8 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-52863 0.819 PKA proteinfamily SIGNOR-PF17 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264961 0.7 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT up-regulates activity phosphorylation Tyr498 YAFSSNIyTRGSHLD 9606 BTO:0000007 27738316 t miannu Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis. SIGNOR-263189 0.363 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates activity phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 20640476 t lperfetto AMPK can directly phosphorylate PGC-1a at Thr177 and Ser538 in in vitro assays PGC-1a phosphorylation might not directly affect its intrinsic coactivation activity, but, rather, release it from its repressor protein p160myb [79] and/or allow deacetylation and subsequent activation by SIRT1 SIGNOR-209940 0.491 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-219269 0.776 TLR4 protein O00206 UNIPROT JUN protein P05412 UNIPROT up-regulates activity 9606 BTO:0000801 19592489 f lperfetto The transcription factor AP-1 consists of a variety of dimers composed of members of the Jun, Fos, and ATF families of proteins. The Jun proteins can both homo- and heterodimerize with Fos members to form transcriptionally active complexes. The stimulation of macrophage TLR4 receptor rapidly activates not only the NF-kappaB pathway but also MAPK pathways, including JNK, ERK, and p38. Many of the downstream targets of MAPK pathways are transcription factors that include c-Jun. SIGNOR-249518 0.451 CAMK2A protein Q9UQM7 UNIPROT GFPT1 protein Q06210 UNIPROT up-regulates phosphorylation Ser261 CNLSRVDsTTCLFPV 9606 17941647 t gcesareni Amp-activated protein kinase and calcium/calmodulin-dependent kinase ii were identified to phosphorylate specifically ser243 in vitro. Phosphorylation by these two kinases results in an increase of enzymatic activity by 1.4-fold. These findings suggest for the first time that hgfat1 may be regulated by kinases other than pka. SIGNOR-158486 0.2 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14976552 t gcesareni We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-122725 0.617 CDC25A protein P30304 UNIPROT PKM protein P14618 UNIPROT up-regulates activity dephosphorylation Ser37 MCRLDIDsPPITARN 9606 27485204 t lperfetto Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop. SIGNOR-276967 0.495 ITCH protein Q96J02 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys371 PTSMVLTkVSASTVP 9606 BTO:0002181 19881509 t Giorgia These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation SIGNOR-260362 0.636 ABL1 protein P00519 UNIPROT DDB2 protein Q92466 UNIPROT down-regulates phosphorylation 9606 12107171 t miannu C-abl might act as a negative regulator of uv-ddb by phosphorylating ddb2 SIGNOR-90446 0.466 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270696 0.828 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253681 0.725 PTPN6 protein P29350 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2274 KNREGLNyMVLATEC 9606 11266449 t gcesareni Phosphorylated ros strongly and directly associates with shp-1.Overexpression Of shp-1 results in ros dephosphorylation and effectively downregulates ros-dependent proliferation and transformation SIGNOR-105919 0.372 PRKCE protein Q02156 UNIPROT SLC4A3 protein P48751 UNIPROT up-regulates activity phosphorylation Ser67 EKPSRSYsERDFEFH 9606 BTO:0000007 11739292 t lperfetto We conclude that following Ang II stimulation of cells, PKCepsilon phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium. SIGNOR-249127 0.311 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70440 0.2 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257973 0.8 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Ser297 GLRYNRLsAIPRSLA 29383184 t lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. SIGNOR-275567 0.2 BRAP protein Q7Z569 UNIPROT CDC14A protein Q9UNH5 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 19152073 t k63 miannu Brap2 promotes Lys-63 linked ubiquitination of HsCdc14A. Collectively, these results support the idea that Brap2 facilitates Lys-63 linked ubiquitin modification of HsCdc14A, which may not be targeted for degradation, but mainly for protein–protein interactions or other regulatory functions. SIGNOR-271777 0.34 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1651 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273090 0.749 Reduced Vitamin K smallmolecule CHEBI:8784 ChEBI vitamin K epoxide smallmolecule CHEBI:28371 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto GGCX carboxylates the glutamic acid residues of vitamin K-dependent proteins (VKDP) to Gla using reduced vitamin K, while simultaneously oxidizing the reduced form of vitamin K to an epoxide form. SIGNOR-265909 0.8 MAP3K7 protein O43318 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease SIGNOR-260266 0.253 TBL1XR1 protein Q9BZK7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates ubiquitination 9606 20547759 t miannu We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation SIGNOR-166111 0.407 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser672 TLYDRYSsPPASTTR 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) SIGNOR-104715 0.673 JUN protein P05412 UNIPROT SPI1 protein P17947 UNIPROT up-regulates activity binding 9606 BTO:0004136 12393465 t apalma These results indicate that AML1-ETO competes c-Jun away from binding to the β3β4 domain of PU.1. Thus, the c-Jun coactivation function of PU.1 is down-regulated and this in turn down-regulates transcriptional activity of PU.1. SIGNOR-255660 0.566 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr795 AAERPGGtPTPVIAY -1 19448668 t miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. SIGNOR-262880 0.384 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 14679200 t lperfetto Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro SIGNOR-120347 0.732 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR ID2 protein Q02363 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f Also comparable with ID1, RARα, RXR, PML, PLZF-RARα, and RARα/RXR did not transactivate the ID2 promoter, whereas PML-RARα did. Together, these data show that like ID1, ID2 may also be transactivated by PML-RARα without direct DNA binding of the fusion protein. SIGNOR-255727 0.2 JAK3 protein P52333 UNIPROT JAK3 protein P52333 UNIPROT up-regulates phosphorylation Tyr904 SLRLVMEyLPSGCLR 9606 18250158 t lperfetto Y904 and y939 are required for optimal jak3 autophosphorylation and kinase activity in vitro SIGNOR-160664 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2C protein O00762 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271356 0.605 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017876 t llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. SIGNOR-176862 0.659 TOPBP1 protein Q92547 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates binding 9606 20068082 t gcesareni Topbp1 directly activates atr/atrip and promotes atr-mediated chk1 phosphorylation. SIGNOR-163214 0.792 ARF6 protein P62330 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272153 0.7 TLRs proteinfamily SIGNOR-PF20 SIGNOR TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252095 0.2 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 SIGNOR-C15 18303014 t gcesareni The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner SIGNOR-160838 0.286 PYG proteinfamily SIGNOR-PF96 SIGNOR glycogen smallmolecule CHEBI:28087 ChEBI down-regulates quantity chemical modification 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267953 0.8 RB1 protein P06400 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 21902831 t gcesareni Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation. SIGNOR-176563 0.4 NGF protein P01138 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates binding 9606 11114882 t gcesareni Ngf is the preferred ligand for trka, bdnf and nt4/5 are preferred for trkb, and nt3 for trkc (barbacid 1994). These specificities are not absolute, and nt3 is also a ligand for trka and trkb. SIGNOR-85114 0.955 GTF2F2 protein P13984 UNIPROT POLR2E protein P19388 UNIPROT up-regulates activity binding 9534 11278533 t miannu Direct Interaction Between the Subunit RAP30 of Transcription Factor IIF (TFIIF) and RNA Polymerase Subunit 5, Which Contributes to the Association Between TFIIF and RNA Polymerase II. we showed that RPB5 binds RAP30 but not RAP74 and associates to TFIIF through the binding to RAP30. SIGNOR-261179 0.92 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B SIGNOR-251237 0.568 MAPK1 protein P28482 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates phosphorylation Thr132 SSPPTPTtPGFQVQH 9606 BTO:0000938 BTO:0000142 17681692 t llicata We have shown that erk2 is a kinase to phosphorylate nurr1 on multiple sites. S126 and t132, which are located near af1 core of nurr1, are dominant sites phosphorylated by erk2. reporter gene assays show that nurr1delta124-133/t185a, an erk2 phospho-site mutant form, could not further increase its transcriptional activity on th promoter, suggesting that nurr1 phosphorylation by erk2 may regulate its transcriptional activity on th promoter. SIGNOR-157171 0.401 SPI1 protein P17947 UNIPROT ANXA1 protein P04083 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19428102 f miannu Identification of annexin 1 as a PU.1 target gene in leukemia cells. PU.1 is a master regulator, and critical for the developmen tof a common progenitor for lymphoid-myeloid cell lineages in the hematopoietic system. From microarray analysis, we found that several genes including annexin 1 were markedly induced in K562PU.1KD cells. Annexin 1 is a calcium- and phospholipid-binding protein and increased expression leads to the constitutive activation of extracellular signal-regulated kinase (ERK) SIGNOR-261688 0.2 MYOG protein P15173 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 t P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells SIGNOR-251575 0.336 SLC9A3R1 protein O14745 UNIPROT ADRB2 protein P07550 UNIPROT up-regulates activity binding -1 9671706 t lperfetto The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of the beta2-adrenergic receptor and plays a role in adrenergic regulation of Na+/H+ exchange. NHERF contains two PDZ domains, the first of which is required for its interaction with the beta2 receptor. SIGNOR-262598 0.587 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT up-regulates activity phosphorylation Tyr144 MVPDEVEyLLKKVLS 9606 BTO:0000661 18976935 t lperfetto Here, we report that the T cell receptor (TCR)-induced translocation of SLAT to the immunological synapse required Lck-mediated phosphorylation of two tyrosine residues located in an immunoreceptor tyrosine-based activation motif-like sequence but was independent of the SLAT PH domain. This subcellular relocalization was coupled to, and necessary for, activation of the NFAT pathway|These results indicate that SLAT undergoes Lck-dependent phosphorylation on Tyr-144 and Tyr-133 upon TCR and CD28 stimulation. SIGNOR-253368 0.509 DYRK1A protein Q13627 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000938 20696760 t gcesareni Dyrk1a phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. we found that dyrk1a phosphorylates p53 at ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor h19-7 cells. In addition, dyrk1a-induced p53 phosphorylation at ser-15 led to a robust induction of p53 target genes SIGNOR-167407 0.425 RUNX3 protein Q13761 UNIPROT PEA15 protein Q15121 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255097 0.2 APC-c complex SIGNOR-C150 SIGNOR USP37 protein Q86T82 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 21596315 t lperfetto USP37 is ubiquitinated by APCCDH1 in late mitosis and early G1 phase||Inactive USP37 now becomes a substrate for APCCDH1, undergoing K11-linked polyubiquitination and proteasomal degradation. Elimination of USP37 ensures that it does not antagonize APC/C substrate degradation during mitosis. SIGNOR-265048 0.293 CBS protein P35520 UNIPROT L-homocysteine zwitterion smallmolecule CHEBI:58199 ChEBI down-regulates quantity chemical modification 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275828 0.8 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI up-regulates quantity precursor of 9606 9914248 t miannu Glutamine PRPP amidotransferase (GPATase) catalyzes the first step of de novo purine biosynthesis, the conversion of 5-phosphoribosyl-(~)l-pyrophosphate (PRPP) to 5-phosphoribosyl-([3)l-amine (PRA). The nitrogen source for the reaction is the amide group of glutamine. SIGNOR-267292 0.8 NEFH protein P12036 UNIPROT Neurofilament L/H complex SIGNOR-C208 SIGNOR form complex binding 9606 BTO:0000938 19468066 t miannu Neurofilaments are obligate heteropolymers that are minimally comprised of the low molecular neurofilament protein L (NFL) plus the medium and/or high molecular weight proteins neurofilament protein M (NFM) and neurofilament protein H SIGNOR-255273 0.442 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159454 0.259 FBXW7 protein Q969H0 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 26971449 t lperfetto We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system. SIGNOR-253394 0.403 RPS6KB1 protein P23443 UNIPROT LTC4S protein Q16873 UNIPROT down-regulates activity phosphorylation Ser36 ARRAFRVsPPLTTGP -1 27365393 t miannu Here, we identified Ser(36) as the major p70S6k phosphorylation site, along with a low frequency site at Thr(40), using an in vitro phosphorylation assay combined with mass spectrometry. Cellular LTC4S activity is suppressed by PKC-mediated phosphorylation, and recently a downstream p70S6k was shown to play an important role in this process. SIGNOR-277256 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 f Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) SIGNOR-254039 0.7 (~{s})-(4-Fluoranyl-2-Propyl-Phenyl)-(1~{h}-Imidazol-2-Yl)methanol chemical CID:126961334 PUBCHEM F2RL1 protein P55085 UNIPROT down-regulates activity chemical inhibition -1 28445455 t Simone Vumbaca The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. | Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. SIGNOR-261118 0.8 RPS6KA3 protein P51812 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70432 0.2 RNF8 protein O76064 UNIPROT ACD protein Q96AP0 UNIPROT up-regulates quantity by stabilization polyubiquitination Lys147 QDLDVQKkLYDCLEE 9606 22101936 t miannu The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. SIGNOR-272722 0.2 TRAF6 protein Q9Y4K3 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 17135271 t These data establish a signaling cascade in which regulated site-specific Lys-63-linked TRAF6 auto-ubiquitination is the critical upstream mediator of IKK. SIGNOR-252099 0.2 TDG protein Q13569 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275713 0.7 sulpiride chemical CHEBI:32168 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. When receptors were labeled with [lzs1]-NCQ-298, D2 and D3 receptors displayed similar potencies for sulpiride, a D2 receptor antagonist (Figure 3A, Table I). SIGNOR-258431 0.8 SNRPE protein P62304 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270657 0.723 TLR4 protein O00206 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates binding 9606 18221795 t fstefani Mappit analysis of early toll-like receptor signalling events. SIGNOR-160424 0.727 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 21317289 t gcesareni We report that Sufu is phosphorylated at Ser-342 and Ser-346 by GSK3? and cAMP-dependent protein kinase A (PKA), respectively, and phosphorylation at this dual site stabilizes Sufu against Shh signaling-induced degradation SIGNOR-200496 0.453 PTH1R protein Q03431 UNIPROT CYP27B1 protein O15528 UNIPROT up-regulates quantity 28363951 f lperfetto These PTH actions are mainly mediated by Gsalpha signaling, which induces the expression of the gene encoding 25-hydroxyvitamin D 1alpha-hydroxylase (Cyp27b1) and destabilizes the transcript encoding vitamin D 24-hydroxylase (Cyp24a1) SIGNOR-270554 0.305 DDAH2 protein O95865 UNIPROT nitric oxide smallmolecule CHEBI:16480 ChEBI up-regulates quantity 33850055 f lperfetto Upon viral infection, DDAH2 relocated to mitochondria, where it induced the production of nitric oxide (NO) and the activation of dynamin-related protein 1 (Drp1) SIGNOR-275649 0.8 succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271805 0.8 methiothepin chemical CHEBI:64203 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258853 0.8 PTPN22 protein Q9Y2R2 UNIPROT ZAP70 protein P43403 UNIPROT down-regulates dephosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000007 16461343 t miannu Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70). SIGNOR-144345 0.698 POU5F1 protein Q01860 UNIPROT RARG protein P13631 UNIPROT up-regulates quantity 27499297 f SimoneGraziosi OCT4 positively controls the level of RARgamma SIGNOR-269222 0.305 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-59153 0.745 HNF1B protein P35680 UNIPROT AKR1C4 protein P17516 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003846 2044952 f 2 miannu Hepatocyte nuclear factor (HNF)-4_/_, HNF-1_, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene.HNF-1_ binds to the target element in the rat DBP gene in the liver, while vHNF-1 recognizes a target element in extrahepatic tissues. The ability of vHNF-1-A to activate the rat DBP gene is much higher than that of vHNF-1-C. SIGNOR-239960 0.2 PRKG1 protein Q13976 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t Translocation from Endosome to Lysosome fspada A specific pkg inhibitor inhibits h1r downregulation in cho cells (37). However, direct activation of pkg in these cells does not cause h1r down-regulation, indicating that more studies are required to clarify the role of pkg in h1r down-regulation. SIGNOR-124360 0.2 SNARE_complex complex SIGNOR-C346 SIGNOR Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 30267828 f miannu The best-studied SNARE-complex is the one formed between three proteins, VAMP2/synaptobrevin-2, syntaxin-1, and SNAP-25, that mediate fast exocytosis in neuronal cells. SIGNOR-265065 0.7 G3BP1 protein Q13283 UNIPROT G3BP2 protein Q9UN86 UNIPROT up-regulates activity binding 9606 BTO:0000007 23279204 t miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260862 0.465 ZAP70 protein P43403 UNIPROT SH2B3 protein Q9UQQ2 UNIPROT up-regulates phosphorylation Tyr273 LEMPDNLyTFVLKVK 9606 BTO:0000782 9169414 t lperfetto In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation. SIGNOR-48854 0.367 EP300 protein Q09472 UNIPROT MEF2D protein Q14814 UNIPROT up-regulates binding 9606 11796223 t lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. SIGNOR-232162 0.736 decanoic acid chemical CHEBI:30813 ChEBI GPR84 protein Q9NQS5 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257508 0.8 CDK3 protein Q00526 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 t gcesareni Egf-induced cdk3 activation caused c-jun phosphorylation at ser63 and ser73, resulting in increased ap-1 transactivation. SIGNOR-183009 0.451 TFPI protein P10646 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi SIGNOR-106353 0.259 KAT6B protein Q8WYB5 UNIPROT KAT6A/KAT6B complex SIGNOR-C54 SIGNOR form complex binding 9606 17694082 t miannu Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity. SIGNOR-157307 0.4 PLCD4 protein Q9BRC7 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 9125218 t gcesareni A key pathway is the hydrolysis of PIP2 . This is mediated by PLC, and yields the two second messengers 1,4,5-IP3 and DAG SIGNOR-195516 0.8 UCK1 protein Q9HA47 UNIPROT uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity chemical modification 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275858 0.8 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation -1 8454633 t gcesareni Intrinsic activity was demonstrated in vitro against a variety of phosphotyrosine-containing substrates including BIRK, the autophosphorylated cytoplasmic kinase domain of the insulin receptor beta subunit. SIGNOR-39155 0.382 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269357 0.721 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1924 SPTSPKYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176829 0.778 AMPK complex SIGNOR-C15 SIGNOR Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 20647423 t lperfetto Ampk recruitment and h2b ser36 phosphorylation colocalized within genes activated by ampk-dependent pathways, both in promoters and in transcribed regions. SIGNOR-216471 0.2 RBX1 protein P62877 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000093 20130088 t miannu I3C-dependent activation of the aryl hydrocarbon receptor (AhR) initiates Rbx-1 E3 ligase-mediated ubiquitination and proteasomal degradation of ERalpha protein. SIGNOR-271434 0.347 FOXJ1 protein Q92949 UNIPROT DNAI1 protein Q9UI46 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266932 0.373 NR4A1 protein P22736 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 f gcesareni Our data suggest a mechanism for transrepression between two nuclear receptors, gr and ngfi-b. SIGNOR-132312 0.327 COL21A1 protein Q96P44 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 t lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  SIGNOR-272343 0.2 IL4R protein P24394 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 BTO:0000776 7538655 f gcesareni The overlapping and distinct protein tyrosine phosphorylation and activation of the same jak1 kinase in t lymphocytes strongly suggests that il-4 and il-9 share the common signal transduction pathways. SIGNOR-28399 0.668 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-250846 0.546 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-252808 0.2 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser793 PRPSPLPsPQPAPRR 9606 BTO:0000007 17711861 t miannu  The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3.  SIGNOR-276072 0.339 MKRN1 protein Q9UHC7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys292 EEENLRKkGEPHHEL 9606 BTO:0002552 19536131 t miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53 SIGNOR-271847 0.438 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 18570871 t gcesareni Together, our findings demonstrate that jnk1-mediated multisite phosphorylation of bcl-2 stimulates starvation-induced autophagy by disrupting the bcl-2/beclin 1 complex. SIGNOR-179096 0.571 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266520 0.8 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273105 0.749 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser371 AHSSHLKsKKGQSTS 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269327 0.442 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR NAMPT protein P43490 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19299583 t miannu Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1. Transduction of Clock/Bmal1 into mouse embryonic fibroblasts appeared to up-regulate Nampt expression ∼1.6-fold (Fig. 3E). SIGNOR-268021 0.604 MAP2K1 protein Q02750 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni Pd98059, a specific inhibitor of mek in addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-178636 0.665 BAD protein Q92934 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity relocalization 9606 BTO:0000007 15694340 t lperfetto Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. SIGNOR-133756 0.796 CDH1 protein P12830 UNIPROT AE/b7 integrin complex SIGNOR-C186 SIGNOR up-regulates binding 9606 BTO:0000782 7969453 t gcesareni Here we show that heterotypic adhesive interactions between epithelial cells and intraepithelial lymphocytes in vitro are mediated by e-cadherin and the alpha e beta 7 integrin. SIGNOR-35210 0.644 DLX5 protein P56178 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity transcriptional regulation 9031 17335796 t gcesareni Dlx5 initiates a complete osteogenic differentiation in these early primary cells, by triggering Runx2, osteopontin, alkaline phosphatase, and other gene expression according to the sequential temporal sequence observed during skull osteogenesis €œin vivo€. SIGNOR-245340 0.379 BAF250b E3 ligase complex SIGNOR-C522 SIGNOR Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity ubiquitination 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271441 0.2 FLT3 protein P36888 UNIPROT IDH1 protein O75874 UNIPROT up-regulates activity phosphorylation Tyr42 VELDLHSyDLGIENR -1 34289383 t lperfetto Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity SIGNOR-267629 0.432 MAPKAPK5 protein Q8IW41 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001286 17254968 t llicata Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37 SIGNOR-152847 0.755 CHL1 protein O00533 UNIPROT ANK1 protein P16157 UNIPROT up-regulates quantity relocalization 10116 BTO:0000227 7961622 t miannu Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. SIGNOR-266724 0.519 LRP5 protein O75197 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 23209147 t Gianni The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization. SIGNOR-262525 0.681 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates activity dephosphorylation 10090 17158101 t gcesareni Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis. SIGNOR-236867 0.801 TNKS protein O95271 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263383 0.2 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. . These results define tab2 as an adaptor linking tak1 and traf6 and as a mediator of tak1 activation in the il-1 signaling pathway . taken together, these results indicate that polyubiquitination of rip1 mediates the independent recruitment of tab2 and nemo, which in turn recruits tak1 and ikk, respectively, to tnf-r1. SIGNOR-105860 0.935 EIF4B protein P23588 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 t Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability SIGNOR-261293 0.864 ER stress stimulus SIGNOR-ST9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates 9606 22492984 f gcesareni Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins SIGNOR-196941 0.7 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates binding 9606 19029956 t lperfetto At the cellular level, the ligands IGF1, IGF2 and insulin bind to various members of the insulin receptor (IR) - IGF1 receptor (IGF1R) family. SIGNOR-182484 0.956 PPP1R3B protein Q86XI6 UNIPROT GYS1 protein P13807 UNIPROT up-regulates binding 9606 BTO:0000759 36551183 t miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) SIGNOR-271734 0.713 TAB1 protein Q15750 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205437 0.39 RPS23 protein P62266 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262428 0.894 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation 9606 BTO:0000130 16778989 t inferred from 70% family members gcesareni Inhibitors of the erk1/2 pathway abrogated gm-csf-induced phosphorylation of ser345, while p38 mapk inhibitor abrogated tnf-alpha-induced phosphorylation of ser345.These results show that the ala-mutated p47phox acts as a dominant-negative inhibitor of endogenous p47phox and clearly indicate that phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells. SIGNOR-270187 0.2 GSK3B protein P49841 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Thr687 PRGMGPGtPAGYGRG 9606 20932480 t lperfetto We conclude that t687 is the primary site of threonine phosphorylation in psf. Gsk3 directly phosphorylates the splicing regulatory protein psf. In this phosphorylated form, psf is sequestered in a complex with trap150, precluding it from binding the ess1 sequence in cd45 alternatively spliced exons. Upon t?_Cell stimulation, reduced gsk3 activity leads to reduced psf phosphorylation, thereby releasing psf from trap150 and allowing it to participate in activation-induced cd45 exon skipping SIGNOR-168389 0.349 MCHR2 protein Q969V1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257268 0.577 TESK2 protein Q96S53 UNIPROT DSTN protein P60981 UNIPROT down-regulates activity phosphorylation Ser3 sGVQVADE 9606 BTO:0001363 11418599 t lperfetto The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity. SIGNOR-246707 0.428 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 395188 t lperfetto Studies show that aromatization (a reaction sequence unique in steroid biosynthesis) of androgens to estrogens is not limited to the female reproductive organs but also occurs in extragonadal tissue. Aromatization involves the loss of the angular C-19 methyl group and cis elimination of the 1beta and 2beta hydrogens from the androgen precursors, androstenedione and testosterone, to yield estrone and estradiol, respectively. In men, the production of estrone is 18 ug/day and is mainly extraglandular. Aromatase activity has also been shown in a variety of tissues in mammalian and other species. SIGNOR-251528 0.8 Caspase 3 complex complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates activity cleavage Asp403 WRDPDQTdGLGLSYL 9606 9671712 t miannu We showed that human gelsolin was cleaved during Fas-mediated apoptosis in vivo and that the caspase-3 cleavage site of human gelsolin was at D352 of DQTD352G. gelsolin seems to have dual functions, i.e., it both prevents and, once cleaved, induces cell death. SIGNOR-256433 0.63 CDK2 protein P24941 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 17038621 t lperfetto Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1. SIGNOR-252892 0.644 EPHB1 protein P54762 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity relocalization 26319181 t lperfetto The phosphorylated CNK1 interacts with ephrinB1. The binding of ephrinB1 to CNK1 connects RhoA and p115RhoGEF with ephrinB1-associated MKK4, promoting JNK activation and cell migration. SIGNOR-275922 0.2 SYK protein P43405 UNIPROT FCGR2C protein P31995 UNIPROT up-regulates activity phosphorylation Tyr287 PEETNNDyETADGGY -1 8756631 t miannu Fyn and Blk definitely phosphorylate Y-282 in the ITAM of FcgRIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addition to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation SIGNOR-262674 0.2 SMAD4 protein Q13485 UNIPROT SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255832 0.2 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 t miannu In contrast, we demonstrate for the first time that NEK6 phosphorylates SGK1 efficiently at its hydrophobic motif in vitro and peptide-mapping analysis indicates that this is the major site of phosphorylation (Fig 3). Ser377 is a more minor site of phosphorylation located in the kinase domain of SGK1, which has not been reported to undergo phosphorylation previously. the phosphorylation of the hydrophobic motif of SGK1 in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1 SIGNOR-262954 0.341 WNT9B protein O14905 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132111 0.613 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0000007 23279204 f miannu Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli. SIGNOR-260864 0.7 APLNR protein P35414 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256824 0.419 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr410 GVVDSGVyAVPPPAE 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98569 0.258 EGFR protein P00533 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity 10090 BTO:0000667 15284024 f JAK activation occurs upon ligand-mediated receptor multimerization because two JAKs are brought into close proximity, allowing trans-phosphorylation. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates, STATs. lperfetto Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion SIGNOR-235655 0.621 WWTR1 protein Q9GZV5 UNIPROT TEAD proteinfamily SIGNOR-PF22 SIGNOR up-regulates activity binding 9606 23431053 t miannu YAP/TAZ do not contain intrinsic DNA-binding domains but instead bind to the promoters of target genes by interacting with DNA-binding transcription factors. YAP/TAZ mainly bind to the transcription factors TEAD1–4 to regulate genes involved in cell proliferation and cell death SIGNOR-230722 0.896 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 t miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. SIGNOR-276060 0.398 TRIM25 protein Q14258 UNIPROT DDX58 protein O95786 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 17392790 t lys63 miannu The carboxy-terminal SPRY domain of TRIM25 interacts with the N-terminal CARDs of RIG-I; this interaction effectively delivers the Lys 63-linked ubiquitin moiety to the N-terminal CARDs of RIG-I, resulting in a marked increase in RIG-I downstream signalling activity.  Thus, we demonstrate that TRIM25 E3 ubiquitin ligase induces the Lys 63-linked ubiquitination of RIG-I, which is crucial for the cytosolic RIG-I signalling pathway to elicit host antiviral innate immunity. SIGNOR-271645 0.799 BRCA1-BARD1 complex complex SIGNOR-C297 SIGNOR H4C1 protein P62805 UNIPROT up-regulates activity ubiquitination -1 12485996 t lperfetto Strikingly, as well as H2AX, the nucleosome core histones H2A, H2B, H3 and H4 were all ubiquitylated efficiently by BRCA1/BARD1, while the linker histone H1 was not (Figure 3).| Generally, histone proteins are required for compaction of nuclear DNA into chromatin, and their modification is thought to loosen this compaction. Therefore, one might envisage that ubiquitylation of γH2AX by BRCA1/BARD1 at DNA breaks modulates local chromatin packaging to facilitate the action of DNA repair enzymes. SIGNOR-263234 0.2 MAOA protein P21397 UNIPROT 3-methoxytyramine smallmolecule CHEBI:1582 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-263999 0.8 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT up-regulates activity phosphorylation Tyr31 FLSEETPySYPTGNH 9606 15688067 t miannu Paxillin is phosphorylated by FAK–Src on Tyr31 and Tyr118, and this can also promote SH2-mediated binding of Crk to paxillin. Overexpressing paxillin that is mutated at these phosphorylation sites inhibits the turnover of focal contacts6 and cell motility, which therefore supports the presence of multiple routes for FAK–Src-mediated signalling in modulating the dynamics of cell adhesion sites. SIGNOR-28247 0.913 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Thr770 DSILRLQtWDEAVFR 9606 21068236 t lperfetto Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of rig-i are phosphorylated by casein kinase ii (ck2) in the resting state of the cell and dephosphorylated when cells are infected by rna virus. Mutation at aa position 770 or 854 to 855 of rig-i renders it constitutively active SIGNOR-169408 0.2 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser129 ICPSLPYsPVSSPQS 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198122 0.271 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 t inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-270195 0.2 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser181 DQGSLCTsFVGTLQY -1 10022904 t llicata Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays. SIGNOR-250772 0.659 CTNNB1 protein P35222 UNIPROT TRRAP protein Q9Y4A5 UNIPROT up-regulates binding 9606 16510874 t gcesareni The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. SIGNOR-144966 0.568 INPP4B protein O15327 UNIPROT phosphatidylinositol bisphosphate smallmolecule CHEBI:37328 ChEBI down-regulates quantity chemical modification 9606 21127264 t gcesareni Collectively this data indicates INPP4B is the only PtdIns(3,4)P2 4-phosphatase expressed in breast cancer cells and suggests a correlation between INPP4B and hormone receptor status in human breast cancer SIGNOR-252433 0.8 CSF2RB protein P32927 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR form complex binding 9606 BTO:0000876 BTO:0001103 9680354 t apalma The high-affinity GMR is known to be composed of a specific ligand-binding alpha subunit (GMRα) and a common beta subunit (βc), which is also a component of the interleukins-3 (IL-3) and -5 (IL-5) receptors. SIGNOR-255583 0.866 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268072 0.8 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser178 TATETQCsVPIQCTD 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262716 0.738 AURKA protein O14965 UNIPROT FADD protein Q13158 UNIPROT up-regulates phosphorylation Ser203 MSWNSDAsTSEAS 9606 21978935 t lperfetto Here, we report that aur-a phosphorylates s203 of the fas associated with death domain protein (fadd)phosphorylation of s203 by aur-a serves to prime fadd for plk1-mediated phosphorylation at s194 SIGNOR-176739 0.348 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser282 TAPLSPMsPPGYKLV 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249403 0.6 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2029 NAVDDLGkSALHWAA 9606 17636029 t gcesareni This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60. SIGNOR-156911 0.42 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CTTN protein Q14247 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 20444238 t inferred from 70% family members gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-270051 0.2 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr263 NKSESVVyADIRKN 9606 11751924 t lperfetto Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr SIGNOR-113410 0.476 EEF1A2 protein Q05639 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269539 0.8 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA4 protein Q9Y5G9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265675 0.2 PORCN protein Q9H237 UNIPROT WNT3A protein P56704 UNIPROT up-regulates activity palmitoylation Ser209 KCKCHGLsGSCEVKTC 9606 BTO:0000007 20826466 t And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane. SIGNOR-256598 0.693 TGFb proteinfamily SIGNOR-PF5 SIGNOR SNAI1 protein O95863 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 29305973 t miannu Epithelial-mesenchymal transition (EMT) takes place, namely fibrosis, development and cancer. the process of EMT is integral to a number of physiological and disease states. TGF-β1 is a major effector of this process that activates various key transcription factors such as Snai1. SIGNOR-265251 0.2 HIC1 protein Q14526 UNIPROT LRP8 protein Q14114 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001938;BTO:0000815 24076391 f miannu The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1. ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. SIGNOR-254243 0.2 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189141 0.388 POLR2E protein P19388 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270923 0.2 TNKS2 protein Q9H2K2 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 19759537 t lperfetto Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin. SIGNOR-263378 0.698 ASAP2 protein O43150 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 t miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. SIGNOR-269705 0.647 leucine smallmolecule CHEBI:25017 ChEBI SESN2 protein P58004 UNIPROT down-regulates activity chemical inhibition 9606 26449471 t We find that leucine, but not arginine, disrupts the Sestrin2- GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20micromolar, which is the leucine concentration that half-maximally activates mTORC1 SIGNOR-254897 0.8 MLLT10 protein P55197 UNIPROT SS18/MLLT10 complex SIGNOR-C75 SIGNOR form complex binding 9606 11423977 t miannu Based on these results, a model is proposed in which the syt and af10 proteins act in concert as bipartite transcription factors SIGNOR-108924 0.432 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 21525957 t gcesareni Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1. SIGNOR-173437 0.492 SRC protein P12931 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 14699166 t llicata Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells. SIGNOR-120492 0.537 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260112 0.648 MTMR3 protein Q13615 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity 9606 BTO:0000007 26787466 t lperfetto The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity. SIGNOR-245108 0.311 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser634 TFLSPQCsPQHSPLG 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251249 0.403 ILK protein Q13418 UNIPROT NACA protein E9PAV3 UNIPROT up-regulates phosphorylation Ser1906 PELEEQDsTQATTQQ 9606 15299025 t lperfetto The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription SIGNOR-127631 0.411 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown -1 9016777 t lperfetto QM is phosphorylated by PKC and the extent of phosphorylation by PKC is correlated with the extent of inhibition of binding of QM to c-Jun. SIGNOR-248957 0.309 GUCY1A3-B3 complex SIGNOR-C140 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244105 0.8 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR JUN protein P05412 UNIPROT down-regulates activity sumoylation Lys226 HPRLQALkEEPQTVP 9606 BTO:0000567 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263006 0.256 TAOK1 protein Q7L7X3 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 BTO:0000007 9786855 t lperfetto The activation of and binding to MEK3 by TAO1 implicates TAO1 in the regulation of the p38-containing stress-responsive MAP kinase pathway SIGNOR-60818 0.566 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Ser215 KLDTFCGsPPYAAPE 9606 BTO:0000568 12879020 t lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. SIGNOR-104059 0.318 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates phosphorylation 9606 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-217400 0.867 NFKBIA protein P25963 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity binding 9606 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-217394 0.81 SMURF1 protein Q9HCE7 UNIPROT FAF2 protein Q96CS3 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272698 0.283 AMPK complex SIGNOR-C15 SIGNOR ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr356 GNPFDSKtEQGPQVD 10090 BTO:0000801 30375985 t lperfetto Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. SIGNOR-271862 0.254 MMP12 protein P39900 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. SIGNOR-263611 0.333 STK4 protein Q13043 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells SIGNOR-171009 0.2 EGFR protein P00533 UNIPROT PLD2 protein O14939 UNIPROT up-regulates activity phosphorylation Tyr179 RLLTMSFyRNYHAMT 9606 9837959 t llicata Using transiently transfected human embryonic kidney fibroblasts (HEK293), we demonstrate here that PLD1 activity, and to a lesser extent PLD2 activity, is stimulated in response to epidermal growth factor (EGF). PLD2, but not PLD1, associates with the EGF receptor in a ligand-independent manner and becomes tyrosine-phosphorylated upon EGF receptor activation. Tyrosine 11 (Tyr-11) of PLD2 was identified as the specific phosphorylation site. Mutation of this residue to phenylalanine enhanced basal activity almost 2-fold SIGNOR-251095 0.526 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258232 0.8 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr101 EGLSMGNyIGLINRI 9606 BTO:0001282 16373505 t PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. SIGNOR-251112 0.2 PRKCI protein P41743 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr359 YLYEKANtPELKKSV 9606 BTO:0000551 21189248 t gcesareni Our data support a model in which pkc?-Mediated phosphorylation regulates ect2 binding to the oncogenic pkc?-Par6 complex thereby activating rac1 activity and driving transformed growth and invasion. SIGNOR-170790 0.483 UCHL1 protein P09936 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 9521656 t lperfetto These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains SIGNOR-249693 0.861 Tuberoinfundibular peptide of 39 residues smallmolecule CHEBI:80275 ChEBI PTH2R protein P49190 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257576 0.8 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 9606 BTO:0000007 19212654 t miannu The human WW45 protein enhances MST1-mediated apoptosis in vivo In this model, hWW45 binds both MST1 and LATS through its coiled-coil domains and WW domains, respectively, and facilitates the phosphorylation of LATS by MST1. This model could explain the enhanced apoptotic efficacy of MST1 with the over-expression of hWW45 and the attenuated MST1-induced apoptosis with the down-regulation of endogenous hWW45. SIGNOR-263661 0.893 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps. SIGNOR-270215 0.2 cyclosporin A chemical CHEBI:4031 ChEBI TTN protein Q8WZ42 UNIPROT up-regulates 9606 17636278 f Regulation of transcription Cyclosporine A induces titin expression via MAPK/ERK signalling and improves proliferative and invasive potential of human trophoblast cells. SIGNOR-251975 0.8 HBB protein P68871 UNIPROT AHSP protein Q9NZD4 UNIPROT down-regulates activity 9606 2545495 f Regulation miannu EDRF is rapidly inactivated by hemoglobin and superoxide. SIGNOR-251750 0.55 NLGN4Y protein Q8NFZ3 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264163 0.2 MCHR2 protein Q969V1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256938 0.251 PLK4 protein O00444 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 t lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap SIGNOR-166007 0.795 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI up-regulates quantity precursor of 9606 31586547 t miannu The second enzyme in the oxiPPP, 6-phosphogluconolactonase (PGLS), converts 6PGL to 6-phosphogluconate (6PG). SIGNOR-267056 0.8 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser343 TVSKTETsQVAPA -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248968 0.446 MAPK3 protein P27361 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. SIGNOR-169004 0.317 Goserelin chemical CHEBI:5523 ChEBI LHCGR protein P22888 UNIPROT up-regulates activity chemical activation 9606 BTO:0001033 11900209 t miannu LHRH analogues, such as goserelin, reduce circulating concentrations of oestrogen in premenopausal women via an inhibitory effect on the hypothalamic–pituitary–ovarian axis. At the cellular level, LHRH analogues bind to LHRH receptors on pituitary gland cells, an action which causes an initial surge in the secretion of luteinizing hormone (LH). Once bound to ligand, these LHRH receptors form clusters, which are then sequestered within the cell, thereby reducing the number of unoccupied LHRH receptors. SIGNOR-259162 0.8 IFNAR complex SIGNOR-C243 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity by expression 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260852 0.278 DMC1 protein Q14565 UNIPROT SYCP3 protein Q8IZU3 UNIPROT up-regulates activity binding 10090 BTO:0001275 SIGNOR-C351 10525529 t miannu The eukaryotic RecA homologues RAD51 and DMC1 function in homology recognition and formation of joint-molecule recombination intermediates during yeast meiosis. We also show that mouse RAD51 and DMC1 establish protein-protein interactions with each other and with the chromosome core component COR1(SCP3) in a two-hybrid system and in vitro binding analyses. These results suggest that the formation of a multiprotein recombination complex associated with the meiotic chromosome cores is essential for the development and fulfillment of the meiotic recombination process. SIGNOR-264206 0.391 WNT7B protein P56706 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131978 0.639 CREBBP protein Q92793 UNIPROT IRF9 protein Q00978 UNIPROT up-regulates activity acetylation Lys81 TGGPAVWkTRLRCAL 9606 BTO:0000007 17923090 t lperfetto CBP was also the most effective one among the acetyltransferases tested for catalyzing IRF9 acetylation in 293T cells. [²] Figure 5 (F) K81 acetylation is required for IRF9 dimerization between the N-terminal 1-118 and the C-terminal 340-393 regions. In the left panel, Myc-DBD (1- 118) of IRF9 was cotransfected with 118-393, 118-339, or 1-393 (FL) of IRF9 in 293T cells. Anti-IRF9 (C-terminal region) precipitates were analyzed with anti-Myc or anti-IRF9. Anti-IRF9 precipitates, prepared from 293T cells cotransfected with the C-terminal fragment 118-393 of IRF9 and Myctagged DBD of different forms, were analyzed with anti-Myc or anti-IRF9 (right panel). SIGNOR-217787 0.365 pictrelisib chemical CHEBI:65326 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 BTO:0000149 21876152 t gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed SIGNOR-252664 0.8 CTH protein P32929 UNIPROT L-selenocystathionine zwitterion smallmolecule CHEBI:62226 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275823 0.8 Normorphine chemical CHEBI:7633 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258823 0.8 MAPK1 protein P28482 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 16282323 t lperfetto Erk phosphorylation serves as a signal for bim ubiquitination and proteasomal degradation SIGNOR-141584 0.709 exemestane chemical CHEBI:4953 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191520 0.8 CSNK1D protein P48730 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser247 KTFLSRHsLDMKFSY 9606 20699359 t lperfetto In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha SIGNOR-167476 0.327 MYC protein P01106 UNIPROT CDKN2B protein P42772 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001271 12835716 f gcesareni Miz1 is a zinc finger transcription factor with an n-terminal poz domain. Complexes with myc, bcl-6 or gfi-1 repress expression of genes like cdkn2b (p15(ink4)) or cdkn1a (p21(cip1)). SIGNOR-102746 0.592 F2RL2 protein O00254 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256761 0.2 CENPO protein Q9BU64 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265209 0.823 C1QBP protein Q07021 UNIPROT C1QB protein P02746 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263403 0.344 AURKB protein Q96GD4 UNIPROT SSU72 protein Q9NP77 UNIPROT down-regulates quantity by destabilization phosphorylation Ser19 CSSNQNRsMEAHNIL 24149858 t lperfetto Here we report that Aurora B kinase directly interacts with and phosphorylates Ssu72, a new cohesin-binding phosphatase, at Ser 19 in vitro and in vivo. The Aurora B-mediated phosphorylation of Ssu72 causes the structural modification of Ssu72 protein, downregulates phosphatase activity and triggers the ubiquitin-dependent degradation of Ssu72. SIGNOR-275529 0.255 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120100 0.314 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser880 YNVYGIEsVKI 9606 BTO:0000007 10501226 t lperfetto Here, we show that the C terminus of GluR2 of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor is phosphorylated by protein kinase C and that serine-880 is the major phosphorylation site. This phosphorylation also occurs in human embryonic kidney (HEK) cells by addition of 12-O-tetradecanoylphorbol 13-acetate. SIGNOR-249022 0.702 IRF2BP2 protein Q7Z5L9 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 t miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. SIGNOR-224073 0.644 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser717 GVARVRKsKGKYAYL -1 8848293 t lperfetto Only two peptides containing Ser-662 and Ser-696 were found to be efficiently phosphorylated by protein kinase C (PKC). The peptide including Ser-696 was also phosphorylated by protein kinase G (PKG). SIGNOR-248955 0.702 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates activity phosphorylation Tyr139 Y-->K -1 18775312 t miannu In addition, we analyzed Fes SH2-kinase that had been autophosphorylated on the kinase activation segment (Y713) in complex with a substrate peptide. SIGNOR-277898 0.2 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser279 SSPTAPLsPMSPPGY 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249402 0.6 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser553 ARPPASPsPQRQAGP 9606 10880969 t lperfetto Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin. SIGNOR-78887 0.575 Caspase 3 complex complex SIGNOR-C221 SIGNOR GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 t amattioni Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation. SIGNOR-256461 0.63 CDK1 protein P06493 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Ser537 GTFSPGAsPGSEART 9606 BTO:0000567 31981797 t miannu CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines. SIGNOR-276833 0.421 cinolazepam chemical CHEBI:59514 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263801 0.8 PKN1 protein Q16512 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 14970201 t lperfetto Here we identify a region in the carboxyl terminus of gef-h1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein includes a coiled-coil motif, a proline-rich motif that may interact with src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We show that phosphorylation of gef-h1 at ser(885) by pak1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. SIGNOR-122191 0.293 MAPK1 protein P28482 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000567 9535909 t lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-249401 0.6 RNF11 protein Q9Y3C5 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity binding 9606 BTO:0000150 19131965 t lperfetto Rnf11, together with tax1bp1 and itch, is an essential component of an a20 ubiquitin-editing protein complex; rnf11 is required for a20 to interact with and inactivate rip1 to inhibit tnf-mediated nf-_kb activation. SIGNOR-183188 0.564 ALK protein Q9UM73 UNIPROT STAT3 protein P40763 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 t gcesareni Npm-alk has been shown to activate signal transducer and activator of transcription (stat) 3, a transcriptional regulator of cyclin d3.Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. SIGNOR-122085 0.447 IKBKE protein Q14164 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser419 TPDDFLNsVDEMDTG 9606 28481329 t miannu Virus-activated kinase IKKɛ phosphorylated YAP at Ser403 and thereby triggered degradation of YAP in lysosomes and, consequently, relief of YAP-mediated inhibition of the cellular antiviral response.  SIGNOR-277355 0.447 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser152 PTPAKRRsSALWSEM -1 15684429 t miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. SIGNOR-263019 0.251 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5). SIGNOR-249225 0.32 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR PTGS2 protein P35354 UNIPROT up-regulates quantity by expression 9606 17705188 f lperfetto Inflammatory stimuli can activate IkappaB kinase (IKK) signalsome and subsequently the nuclear factor kappa B (NF-kappaB), which influences gene expression of cyclooxygenase-2 (Cox-2) along with other transcription factors. SIGNOR-260262 0.37 PAK1 protein Q13153 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 21822311 t lperfetto Pak1 directly phosphorylates _-catenin proteins at ser675 site and this leads to more stable and transcriptional active _-catenin SIGNOR-175944 0.547 GOLGA3 protein Q08378 UNIPROT GOPC protein Q9HD26 UNIPROT up-regulates activity binding 9606 BTO:0000567 15951434 t miannu Golgin-160 belongs to the golgin family of Golgi-localized proteins, which have been implicated in Golgi structure and function. PIST (also known as GOPC, CAL, and FIG) has been implicated in the trafficking of a subset of plasma membrane proteins, supporting a role of golgin-160 in vesicular trafficking. binding of golgin-160, TC10, and syntaxin-6 to PIST may coordinate membrane trafficking of some plasma membrane proteins in cell types where these proteins are expressed. SIGNOR-261234 0.489 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr771 ADIESSNyMAPYDNY 9606 18567737 t gcesareni Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr. SIGNOR-179080 0.684 CSNK2A1 protein P68400 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity phosphorylation Ser131 DESLANLsEDEYYSE 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276902 0.321 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser183 PPTQKPPsPPMSGRG 9606 21419341 t lperfetto Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex. SIGNOR-172869 0.43 LFNG protein Q8NES3 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates binding 9606 11346656 t gcesareni Although both manic fringe (mfng) and lunatic fringe (lfng) decreased the binding of jagged1 to notch2 and not that of delta1, the decrease by mfng was greater in degree than that by lfng. We also found that both fringe proteins reduced jagged1-triggered notch2 signaling, whereas neither affected delta1-triggered notch2 signaling. SIGNOR-107705 0.69 LNX1 protein Q8TBB1 UNIPROT CLDN17 protein P56750 UNIPROT down-regulates quantity by destabilization ubiquitination -1 22889411 t miannu We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo. SIGNOR-272900 0.297 PELP1 protein Q8IZL8 UNIPROT Rix1 complex complex SIGNOR-C373 SIGNOR form complex binding 9606 BTO:0000007 22190735 t miannu LAS1L was first described as a nucleolar protein required for maturation of the 60S preribosomal subunit. In this paper, we demonstrate that LAS1L interacts with PELP1, TEX10, and WDR18, the mammalian homologues of the budding yeast Rix1 complex, along with NOL9 and SENP3, to form a novel nucleolar complex that cofractionates with the 60S preribosomal subunit. our data identify a novel mammalian complex required for 60S ribosomal subunit synthesis, providing further insight into the intricate, yet poorly described, process of ribosome biogenesis in higher eukaryotes. SIGNOR-265469 0.796 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 12024016 t gcesareni Results from this study indicate that the checkpoint protein kinase atm (mutated in ataxia telangiectasia) was required for phosphorylation of brca1 in response to ionizing radiation. Brca1 is phosphorylated at tyrosine residues in an atm-dependent, radiation-dependent manner. SIGNOR-87845 0.816 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates phosphorylation Thr182 KSGEPLStWCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122784 0.573 AEBP2 protein Q6ZN18 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 t lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). SIGNOR-241903 0.864 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser13 ESFTMASsPAQRRRG 9606 16446360 t gcesareni In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2 SIGNOR-143984 0.961 SP3 protein Q02447 UNIPROT ITGA11 protein Q9UKX5 UNIPROT up-regulates quantity by expression 9606 BTO:0001282 16300938 t lperfetto We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors. SIGNOR-253351 0.2 PRKCD protein Q05655 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Ser727 TDNLLPMsPEEFDEV 9606 17502367 t gcesareni All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below). SIGNOR-154791 0.578 MAPK14 protein Q16539 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR up-regulates activity phosphorylation 10029 BTO:0005787 20887952 t The chromatin redistribution of PRC2 in differentiating SCs is regulated by the p38a kinase, which promotes the formation of a complex containing p38a, EZH2, and YY1, via direct phosphorylation of EZH2. SIGNOR-253599 0.33 NPFFR2 protein Q9Y5X5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256988 0.274 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr67 LSILSGGtPKRCLDL 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216777 0.842 GNRHR protein P30968 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257064 0.251 TANC2 protein Q9HCD6 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 t miannu Kinesin-3 Family Member KIF1A Interacts with Liprin-α and TANC2. TANC2 and Liprin-α Recruit KIF1A-Driven DCVs in Dendritic Spines. Upon Ca2+/CaM binding, KIF1A is activated, allowing for DCV loading and motility. KIF1A-driven DCVs are recruited in dendritic spines by liprin-α and TANC2, which ensure a precise mechanism of synaptic tagging for the vesicles. SIGNOR-266891 0.249 COPS4 protein Q9BT78 UNIPROT COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270762 0.937 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 10737616 t lperfetto Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease. SIGNOR-249418 0.558 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser189 DEEFREPsTGKTCLP 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260884 0.366 (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O5-[3-(4,4-diphenyl-1-piperidinyl)propyl] ester O3-methyl ester chemical CHEBI:103931 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258463 0.8 SMC3 protein Q9UQE7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR form complex binding 28430577 t lperfetto Cohesin is an evolutionarily conserved complex composed of four core proteins (SMC1A, SMC3, RAD21 and either STAG2 or STAG1) that form a ring-shaped structure able to encircle chromatin SIGNOR-263312 0.91 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNA2 protein P20248 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189966 0.8 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Thr160 NKLRRYTtFSKRKTG 10753652 t llicata Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors. SIGNOR-250639 0.373 PML protein P29590 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity binding 9606 15356634 t lperfetto Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-232090 0.535 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Thr520 DNTPHTPtPFKNALE 9606 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250741 0.714 PTPN21 protein Q16825 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 15143158 t Dephosphorylation of Y527 was more pronounced in cells expressing PTPD1 at each time point tested. PTPD1C1108S drastically inhibited Y527 dephosphorylation|Activation of src requires dephosphorylation of src residue Y527. This promotes displacement of the SH2 domain from this residue and subsequent autophosphorylation of residue Y416 within the activation loop SIGNOR-248725 0.634 CHRM5 protein P08912 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257291 0.368 AKT1 protein P31749 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-84971 0.761 PIGF protein Q07326 UNIPROT PIGG protein Q5H8A4 UNIPROT up-regulates quantity by stabilization binding 10029 BTO:0000246 15632136 t miannu We show that the human homolog of Gpi7p, termed hGPI7, binds to and is stabilized by PIG-F and that hGPI7 competes with PIG-O for binding to PIG-F. PIG-F Binds to and Stabilizes hGPI7 and PIG-O Independently. These results are consistent with the hypothesis that overexpression of hGPI7 decreases the biosynthetic activity of PIG-O by decreasing the available PIG-F, thereby destabilizing PIG-O. SIGNOR-261358 0.636 GUCY1A2-B3 complex SIGNOR-C138 SIGNOR 3',5'-cyclic GMP smallmolecule CHEBI:16356 ChEBI up-regulates quantity chemical modification 9606 10977868 t gcesareni Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types SIGNOR-244093 0.8 MICU1 protein Q9BPX6 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270871 0.692 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser890 RQRKRKLsFRRRTDK 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70726 0.309 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273043 0.55 CHRM1 protein P11229 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256735 0.39 FUS protein P35637 UNIPROT VPS16 protein Q9H269 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262808 0.2 AKT1 protein P31749 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates activity phosphorylation Ser971 STRLRQQsSSSKGDS 9606 27858941 t miannu DAB2IP can be phosphorylated by RIP1 on Ser 604 within the PER domain, and by AKT1 on Ser 847 within the proline-rich domain. Although RIP1-mediated phosphorylation is stimulatory,40 a recent study reported that AKT-mediated phosphorylation inhibits DAB2IP functions SIGNOR-254780 0.506 CUX1 protein P39880 UNIPROT PIK3IP1 protein Q96FE7 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24316979 t miannu We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. SIGNOR-260072 0.374 CDK5 protein Q00535 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates activity phosphorylation Thr668 ENLDLKLtPYKVLAT 9606 BTO:0000007 20513426 t miannu Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. two additional amino acids in Vps34, Thr159 and Thr668, were found to be phosphorylated only after co-transfection with Cdk5/p25 SIGNOR-259811 0.362 MEF2C protein Q06413 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 10082551 f lperfetto During embryogenesis, the MEF2 genes are expressed throughout developing skeletal and cardiac muscle lineages, as well as in the nervous system (19, 42, 65, 68).MEF2C is the first member of the family to be expressed in developing muscle cell lineages, with transcripts appearing in precardiac cells by about embryonic day 7.75 and in skeletal muscle precursor cells within the myotome of the developing somites by embryonic day 8.5. Soon thereafter, the other MEF2 genes are expressed in overlapping patterns (19). After birth, the expression of MEF2A, -B, and -Dbecomes ubiquitous, whereas the expression of MEF2C becomes restricted to skeletal muscle, brain, and spleen SIGNOR-219368 0.7 POU5F1 protein Q01860 UNIPROT TBXT protein O15178 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254929 0.2 LRRC4 protein Q9HBW1 UNIPROT CDK4 protein P11802 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264059 0.2 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248349 0.479 PLK1 protein P53350 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-189045 0.355 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR Helper_T-lymphocyte_activation phenotype SIGNOR-PH196 SIGNOR up-regulates 9606 31810556 f scontino Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies. SIGNOR-267874 0.7 S3I-201 chemical CHEBI:91224 ChEBI STAT3 protein P40763 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194847 0.8 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 BTO:0000567 9271440 t gcesareni The activation of p70s6k is associated with multiple phosphorylations at two sets of sites. The first set, s411, s418, t421, and s424, reside within the autoinhibitory domain, mutations of s371 abolished kinase activity. In mitotic hela cells, when the activity of cdc2 is high, s6k1 is phosphorylated at multiple ser/thr, pro (s/tp) sites, including ser(371), ser(411), thr(421), and ser(424). SIGNOR-50607 0.388 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1 protein P68104 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269387 0.92 EGFR protein P00533 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266319 0.349 NRXN1 protein Q9ULB1 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265458 0.411 UNII-XH2662798I chemical CID:16156006 PUBCHEM Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates 9606 20068082 f gcesareni Pf-00477736 also significantly enhances docetaxel efficacy in vitro and in vivo, in association with decreased cdc25c cytoplasmic phosphorylation (ser216) and histone h3 phosphorylation (ser10)(42). SIGNOR-265352 0.8 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity phosphorylation Ser416 SVDDLANsGQVGTAR 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function. SIGNOR-246737 0.2 LE-TGN SNARE complex SIGNOR-C157 SIGNOR IGF2R protein P11717 UNIPROT up-regulates activity relocalization 9606 18195106 t lperfetto These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function. SIGNOR-253083 0.474 PSMC3 protein P17980 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263369 0.874 5-azacytidine chemical CHEBI:2038 ChEBI DNMT1 protein P26358 UNIPROT down-regulates activity chemical inhibition 9606 14585280 t miannu Both Azacitidine and Decitabine may also exert antitumor activity through induction of DNA hypomethylation, by forming a covalent complex with the major DNA methyltransferase (now termed DNMT1).Azacitidine and Decitabine effectively deplete the cell of functional DNA methylating activity, which results in profound hypomethylation after several rounds of DNA replication (Fig. 2). DNMT1 is considered a bona fide anticancer target at different levels SIGNOR-259293 0.8 CSNK1A1 protein P48729 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 t gcesareni We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation. SIGNOR-174542 0.508 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201274 0.599 BCAR1 protein P56945 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22431919 f miannu In MCF-7 cells, we identified a positive feedback loop where p130(Cas) positively regulates EGR1 and NAB2, which in turn induce p130(Cas) expression. SIGNOR-253892 0.2 RACK1 protein P63244 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 24726876 t miannu RACK1 Mediates the Formation of the IRF3-RACK1-PP2A Complex and Promotes the Dephosphorylation of IRF3.Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. SIGNOR-260945 0.2 IL1B protein P01584 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity 9606 BTO:0002417 32454942 f miannu IL-1β, an inflammatory cytokine primarily expressed in activated macrophages, monocytes, and microglia, significantly contributes to MS development. IL-1β promotes differentiation of T cells into Th17 cells via the STAT3 pathway and thereby promotes and aggravates the inflammatory environment in the CNS SIGNOR-263820 0.579 PTEN protein P60484 UNIPROT EGR2 protein P11161 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260049 0.309 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser283 CASVRRAsSADDIEA 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70722 0.309 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates 9606 BTO:0000007;BTO:0000782 11073940 f gcesareni Mekk2 activated bmk1/erk5 to a greater extent, which might correlate with a higher affinity mekk2-mek5 interaction. A dominant negative form of mek5 blocked the activation of bmk1/erk5 by mekk2 SIGNOR-84184 0.755 ROR2 protein Q01974 UNIPROT FLNA protein P21333 UNIPROT up-regulates binding 9606 18667433 t gcesareni Additionally, the association of ror2 with the actin-binding protein filamin a is required for wnt5a-induced jnk activation and polarized cell migration. SIGNOR-179668 0.424 EIF2S3 protein P41091 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269116 0.939 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR PI3K complex SIGNOR-C156 SIGNOR down-regulates 26721223 f Excessive accumulation of Aβ protein in the AD brain may lead to a decrease in the levels of phosphatidylinositol-3 kinase (PI3K) and the serine/threonine protein kinase B (Akt) activity. SIGNOR-255492 0.7 GUCY1B1 protein Q02153 UNIPROT GUCY1A2-B3 complex SIGNOR-C138 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243980 0.2 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PKA proteinfamily SIGNOR-PF17 SIGNOR up-regulates activity chemical activation 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258763 0.8 SSTR4 protein P31391 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256823 0.435 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 BTO:0000887;BTO:0001103 14579029 t gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-118857 0.769 SDC3 protein O75056 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity binding 10090 BTO:0002314 20696709 t gcesareni Furthermore, we show that Syndecan-3 interacts with Notch and is required for Notch processing by ADAM17/tumor necrosis factor-€“converting enzyme (TACE) and signal transduction. Together, our data support the conclusion that Syndecan-3 and Notch cooperate in regulating homeostasis of the satellite cell population and myofiber size. SIGNOR-254329 0.388 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT up-regulates activity phosphorylation Ser2 sPKRIAKR -1 15014043 t miannu Human RCC1 is phosphorylated on Ser 2 and Ser 11 in mitosis by Cdc2 kinase. We show here that Cdc2 kinase phosphorylates the serines located in or near the nuclear localization signal (NLS) of human RCC1, the nucleotide exchange factor for Ran. This phosphorylation is necessary for RCC1 to generate RanGTP on mitotic chromosomes in mammalian cells, which in turn is required for spindle assembly and chromosome segregation. SIGNOR-262701 0.513 PDZRN3 protein Q9UPQ7 UNIPROT MUSK protein O15146 UNIPROT down-regulates quantity ubiquitination 9534 BTO:0000298 17576800 t miannu We have identified a PDZ domain containing RING finger 3 (PDZRN3) as a synapse-associated E3 ubiquitin ligase and have demonstrated that it regulates the surface expression of muscle-specific receptor tyrosine kinase (MuSK), the key organizer of postsynaptic development at the mammalian neuromuscular junction. PDZRN3 binds to MuSK and promotes its ubiquitination. Together, these data demonstrate that PDZRN3 is a catalytically active RING-type E3 ubiquitin ligase SIGNOR-271664 0.554 MAPK1 protein P28482 UNIPROT ATP1A1 protein P05023 UNIPROT down-regulates activity phosphorylation Ser16 KYEPAAVsEQGDKKG 1792 BTO:0003069 14976217 t miannu Parathyroid hormone (PTH) inhibits Na+,K+-ATPase activity through protein kinase C- (PKC) and extracellular signal-regulated kinase- (ERK) dependent pathways and increases serine phosphorylation of the α1-subunit. These results suggest that PTH regulates Na(+),K(+)-ATPase by PKC and ERK-dependent alpha(1)-subunit phosphorylation and that the phosphorylation requires the expression of a serine at the 11 position of the Na(+),K(+)-ATPase alpha(1)-subunit. SIGNOR-262940 0.513 ARID3A protein Q99856 UNIPROT Immunoglobulin delta heavy chain protein P0DOX3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 16738337 t lperfetto In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure ​3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene. SIGNOR-268531 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI AKT1 protein P31749 UNIPROT up-regulates activity relocalization 9606 23119004 t lperfetto Binding of igf to igf-ir activates pi3k to generate pip3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including akt and pdk1. SIGNOR-252642 0.8 PKN1 protein Q16512 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 t llicata Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-91602 0.256 NR0B2 protein Q15466 UNIPROT ESR2 protein Q92731 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10648597 f gcesareni These novel insights provide a mechanistic explanation for the inhibitory role of shp in nuclear receptor signaling, and they may explain how shp functions as a negative coregulator or corepressor for ligand-activated receptors, a novel and unique function for an orphan nuclear receptor. SIGNOR-74291 0.615 ESR1 protein P03372 UNIPROT TFF1 protein P04155 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253938 0.748 ITGB1 protein P05556 UNIPROT Av/b1 integrin complex SIGNOR-C175 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253202 0.832 PTPN3 protein P26045 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity dephosphorylation Tyr537 CKNVVPLyDLLLEML 9606 26079946 t miannu Our recent studies further demonstrated that PTPH1 dephosphorylates estrogen receptor at Y537, increases estrogen receptor stability and nuclear accumulation, and enhances breast cancer sensitivity to anti-estrogens [ ]. SIGNOR-277127 0.2 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 BTO:0000801 11842088 f gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-114771 0.495 AKT proteinfamily SIGNOR-PF24 SIGNOR ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively, and overexpression of the phosphomimic mutants ADAR1p110 (T738D) and ADAR2 (T553D) resulted in a 50-100% reduction in editase activity. SIGNOR-266357 0.2 RPL37 protein P61927 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262463 0.832 MYOD1 protein P15172 UNIPROT SP1 protein P08047 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 9148896 t lperfetto These data suggest a regulatory model in which MyoD activation during myogenesis causes the down-regulation of Sp1, which contributes to the repression of GLUT1 gene transcription and, therefore, leads to the reduction in GLUT1 expression and glucose transport. SIGNOR-241765 0.378 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249324 0.758 DR1 protein Q01658 UNIPROT NC2 complex complex SIGNOR-C108 SIGNOR form complex binding 9606 BTO:0000567 18838386 t miannu NC2_ co-fractionated with NC2_ only in the low molecular weight complex (fractions 86–94) and an NC2_ antibody co-immunoprecipitated NC2_ (but not GCN5) in these fractions, which thus contain the classical NC2 complex SIGNOR-226405 0.765 FLT3 protein P36888 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates activity binding 10090 BTO:0001516 23246379 t These results suggest that Grb10 binds to both normal and oncogenic FLT3 and induces PI3K–Akt and STAT5 signaling pathways resulting in an enhanced proliferation, survival and colony formation of hematopoietic cells. SIGNOR-255947 0.368 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser733 TVREQDQsFTALDWS 9606 SIGNOR-C14 SIGNOR-C14 10195894 t lperfetto Once activated, ikkbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased ikk activity and may prevent prolonged activation of the inflammatory response SIGNOR-66344 0.2 terazosin chemical CHEBI:9445 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 9606 9379432 t miannu Pharmacological management of benign prostatic hyperplasia (BPH) has most successfully been achieved by administration of α1 antagonists, which function via relaxation of prostatic smooth muscle. Terazosin2 (2), doxazosin3 (3), and alfuzosin4 (4), agents currently approved for this indication SIGNOR-258670 0.8 CSNK1E protein P49674 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 12000790 t gcesareni We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms. SIGNOR-87444 0.741 MAPK3 protein P27361 UNIPROT POU5F1 protein Q01860 UNIPROT down-regulates phosphorylation Ser111 ESNSDGAsPEPCTVT 9606 23024368 t gcesareni Phosphorylation of this site downregulates nanog, sox2, rex1 and upregulates bmp4, gata6, ddlx5. SIGNOR-192101 0.348 CAD protein P27708 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267418 0.8 GRK3 protein P35626 UNIPROT CCR5 protein P51681 UNIPROT down-regulates activity phosphorylation Ser349 STGEQEIsVGL 9534 BTO:0000298 10085131 t gcesareni Phosphoamino acid analysis revealed that RANTES-induced CCR5 phosphorylation selectively occurs on serine residues. Our findings with receptor mutants indicate that serine residues at positions 336, 337, 342, and 349 represent GRK phosphorylation sites on CCR5. SIGNOR-249679 0.2 DNMT3B protein Q9UBC3 UNIPROT DPP6 protein P42658 UNIPROT down-regulates quantity by repression transcriptional regulation 23409053 t lperfetto Dnmt3b was responsible for transcriptional silencing of Dpp6 gene as depletion of Dnmt3b resulted in increased mRNA and protein expression of Dpp6. SIGNOR-268963 0.331 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17339337 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability. We have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-153463 0.787 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 15328002 t gcesareni Two amino acid residues (ser396, ser398) on hr1 were determined to be pkc phosphorylation sites by in vitro phosphorylation studies.Site-directed mutagenesis studies suggests that the ser398 residue was primarily involved in pkc-mediated desensitization. Possibly, phosphorylation of the residues is required for receptor transport from endosomes to lysosomes. SIGNOR-128415 0.2 PRKG1 protein Q13976 UNIPROT SF1 protein Q15637 UNIPROT down-regulates activity phosphorylation Ser20 PSKKRKRsRWNQDTM 10116 BTO:0000947 10449420 t lperfetto PKG phosphorylates SF1 at Ser20, which inhibits the SF1-U2AF65 interaction leading to a block of pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating that Ser20 is essential for binding. SIGNOR-249018 0.445 PER2 protein O15055 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001939 23836662 f miannu PER2 Suppresses TWIST1 and SLUG Transcription by Recruiting EZH2, SUZ12, and HDAC2. SIGNOR-254147 0.2 nintedanib chemical CHEBI:85164 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257804 0.8 ARHGAP11B protein Q3KRB8 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260468 0.476 EIF2B3 protein Q9NR50 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269126 0.829 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264927 0.8 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck) SIGNOR-166358 0.354 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ABI1 protein Q8IZP0 UNIPROT down-regulates activity phosphorylation Ser216 VPNDYMTsPARLGSQ 9606 BTO:0000567 21900237 t lperfetto We identified serine 216 of Abi1 as a target of CDK1/cyclin B kinase that is phosphorylated in cells at the onset of mitosis.|Bcr-Abl-induced actin polymerization requires the Abi1 pathway, as the blockade of the signal transduction from Bcr-Abl to Abi1 abolishes the F-actin assembly|serine phosphorylation of Abi1 by CDK1/cyclin B serves as a cell cycle-dependent regulatory mechanism that inhibits actin assembly SIGNOR-264452 0.426 RPS6KA5 protein O75582 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts SIGNOR-249144 0.683 GSK3B protein P49841 UNIPROT RICTOR protein Q6R327 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1695 EAEAVLAtPPKQPIV 9606 BTO:0002181 25897075 t miannu We show that this process is dependent on glycogen synthase kinase 3 (GSK3): GSK3 was associated with rictor and directly phosphorylated the Thr-1695 site in a putative CDC4 phospho-degron motif of rictor; mutation of this site impaired the interaction between rictor and FBXW7, decreased rictor ubiquitination, and increased rictor stability.  SIGNOR-276898 0.415 SLC34A1 protein Q06495 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI up-regulates quantity relocalization 9606 BTO:0000671 20335586 t lperfetto Genetic analysis revealed a homozygous in-frame duplication of 21 bp in SLC34A1, which encodes the renal sodium-inorganic phosphate cotransporter NaPi-IIa, SIGNOR-270576 0.8 pimozide chemical CHEBI:8212 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258379 0.8 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein P58401 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264160 0.764 Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR CREB3L2 protein Q70SY1 UNIPROT up-regulates 9606 17178827 f miannu Although bbf2h7 protein is not expressed under normal conditions, it is markedly induced at the translational level during er stress, suggesting that bbf2h7 might contribute to only the late phase of unfolded protein response signaling. SIGNOR-151312 0.7 TACR1 protein P25103 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256919 0.2 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates activity phosphorylation Tyr1023 DLVDAEEyLVPQQGF 9606 1706616 t Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-251129 0.2 vincaleukoblastine sulfate chemical CHEBI:9984 ChEBI TUBD1 protein Q9UJT1 UNIPROT down-regulates activity chemical inhibition 9606 15579115 t miannu Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. SIGNOR-259257 0.8 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT up-regulates activity phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 BTO:0000873 12573241 t lperfetto Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk SIGNOR-246647 0.335 TPO protein P07202 UNIPROT diiodine smallmolecule CHEBI:17606 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino TPO is considered the key enzyme in thyroid hormonogenesis. It catalyzes the oxidation of iodide that is necessary for the iodinationof the TG tyrosyl residues (the organification reaction). SIGNOR-266959 0.8 TAF4 protein O00268 UNIPROT ATF7 protein P17544 UNIPROT down-regulates activity binding 9534 BTO:0004055 15735663 t miannu These results not only demonstrate an interaction between ATF7 and TAF4 but also indicate, as in the case of TAF12 (see Figure 3e), that no additional cellular component is required for this binding. They also suggest that TAF4 may interfere with the formation of ATF7–TAF12 subcomplexes, thereby inhibiting ATF7-induced transactivation. SIGNOR-225300 0.402 ID1 protein P41134 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241128 0.566 SOX17 protein Q9H6I2 UNIPROT SOX17/POU5F1 complex SIGNOR-C451 SIGNOR form complex binding 23474895 t SimoneGraziosi Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. SIGNOR-269220 0.621 NEDD4 protein P46934 UNIPROT SAG protein P10523 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25216516 t miannu Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.  SIGNOR-272843 0.379 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 BTO:0000782 15623513 t lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. SIGNOR-132898 0.487 lapatinib chemical CHEBI:49603 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 22056878 t Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. gcesareni In estrogen-receptor-negative cellular models showing coamplification of erbb2 and rara, simultaneous targeting of the corresponding gene products with combinations of lapatinib and atra causes synergistic growth inhibition, cyto-differentiation and apoptosis. SIGNOR-177081 0.8 QRICH1 protein Q2TAL8 UNIPROT IARS1 protein P41252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269406 0.2 AP-2 complex complex SIGNOR-C245 SIGNOR AAK1 protein Q2M2I8 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 t Giorgia We therefore characterised protein ligands using liquid chromatography tandem mass spectrometry (LC‐MS/MS) and confirmed this using Western blotting to recognise both major and minor bands. Some of the more minor interactors are very strongly enriched (AAK, auxilin, Dab2, eps15, epsin1 and synaptojanin170). All these enriched proteins have multiple copies of short alpha‐appendage interaction motifs SIGNOR-260393 0.646 LPAR3 protein Q9UBY5 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257406 0.421 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI DIO2 protein Q92813 UNIPROT up-regulates quantity by expression 9606 29892818 f scontino Dio2 is a cAMP responsive gene. Thus, any signaling pathway or molecule that increases cAMP concentration will stimulate D2 activity. SIGNOR-267281 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2B protein P63146 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271334 0.75 FYN protein P06241 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268207 0.625 EYA1 protein Q99502 UNIPROT H2AX protein P16104 UNIPROT down-regulates dephosphorylation Tyr143 ATQASQEy 9606 20965415 t gcesareni Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3. SIGNOR-168879 0.2 MST1 protein P26927 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277179 0.2 BCR-Dl complex SIGNOR-C436 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268442 0.708 TLN1 protein Q9Y490 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR up-regulates activity binding 9606 BTO:0000132 16418530 t lperfetto In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation. SIGNOR-253358 0.691 NLRP1 inflammasome complex SIGNOR-C224 SIGNOR Caspase 1 complex complex SIGNOR-C220 SIGNOR up-regulates activity cleavage 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256380 0.2 AGTR2 protein P50052 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252268 0.7 ATG7 protein O95352 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates binding 9606 22170151 t gcesareni These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3. SIGNOR-195239 0.871 MAPK14 protein Q16539 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates activity phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 BTO:0000132 8910365 t lperfetto These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets SIGNOR-44673 0.66 hexadecanoic acid smallmolecule CHEBI:15756 ChEBI palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI up-regulates quantity precursor of 9606 21242590 t miannu Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. On the other hand, overexpression of ACSL1 resulted in large increases in oleoyl-CoA synthesis and palmitoyl-CoA synthesis in SMC lysates (Fig. 4A). SIGNOR-267876 0.8 ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 23863160 f lperfetto In mammals, two protein complexes, namely the ULK1/Atg13/FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin/Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209907 0.7 NUP62 protein P37198 UNIPROT SASS6 protein Q6UVJ0 UNIPROT up-regulates activity binding 9606 BTO:0000567 24107630 t Simone Furthermore, we found interactions and co-localization with γ-tubulin and SAS-6. Our results also point to a potential role of Nup62 in targeting gamma-tubulin and SAS-6 to the centrioles. SIGNOR-261256 0.2 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm). SIGNOR-163234 0.8 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 14633703 t lperfetto Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-264659 0.448 EEF1B complex complex SIGNOR-C460 SIGNOR EEF1A1P5 protein Q5VTE0 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. SIGNOR-269389 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273081 0.635 CREB5 protein Q02930 UNIPROT CFB protein P00751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002809 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253802 0.2 SYK protein P43405 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation 9606 BTO:0003079 27181361 t Gianni PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation. SIGNOR-269084 0.429 SRC protein P12931 UNIPROT SH3PXD2B protein A1X283 UNIPROT up-regulates activity phosphorylation Tyr508 DMSASAGyEEISDPD 9606 20943948 t lperfetto C-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells|Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation. SIGNOR-264705 0.522 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248303 0.486 PTK2 protein Q05397 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t llicata These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. SIGNOR-139146 0.419 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 12832467 t lperfetto Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-252760 0.723 PSMF1 protein Q92530 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR down-regulates activity binding 9606 BTO:0000007 23622245 t lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. SIGNOR-263341 0.514 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 BTO:0000093 12777400 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-101310 0.343 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr930 LAHGADPtMKNQEGQ 9606 BTO:0000567 21818122 t miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  SIGNOR-276243 0.434 CRHR1 protein P34998 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 f lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). SIGNOR-268612 0.646 SNX6 protein Q9UNH7 UNIPROT IGF2R protein P11717 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 t miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. SIGNOR-269443 0.369 PIK3CG protein P48736 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates binding 9606 9768361 t gcesareni Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k. SIGNOR-60567 0.623 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser540 HVSEDSSsPERTSPP 9606 19107194 t lperfetto We identified cyclinb/cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates sirt1. Mutation of two residues phosphorylated by cyclin b/cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in sirt1-deficient cells SIGNOR-216841 0.483 DLG5 protein Q8TDM6 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270893 0.318 MINK1 protein Q8N4C8 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates binding 9606 9230439 t miannu Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density. SIGNOR-49869 0.287 NMDA proteinfamily SIGNOR-PF56 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266598 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273074 0.635 ATF6 protein P18850 UNIPROT ATF6 protein P18850 UNIPROT up-regulates activity binding -1 12805554 t miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins SIGNOR-224202 0.2 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 11416147 t gcesareni We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling. SIGNOR-243345 0.2 MAP4K2 protein Q12851 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273900 0.2 SIRT7 protein Q9NRC8 UNIPROT TP53 protein P04637 UNIPROT down-regulates deacetylation 9606 18239138 t gcesareni We found that sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo. SIGNOR-160539 0.508 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT down-regulates activity sumoylation Lys404 VSPTGIkNEKRGTS 9606 16442531 t We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. SIGNOR-256129 0.371 Exosome_Complex complex SIGNOR-C255 SIGNOR FUS protein P35637 UNIPROT up-regulates activity relocalization 9606 BTO:0000793 27460707 t P35637:p.Arg495_Tyr526del (mutation increasing interaction) We hypothesized that FUS could be secreted via the exosome pathway. We tested and confirmed that FUS was indeed present in exosomes in both SH-SY5Y and N2A cells (Fig. 6 and Supplemental Fig. 2). It is also noted that the level of the R495X mutant in exosomes was significantly higher than that of WT or the R521G mutant. |It raises the possibility that the exosome-mediated secretion of FUS may contribute to the cell-to-cell propagation of FUS pathology. SIGNOR-262812 0.233 Succinyl-CoA GTP variant complex SIGNOR-C399 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266270 0.8 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249281 0.401 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr139 EKLRVLGyNQNGEWS -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277302 0.306 RAD1 protein O60671 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner SIGNOR-179379 0.61 CREB5 protein Q02930 UNIPROT TNFRSF11B protein O00300 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253812 0.2 ARHGEF7 protein Q14155 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 17562871 f gcesareni We propose that the association of plcgamma1 with complexes containing git1 and beta-pix is essential for its role in integrin-mediated cell spreading and motility. As a component of this complex, plcgamma1 is also involved in the activation of cdc42 and rac1. SIGNOR-155744 0.628 IRF3 protein Q14653 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216316 0.7 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 BTO:0002181 23279204 f SARA G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs SIGNOR-260984 0.7 PRRX1 protein P54821 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221899 0.308 CEBPD protein P49716 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 23028973 f CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. SIGNOR-254060 0.275 NCOR1 protein O75376 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 t miannu The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. SIGNOR-252239 0.58 STAT3 protein P40763 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255240 0.321 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI PDE1B protein Q01064 UNIPROT down-regulates activity chemical inhibition 9606 22014080 t Until now, very few inhibitors of PDE1 were available for evaluating the contribution of PDE1 in tissue and cell function. Vinpocetine (Ahn et al., 1989) and 8-methoxymethyl-IBMX (Ahn et al., 1997) are common PDE1 inhibitors. SIGNOR-253400 0.8 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273062 0.635 UBQLN2 protein Q9UHD9 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates quantity by stabilization binding 25616961 t lperfetto Confirmation of binding of recombinant full-length hnRNPA1 and hnRNPU proteins with ubiquilin-2 by GST-pull-down assays|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein SIGNOR-262271 0.337 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000007 10488065 t gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. SIGNOR-70667 0.517 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr632 GRKGSGDyMPMSPKS 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236741 0.913 HBB protein P68871 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000876 11901318 f Regulation of expression miannu Free hemoglobin enhances tumor necrosis factor-alpha production in isolated human monocytes. SIGNOR-251752 0.303 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248808 0.851 MIB1 protein Q86YT6 UNIPROT MIB1 protein Q86YT6 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12351649 t miannu The RING finger motifs of DIP-1 have E3 ligase activity that can auto-ubiquitinate DIP-1 in vitro. In vivo, DIP-1 is detected as a polyubiquitinated protein, suggesting that the intracellular levels of DIP-1 are regulated by the ubiquitin-proteasome system.  SIGNOR-272603 0.2 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser122 DQHLMKCsPAQLLCS 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78416 0.855 PPM1A protein P35813 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2C_ dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity SIGNOR-252724 0.327 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY -1 21880142 t miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266310 0.309 RARG protein P13631 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16659 0.677 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser358 ELRKTQTsMSLGTTR 10090 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266427 0.746 DYRK1A protein Q13627 UNIPROT FOXO6 protein A8MYZ6 UNIPROT down-regulates phosphorylation 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity SIGNOR-183680 0.309 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-238804 0.513 DTNBP1 protein Q96EV8 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates activity binding 10116 BTO:0000601 20531346 t miannu Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation. Although dysbindin-1, WAVE2 and Abi-1 form a ternary complex, dysbindin-1 promoted the binding of WAVE2 to Abi-1. SIGNOR-265660 0.358 clozapine chemical CHEBI:3766 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258835 0.8 VRK1 protein Q99986 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 9606 17938195 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis. SIGNOR-158436 0.2 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC10 protein Q969S8 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-202108 0.8 ADRA2B protein P18089 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257201 0.363 PRKCA protein P17252 UNIPROT PRKG1 protein Q13976 UNIPROT up-regulates phosphorylation Thr59 THIGPRTtRAQGISA 9606 12609995 t gcesareni Antibodies generated against phosphorylated threonine 58 were used to demonstrate phosphorylation in response to pma treatment of the cells with kinetics similar to vasodilator-stimulated phosphoprotein phosphorylation. A phospho-mimetic mutation at this site (t58e) generated a partially activated pkg that was more sensitive to cgmp levels. A phospho- mutation (t58a) revealed that this residue is important but not sufficient for pkg activation by pkc. SIGNOR-98803 0.348 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252754 0.755 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 t Manara These results suggested that ASK2 activates ASK1 by direct phosphorylation of Thr838 of ASK1. SIGNOR-260773 0.538 sapitinib chemical CHEBI:132986 ChEBI SHC3 protein Q92529 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 20145185 t gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-163733 0.8 PRKCA protein P17252 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97279 0.2 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT up-regulates activity phosphorylation His118 QVGRNIIhGSDSVKS -1 8132589 t miannu Using site-directed mutagenesis of the cDNA encoding NM23-H2, we have created a mutant substituting for the amino acid histidine 118, the presumed site of phosphorylation in the formation of the phosphoenzyme intermediate, the nonphosphorylatable amino acid phenylalanine. The H118F mutant protein is shown to be catalytically inactive SIGNOR-250304 0.2 CDK2 protein P24941 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72091 0.669 TLE4 protein Q04727 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates activity binding 9606 BTO:0000007 25631048 t In cell culture, Grg4 suppresses Pax2-mediated transcriptional activation and inhibits phosphorylation of the Pax2 activation domain by WNT signaling and JNK SIGNOR-251710 0.464 all-cis-5,8,11,14,17-icosapentaenoic acid smallmolecule CHEBI:28364 ChEBI FBN1 protein P35555 UNIPROT up-regulates quantity by expression 9606 16467281 f Regulation of expression miannu It was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. SIGNOR-251910 0.8 CABIN1 protein Q9Y6J0 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates 9606 17172641 f gcesareni Thus, cabin1 recruits chromatin-modifying enzymes, both histone deacetylases and a histone methyltransferase, to repress mef2 transcriptional activity. SIGNOR-151205 0.66 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266521 0.8 CKM protein P06732 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265788 0.8 MECP2 protein P51608 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 23242655 f Our previous studies demonstrated that mutant p53 along with repression complex proteins including DNMT1, HDAC1 and MeCP2 is associated with ER-negative promoter in MDA-MB-468 cells. SIGNOR-254024 0.396 FGF2 protein P09038 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 15765505 f gcesareni Runx2 is an important mediator of the expression of bmp-2 in response to fgf stimulation in cranial bone development. SIGNOR-134512 0.448 RELA protein Q04206 UNIPROT CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 12860928 f Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. Our results show that BCL6 prevents CD40-induced expression of CD80 by binding its promoter region in vivo and suppressing its transcriptional activation by NF-kappaB. Consistent with a physiologic role for BCL6 in suppressing CD80, the expression of these two genes is mutually exclusive in B cells, and BCL6-defective mice show increased expression of CD80 in B cells. SIGNOR-253935 0.299 NCOA2 protein Q15596 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11851396 t gcesareni Here, it is demonstrated that mutation of the h11 phenylalanine residues diminishes the ability of rxr to associate with the p160 coactivators tif2 and p/cip, but has little effect on ligand-dependent interactions of the receptor with the unrelated coactivator tif1. SIGNOR-114847 0.792 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser296 SPSALSSsPNNLSPT 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-143692 0.625 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR G0/G1_transition phenotype SIGNOR-PH219 SIGNOR up-regulates 12640120 f lperfetto Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0. SIGNOR-273193 0.7 CDK1 protein P06493 UNIPROT CREM protein Q03060 UNIPROT down-regulates quantity phosphorylation Ser271 QGVVMAAsPGSLHSP 9606 BTO:0001033 21767532 t miannu In this report data is presented demonstrating that ICER is phosphorylated by the mitotic kinase cdk1. Phosphorylation of ICER on a discrete residue targeted ICER to be monoubiquitinated. Different from unphosphorylated, phosphorylated and polyubiquitinated ICER, monoubiquitinated ICER was found to be cytosolic. Taken together, these results hinted on a mechanism for the observed abnormal subcellular localization of ICER in human prostate tumors. SIGNOR-276346 0.298 DGC complex SIGNOR-C217 SIGNOR GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265433 0.2 LTK protein P29376 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000938 9223670 t gcesareni Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85 SIGNOR-49622 0.255 DLGAP3 protein O95886 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264593 0.782 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263771 0.528 CTNND1 protein O60716 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0003564 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252124 0.746 DLK1 protein P80370 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates activity binding 10090 BTO:0002572 21419176 t gcesareni Moreover, the interaction of DLK1 with NOTCH1 caused an inhibition of basal NOTCH signaling in preadipocytes and mesenchymal multipotent cells. In this work, we demonstrate, for the first time, that DLK2 interacts with itself, with DLK1, and with the same NOTCH1 receptor region as DLK1 does. We demonstrate also that the interaction of DLK2 with NOTCH1 similarly results in an inhibition of NOTCH signaling in preadipocytes and Mouse Embryo fibloblasts. SIGNOR-172830 0.505 PFKL protein P17858 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266472 0.8 OPTN protein Q96CV9 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259880 0.2 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258848 0.8 SIRT2 protein Q8IXJ6 UNIPROT NEDD4 protein P46934 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23175188 f miannu SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. SIGNOR-255144 0.264 PRKACA protein P17612 UNIPROT ARFGEF1 protein Q9Y6D6 UNIPROT up-regulates activity phosphorylation Ser883 EIAGKKIsMKETKEL 9606 BTO:0000599 16467138 t lperfetto Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site SIGNOR-272146 0.2 MMP14 protein P50281 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu105 NNKDSHSlTTNIMEI -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263619 0.2 TBX5 protein Q99593 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255253 0.269 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser55 KPRHKIIsIFSGTEK -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. SIGNOR-250229 0.2 CSNK1A1 protein P48729 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-250793 0.325 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t lperfetto Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-244754 0.2 NR5A2 protein O00482 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254870 0.356 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 19001501 t done miannu Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.  SIGNOR-273887 0.651 MAPK1 protein P28482 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 16778989 t gcesareni Erk1/2 are the kinases involved in p47phox_ phosphorylation on ser345 in gm-csfprimed human neutrophils._ Phosphorylation of ser345 is required for the priming of nadph oxidase activity in neutrophil-like cells SIGNOR-147170 0.458 NCOR2 protein Q9Y618 UNIPROT PGR protein P06401 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 t gcesareni In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. SIGNOR-101289 0.598 ITCH protein Q96J02 UNIPROT TRPC4 protein Q9UBN4 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 17110928 t miannu Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane. SIGNOR-272624 0.354 DAPK1 protein P53355 UNIPROT MAP1B protein P46821 UNIPROT up-regulates binding 9606 18806760 t gcesareni Dapk-1 interacts with the microtubule-associated protein map1b, in particular in conditions of amino-acid starvation. SIGNOR-181305 0.264 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273051 0.55 PDHA1 protein P08559 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266544 0.804 TAF7 protein Q15545 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263928 0.898 EGR1 protein P18146 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001007 12456801 t Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. SIGNOR-254265 0.2 CTNND1 protein O60716 UNIPROT ZBTB33 protein Q86T24 UNIPROT down-regulates 9606 23481205 f gcesareni Nuclear signaling is affected by the interaction ofp120with kaiso, a transcription factor regulatingwnt-responsive genes. in addition, p120 cytoplasmic localization results in sequestration of kaiso in the cytoplasm and its inactivation SIGNOR-192369 0.821 PKN1 protein Q16512 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 t lperfetto Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functionswe found for the first time that pak1 promotes transcription repression activity of snail from e-cadherin, occludin, and aromatase promoters. Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions. SIGNOR-135609 0.2 GSK3A protein P49840 UNIPROT MAF protein O75444 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159361 0.2 PRKCE protein Q02156 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates phosphorylation Ser782 PLEQYSPsYPDTRSS 9606 BTO:0000938 23564461 t lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation SIGNOR-201675 0.2 FOXL2 protein P58012 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21862621 f miannu We previously demonstrated that FOXL2 is a transcriptional repressor of the steroidogenic acute regulatory (StAR), P450SCC (CYP11A), P450aromatase (CYP19), and cyclin D2 (CCND2) genes, markers of ovarian follicle proliferation and differentiation. SIGNOR-254178 0.398 FLT3 protein P36888 UNIPROT CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249635 0.627 TFE3 protein P19532 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276816 0.286 metoprolol chemical CHEBI:6904 ChEBI ADRB1 protein P08588 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 10079020 t Luana In our CHO cells transfected with the human β1- and β2-adrenoceptors, the binding affinities of atenolol, metoprolol, betaxolol and practolol correlate with previously published β1- (P=0.03) and β2-adrenoceptor (P=0.03) binding affinities in human lung tissue SIGNOR-258337 0.8 MYC protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The mRNA levels of IMPDH1 and IMPDH2, the rate-limiting enzyme in purine de novo synthesis, increased with MYC induction both in vitro and in vivo. SIGNOR-267377 0.297 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser65 PCSSVPSsPSFCAPS 9606 BTO:0000567 11416124 t lperfetto These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription. SIGNOR-108564 0.338 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR KRT8 protein P05787 UNIPROT unknown phosphorylation 16554440 t inferred from 70% family members lperfetto Also, several probable in vivo K8 kinases have been identified including Erk1/2 for K8 Ser431 (Ku and Omary, 1997), and p38 and Jun kinases for K8 Ser73 (Ku et al., 2002a; He et al., 2002). SIGNOR-270135 0.2 CHEK1 protein O14757 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation Ser273 SMLNKNPsLRPSAIE 9606 19734889 t lperfetto We demonstrate that chk1 (checkpoint kinase 1) directly activates nek11 by phosphorylating it on ser 273 SIGNOR-187863 0.266 ACO1 protein P21399 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266245 0.8 GFI1 protein Q99684 UNIPROT CYP27B1 protein O15528 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15947108 f miannu Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells. SIGNOR-254205 0.2 RAD50 protein Q92878 UNIPROT RINT1 protein Q6NUQ1 UNIPROT up-regulates activity binding 9606 BTO:0004784 16600870 t lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  SIGNOR-265030 0.478 ZBED1 protein O96006 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001138 22021382 f 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. SIGNOR-239736 0.2 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys70 EGILRRLkKYDNCWL 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267597 0.533 RNF34 protein Q969K3 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT down-regulates quantity by destabilization ubiquitination 26971449 t lperfetto We then examined the effect of necdin on ubiquitin-dependent degradation of PGC-1α using Rnf34, a PGC-1α E3 ubiquitin ligase22. Rnf34 reduced the PGC-1α level, and necdin completely inhibited the reduction (Fig. 4i). In addition, necdin strongly suppressed Rnf34-mediated ubiquitination of PGC-1α (Fig. 4j). Necdin also protected PGC-1α against ubiquitination mediated by Fbxw7, another PGC-1α E3 ubiquitin ligase23 (Fig. 4k). These data indicate that necdin stabilizes PGC-1α by inhibiting its degradation in the ubiquitin-proteasomal system. SIGNOR-253393 0.322 PPM1L protein Q5SGD2 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation -1 12556533 t miannu Co-immunoprecipitation experiments indicated that PP2Cepsilon associates stably with TAK1 and attenuates the binding of TAK1 to MKK4 or MKK6.|PP2Cepsilon dephosphorylated TAK1 in vitro. SIGNOR-277114 0.597 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191433 0.8 HBA1 protein P69905 UNIPROT AHSP protein Q9NZD4 UNIPROT down-regulates activity 9606 2545495 f Regulation miannu EDRF is rapidly inactivated by hemoglobin and superoxide. SIGNOR-251751 0.772 KCNQ2 protein O43526 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265982 0.8 PPP5C protein P53041 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates activity dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 16954377 t llicata MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation.| Protein phosphatase 5 (PP5) interacts with MRK in a complex and dephosphorylates MRK at T157 in vitro and in situ. SIGNOR-248541 0.2 phentolamine chemical CHEBI:8081 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258444 0.8 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB4 protein Q9UN71 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265679 0.2 PINK1 protein Q9BXM7 UNIPROT HIF3A protein Q9Y2N7 UNIPROT down-regulates activity phosphorylation Thr12 LQRARSTtELRKEKS 9606 BTO:0000793 27551449 t Parkinson miannu Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur. SIGNOR-263090 0.352 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269339 0.721 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120192 0.319 NAMPT protein P43490 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI up-regulates quantity chemical modification 9606 12555668 t gcesareni Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesi SIGNOR-238602 0.8 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81137 0.529 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser358 WPLSRTRsEPLPPSA 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248605 0.2 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH23 protein Q9H251 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265839 0.8 FBXO31 protein Q5XUX0 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 t miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. SIGNOR-277379 0.419 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Thr185 EGSRQALtLQDWAAQ -1 18184589 t Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. SIGNOR-260803 0.2 IRF2 protein P14316 UNIPROT DST protein Q03001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15560761 f miannu Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. SIGNOR-254493 0.2 SIRT7 protein Q9NRC8 UNIPROT FBL protein P22087 UNIPROT up-regulates activity deacetylation Lys206 DLINLAKkRTNIIPV 30540930 t lperfetto Here, we show that FBL is acetylated at several lysine residues by the acetyltransferase CBP and deacetylated by SIRT7.|hyperacetylation impairs the interaction of FBL with histone H2A and chromatin, thereby compromising H2AQ104 methylation (H2AQ104me) and rDNA transcription. SIRT7-dependent deacetylation of FBL ensures H2AQ104me and high levels of rRNA synthesis during interphase. |Global acetylome studies have shown that FBL is acetylated at four conserved lysine residues (K102, K121, K205, and K206) SIGNOR-275893 0.273 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t p38 MAPK is activated by phosphorylation in response to CDO-BOC interactions. Activated p38 MAPK may translocate into the nucleus to further activate myogenic related transcription factors. gcesareni One way this occurs is via the interaction of JLP with the Cdo cytoplasmic tail. JLP is, in turn, bound to p38α/β. This interaction facilitates p38 activation during differentiation and is important for Cdo's effects in myogenesis. SIGNOR-272542 0.5 GSK3B protein P49841 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264874 0.2 GSK3B protein P49841 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates phosphorylation Ser556 AQKSEGKsLPSSPSS 9606 16174773 t lperfetto Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1 SIGNOR-140609 0.495 CHD8 protein Q9HCK8 UNIPROT DCX protein O43602 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268915 0.2 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR -1 12432067 t miannu Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146 SIGNOR-250074 0.309 BMP2 protein P12643 UNIPROT BMP2 protein P12643 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 t lperfetto Bmps are dimeric proteins with a single interchain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interaction with receptors SIGNOR-236166 0.2 RBCK1 protein Q9BYM8 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18711448 t miannu Here we show that the E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) catalyzes the ubiquitination and degradation of IRF3. We transfected 293 cells with expression plasmids for Flag-IRF3, HA-ubiquitin, and HA-RBCK1. Coimmunoprecipitation and western blot analysis indicated that RBCK1 significantly polyubiquitinated IRF3 (Figure 4D). SIGNOR-271737 0.329 ITGB1BP1 protein O14713 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257648 0.747 FGFR1 protein P11362 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates 9606 12270934 f lperfetto Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-244865 0.313 PRKCA protein P17252 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates activity phosphorylation Ser53 HPQLHIEsKIYKMMQ -1 31096047 t miannu In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity. SIGNOR-277451 0.2 DSCAM protein O60469 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR down-regulates 9606 BTO:0000938 30745319 f miannu Nuclear DSCAM and DSCAML1 impair neurite outgrowth. this demonstrates that enhanced nuclear translocation of the DSCAM and DSCAML1 ICDs profoundly impairs neurite outgrowth and development of primary cortical neurons. SIGNOR-264276 0.7 ACVR1 protein Q04771 UNIPROT AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR up-regulates phosphorylation 9606 9748228 t fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 SIGNOR-210093 0.2 LGALS3 protein P17931 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 f miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. SIGNOR-261906 0.281 EIF2AK2 protein P19525 UNIPROT NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263119 0.329 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 19114990 t lperfetto in immunoprecipitation esperiments, the TGF _ RII receptor was found to be constitutively associated with p85, the regulatory subunity of PI3K SIGNOR-217830 0.454 ITGB1 protein P05556 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253184 0.776 CUL3 protein Q13618 UNIPROT TNFAIP1 protein Q13829 UNIPROT up-regulates activity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264232 0.468 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2G1 protein P62253 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271315 0.756 DAPT chemical CHEBI:86193 ChEBI PSEN1 protein P49768 UNIPROT down-regulates chemical inhibition 9606 16569643 t gcesareni The catalytic aspartates are necessary for binding of the transition state analogue inhibitor, l-685,458, to ps1. It is possible that these catalytic aspartates also contribute to the direct interaction of ps with dapt. SIGNOR-145385 0.8 CSNK2A1 protein P68400 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr145 FYLALPPtVYEAVTK 9606 BTO:0002923 37478541 t miannu CK2 phosphorylates G6PD T145 under ionizing radiation  SIGNOR-277890 0.2 propionic acid chemical CHEBI:30768 ChEBI FFAR2 protein O15552 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257489 0.8 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser675 QDYKKRLsVELTSSL 9606 BTO:0000007 16476742 t lperfetto In the present study, we have shown that (i) beta-catenin can be phosphorylated by protein kinase a (pka) in vitro and in intact cells at two novel sites, ser-552 and ser-675;(ii) phosphorylation by pka promotes the transcriptional activity (tcf/lef transactivation) of beta-catenin SIGNOR-144482 0.466 CTDSPL protein O15194 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity dephosphorylation Ser811 IYISPLKsPYKISEG 9606 15051889 t ppRB (RB phosphorylated at Ser-807/811|Possible Mechanisms of HYA22 Action in Tumorigenesis: Dephosphorylation of RB by Transient Expression of HYA22 Isoforms. SIGNOR-248305 0.301 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser400 PINACELsPKGKEQA -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265956 0.525 DDC protein P20711 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI down-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT SIGNOR-264013 0.8 CSNK1A1 protein P48729 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t llicata Phosphorylation of all three serine residues in the deptor degron (ser286, ser287, and ser291) is necessary for - and directly mediates - the interaction with _trcp. ck1 phosphorylated the degron of deptor, as shown by western blotting with the phospho-specific antibody (fig. S3e-f). In contrast, mtor alone was unable to induce phosphorylation of deptor on ser286, ser287, and ser291. SIGNOR-176875 0.2 FYN protein P06241 UNIPROT CD300LF protein Q8TDQ1 UNIPROT up-regulates activity phosphorylation Tyr263 AEDQEPTyCNMGHLS 17202342 t lperfetto Y236 (YVTM) and Y263 (YCNM) fit with the consensus motif reported to bind the p85α regulatory subunit of PI3K (16). |The association between IREM-1 and p85α was only perceived in the presence of c-Fyn, suggesting that tyrosine phosphorylation of IREM-1 cytoplasmic tail of IREM-1 was required for the interaction. SIGNOR-275620 0.348 RAD50 protein Q92878 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 t lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-251506 0.912 TKT protein P29401 UNIPROT sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267087 0.8 MAPK14 protein Q16539 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser7 sPAPLSPL 9606 BTO:0000150 22128155 t gcesareni Ogether, our results suggest that p38 phosphorylation of foxo3a on ser-7 is essential for its nuclear relocalization in response to doxorubicin SIGNOR-252960 0.517 ACSS1 protein Q9NUB1 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI down-regulates quantity chemical modification 10843999 t lperfetto The gene encodes acetyl-CoA synthetase (ACS), the cytosolic enzyme that activates acetate so that it can be used for lipid synthesis or for energy generation. |The recombinant enzyme produced acetyl-CoA from acetate in a reaction that required ATP. SIGNOR-271831 0.8 E2F2 protein Q14209 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8649818 f gcesareni We have found that cell cycle regulation of cyclin e transcription is mediated by e2f binding sites present in the promoter SIGNOR-42020 0.598 A5/b1 integrin complex SIGNOR-C163 SIGNOR JAG1 protein P78504 UNIPROT up-regulates quantity by expression 10090 25786978 f lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253288 0.308 HHIP protein Q96QV1 UNIPROT IHH protein Q14623 UNIPROT down-regulates activity binding 10090 10050855 t lperfetto Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal. SIGNOR-65075 0.707 PRKD1 protein Q15139 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser356 YALVKAKsVDEIAKI 10029 32570757 t lperfetto Taken together, these data demonstrate that FAM83G S356 phosphorylation modulates HSP27 phosphorylation and apoptosis regulation and that HSP27 is a counterpart of FAM83G.|an active form of PKD1/PKCm could phosphorylate the FAM83G peptide, including the S356 portion.|We also demonstrated that the phosphorylation of the FAM83G S356 residue was required for the reduction of the live cell number, as the CHO cells were unaffected upon the overexpression of a FAM83G S356A mutant resistant to S356 phosphorylation. SIGNOR-264764 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0000007 32989218 t miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. SIGNOR-266376 0.2 CAMP protein P49913 UNIPROT FPR2 protein P25090 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11015447 t gcesareni Ll-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and t cells to sites of microbial invasion by interacting with fprl1. SIGNOR-82701 0.544 SLBP protein Q14493 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265373 0.2 CSNK2A1 protein P68400 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser838 LVFDYEGsGSEAASL 10090 BTO:0000944 10671552 t llicata Casein kinase II phosphorylation of E-cadherin increases E-cadherin/beta-catenin interaction and strengthens cell-cell adhesion. | All mutants showed a clear reduction in phosphorylation. Phosphorylation was completely abolished in the single mutant S855A and the double mutant S853/855A, and phosphorylation in S840A and S853A mutants was reduced to 43 and 28% that of wt GST-ECT. | Expression of the E-cadherin double mutant S853A/S855A in NIH3T3 cells expressing Wnt-1 reduces cell-cell adhesion. SIGNOR-250839 0.406 EIF3F protein O00303 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates deubiquitination 9606 21124883 t gcesareni The activated form of notch needs to be deubiquitinated before being processed by the gamma-secretase activity and entering the nucleus, where it fulfills its transcriptional function. The enzyme accounting for this deubiquitinase activity is eif3f, known so far as a translation initiation factor. SIGNOR-254327 0.427 KAT5 protein Q92993 UNIPROT CHKA protein P35790 UNIPROT up-regulates activity acetylation Lys247 MPFNKEPkWLFGTME 9606 34929314 t lperfetto Glucose deprivation induces the binding of choline kinase α2 (CHKα2) to lipid droplets, followed by a continuous PTMs to promote lipolysis of lipid droplets, which are in turn mediated by AMPK-dependent CHKα2 Serine 279 phosphorylation and KAT5-dependent CHKα2 Lysine 247 acetylation. SIGNOR-267648 0.2 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 9606 BTO:0000567 22749528 f Luana Leucine and Glutamine Activate Glutaminolysis and mTORC1 SIGNOR-268015 0.8 PPP2CB protein P62714 UNIPROT RALA protein P11233 UNIPROT down-regulates dephosphorylation Ser183 RARKMEDsKEKNGKK 9606 17540176 t miannu Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function SIGNOR-155349 0.292 EIF2B5 protein Q13144 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269138 0.813 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser637 HSLLERYsVNEGLVA 9606 BTO:0000567 phosphorylation:Thr550 PPINGSStPNPKIAS 19509060 t lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. SIGNOR-272991 0.61 MAPK3 protein P27361 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity phosphorylation Ser982 KKKSEPSsPDHGSST -1 11287604 t lperfetto Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 SIGNOR-106565 0.418 CDK1 protein P06493 UNIPROT RRM2 protein P31350 UNIPROT down-regulates phosphorylation Thr33 SLVDKENtPPALSGT 9606 22632967 t gcesareni We found that, during g2, following cdk-mediated phosphorylation of thr33, rrm2 is degraded via scf(cyclin f) to maintain balanced dntp pools and genome stability. SIGNOR-197630 0.512 HMGB2 protein P26583 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254429 0.2 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914161 t lpetrilli Phosphorylation of the linker region of Smads mediated by ERK2, GSK3β, and CDK2/4 negatively regulates Smad activity SIGNOR-161609 0.74 TFEB protein P19484 UNIPROT CALCOCO1 protein Q9P1Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276784 0.2 CSRP3 protein P50461 UNIPROT MYOG protein P15173 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 t 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. SIGNOR-241113 0.529 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62788 0.688 PTPN6 protein P29350 UNIPROT KDR protein P35968 UNIPROT down-regulates activity dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 18377662 t Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175 SIGNOR-248475 0.66 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-269969 0.2 GRPR protein P30550 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257046 0.27 DUSP26 protein Q9BV47 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity dephosphorylation 9606 28701747 t miannu NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells SIGNOR-277105 0.376 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159450 0.259 LDHB protein P07195 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI down-regulates quantity chemical modification 9606 24929216 t lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-267656 0.8 ABT-737 chemical CID:11228183 PUBCHEM BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 t gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. SIGNOR-151781 0.8 UTS2R protein Q9UKP6 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257164 0.267 KLF4 protein O43474 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding 9606 BTO:0000093 21746878 t miannu We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. SIGNOR-267237 0.466 KDM4C protein Q9H3R0 UNIPROT H2AC4 protein P04908 UNIPROT down-regulates activity demethylation Lys 10 GRGKQGGkARAKAKT 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263863 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-B receptor complex SIGNOR-C336 SIGNOR up-regulates activity chemical activation 9606 9872316 t brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. SIGNOR-263795 0.8 GRIPAP1 protein Q4V328 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates activity binding 9606 BTO:0002181 17761173 t Giulio We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. SIGNOR-260607 0.315 DUSP19 protein Q8WTR2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 11959861 t gcesareni Skrp1 was highly specific for c-jun n-terminal kinase (jnk) in vitro and effectively suppressed the jnk activation in response to tumor necrosis factor alpha or thapsigargin skrp1 does not bind directly to its target jnk, but co-precipitation of skrp1 with the mapk kinase mkk7, a jnk activator, was found in vitro and in vivo. SIGNOR-117260 0.428 PDK2 protein Q15119 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 19951971 t lperfetto PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a €œgain control€ for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity SIGNOR-249630 0.744 PRKCA protein P17252 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser185 SAYVGRLsARPKLKA -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276025 0.2 SARS1 protein P49591 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270495 0.8 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191406 0.8 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates activity chemical inhibition 9606 7566123 t Monia Consistent with an essential role for FRAP kinase activity in vivo, autophosphorylation of FRAP is inhibited by FKBP12-rapamycin. SIGNOR-261074 0.8 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Tyr223 TSFMMTPyVVTRYYR 9606 15911620 t lperfetto Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19). SIGNOR-137605 0.737 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203536 0.773 SLBP protein Q14493 UNIPROT H2AB1 protein P0C5Y9 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265411 0.2 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates activity phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 10339564 t lperfetto Hscdc6 is an excellent substrate for cdk2 in vitro and is phosphorylated in vivo at three sites (ser-54, ser-74, and ser-106)|An HsCdc6A1A2A3 mutant, which mimics unphosphorylated HsCdc6, is exclusively nuclear, and its expression inhibits initiation of DNA replication. An HsCdc6E1E2E3 mutant, which mimics phosphorylated HsCdc6, is exclusively cytoplasmic and is not associated with the chromatin/nuclear matrix fraction. SIGNOR-67548 0.941 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. SIGNOR-262866 0.326 PRKCA protein P17252 UNIPROT IL2RA protein P01589 UNIPROT unknown phosphorylation Ser268 WQRRQRKsRRTI 9606 BTO:0000782 2303462 t lperfetto The interleukin-2 (il-2) receptor, the leukocyte-specific membrane glycoprotein, t200, and the class i major histocompatibility antigens (hla) have been identified as substrates for protein kinase c from these studies, it was concluded that ser-247 is the major site of phosphorylation in the il-2 receptor and that thr-250 is a minor site. SIGNOR-22984 0.266 DYRK1A protein Q13627 UNIPROT DYRK1A protein Q13627 UNIPROT up-regulates phosphorylation Tyr321 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site SIGNOR-79764 0.2 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto Stat1 was phosphorylated at tyr 701 in jak immune complex kinase reaction. The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-g, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases. SIGNOR-30905 0.786 AMBRA1 protein Q9C0C7 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity binding 9606 BTO:0000007 dephosphorylation:Ser52 KRVELPDsPRSTFLL 23524951 t lperfetto In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. SIGNOR-272963 0.58 TRIM63 protein Q969Q1 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys365 SLASQATkDGKKDKK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). SIGNOR-272741 0.409 Gbeta proteinfamily SIGNOR-PF4 SIGNOR DUSP1 protein P28562 UNIPROT down-regulates phosphorylation 9606 16286470 t inferred from 70% family members lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-270093 0.2 CDK1 protein P06493 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates activity phosphorylation Thr210 SEYSMAEtLVGTPYY 9606 BTO:0000567 21642957 t done miannu We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1. SIGNOR-273889 0.469 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9913 11254391 t miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-266915 0.8 AR protein P10275 UNIPROT ARG2 protein P78540 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20711410 f The regulation of arginase expression following androgen stimulation was dependent on the androgen receptor (AR), as a siRNA treatment targeting the AR inhibited both ARG1 and ARG2 overexpression. This observation was correlated in vivo in patients by immunohistochemistry. SIGNOR-253671 0.264 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser199 PRPEHTKsVYTRSVI 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248599 0.2 RAB7A protein P51149 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity guanine nucleotide exchange factor BTO:0001131 14617358 t Sara The p150 adapter protein is in a complex with rab7. The hVPS34/p150 complex colocalized with rab7 on late endosomes and hVPS34 activity was dependent on nucleotide cycling of rab7 SIGNOR-261302 0.494 RASGEF1B protein Q0VAM2 UNIPROT NRAS protein P01111 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-161481 0.301 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263126 0.7 STK11 protein Q15831 UNIPROT SIK1 protein P57059 UNIPROT up-regulates activity phosphorylation Thr182 KSGEPLStWCGSPPY 9606 18946175 t miannu Salt inducible kinase (SIK) 1, a member of the AMP-activated kinase (AMPK) family, is activated by the AMPK-activator LKB1 which phosphorylates SIK1 at Thr182. SIGNOR-262844 0.573 GSK3B protein P49841 UNIPROT ZNF281 protein Q9Y2X9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser638 PRVDLHTsGEHSELV 9606 BTO:0001615 29179460 t lperfetto GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression| SIGNOR-264890 0.2 morphine chemical CHEBI:17303 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258931 0.8 CCK protein P06307 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 10368033 t gcesareni Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b SIGNOR-66339 0.869 F2R protein P25116 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257293 0.424 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr331 LTEDSTQtSDTATNS -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249676 0.2 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Ser253 APRRRAVsMDNSNKY 9606 20110348 t gcesareni Protein phosphatase 2a reactivates foxo3a through a dynamic interplay with 14-3-3 and aktpp2a-mediated dephosphorylation of t32/s253 is required for dissociation of 14-3-3, nuclear translocation, and transcriptional activation of foxo3a. SIGNOR-163680 0.408 L-serine chemical CHEBI:17115 ChEBI glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity precursor of 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268222 0.8 AKT1 protein P31749 UNIPROT LONP1 protein P36776 UNIPROT up-regulates activity phosphorylation Ser173 VFLKRDDsNESDVVE 9606 BTO:0001061 31406245 t lperfetto In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity. SIGNOR-265724 0.255 CSNK2A1 protein P68400 UNIPROT PIN4 protein Q9Y237 UNIPROT down-regulates activity phosphorylation Ser19 AGKGGAAsGSDSADK 9606 BTO:0000567 12860119 t lperfetto As proved by MALDI-TOF mass spectrometry and MS/MS fragmentation, hPar14 is phosphorylated at Ser19 in vitro and in vivo. In human HeLa cells the protein is most likely modified by casein kinase 2 (CK2). |In contrast to wild-type hPar14, the in vitro DNA-binding affinity of the Glu19 mutant is strongly reduced, suggesting that only the dephosphorylated protein is the active DNA-binding form of hPar14 in the nucleus. SIGNOR-265753 0.329 calcium(2+) smallmolecule CHEBI:29108 ChEBI PPP3CA protein Q08209 UNIPROT up-regulates chemical activation 9606 22944199 t lperfetto Non-canonical Wnt/Ca2+ pathway has also been implicated in multiple functions including cell adhesion and cell movements during gastrulation. In this signaling cascade, binding of Wnt to the Fzd receptor leads to the release of intracellular Ca2+, a process which is mediated through heterotrimeric G proteins, PLC (phospholipase C) and CamKII (calcium-calmodulin-dependent kinae II) as well as PKC (protein kinase C). The increased intracellular Ca2+ concentration also activates the calcineurin phosphatase, leading to activation of the transcription factor NFAT (nuclear factor of activated T cell). SIGNOR-198819 0.8 TP63 protein Q9H3D4 UNIPROT SUN1 protein O94901 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0005098 28595999 t lperfetto Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. SIGNOR-263278 0.2 GOT1 protein P17174 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-268063 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A4 protein P14672 UNIPROT up-regulates 9606 8940145 f Translocation from intracellular compartment to cell surface in muscle and adipose tissue gcesareni The constitutively active Akt induced glucose uptake into adipocytes in the absence of insulin by stimulating translocation of the insulin-responsive glucose transporter 4 to the plasma membrane. SIGNOR-45117 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 12058066 t lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-216662 0.411 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser821 YLRQFSGsLKPEDAE 9534 BTO:0000298 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249233 0.2 VWF protein P04275 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Many studies have contributed to shed light on the importance of von Willebrand factor (VWF) interaction with its platelet receptors, glycoprotein (GP) Ib-IX-V and αIIbβ3 integrin, in promoting primary platelet adhesion and aggregation following vessel injury SIGNOR-261853 0.681 PHKG2 protein P15735 UNIPROT PYGL protein P06737 UNIPROT up-regulates activity phosphorylation Ser15 QEKRRQIsIRGIVGV 9606 BTO:0002049 22225877 t It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15 SIGNOR-267401 0.648 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates activity phosphorylation Ser821 ARDIKNDsNYVVKGN 9823 7539802 t lperfetto We present here the identification of the major phosphorylation sites for PKC in Kit/SCFR. Two serine residues in the kinase insert, Ser-741 and Ser-746, are PKC-dependent phosphorylation sites in vivo and account for all phosphorylation by PKC in vitro. | Two additional serine residues, Ser-821 close to the major tyrosine autophosphorylation site in the kinase domain and Ser-959 in the carboxyl terminus are SCF-stimulated PKC-dependent phosphorylation sites. | Furthermore, the kinase activity of Kit/SCFR(S741A/S746A) toward an exogenous substrate was increased, which was reflected as a decreased Km and an increased Vmax, in accordance with the negative regulatory role of PKC on Kit/SCFR signaling. SIGNOR-248897 0.518 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL11 protein P51671 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16604092 f miannu Rosmarinic acid also inhibited TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha, as well as nuclear translocation of NF-kappaB heterodimer induced by TNF-alpha. This suggests that rosmarinic acid downregulates the expression of CCL11 and CCR3 via the inhibition of NF-kappaB activation signaling. SIGNOR-254661 0.264 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation SIGNOR-275804 0.2 MAP3K10 protein Q02779 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates activity binding -1 12881483 t lperfetto we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2). Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2 SIGNOR-234599 0.336 midostaurin chemical CHEBI:63452 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258247 0.8 AURKA protein O14965 UNIPROT TACC3 protein Q9Y6A5 UNIPROT up-regulates activity phosphorylation Ser558 ESALRKQsLYLKFDP 9606 BTO:0001109 17545617 t miannu We show that this conserved serine on human TACC3 (Ser(558)) is also phosphorylated by Aurora A. Moreover, phosphorylation of TACC3 by Aurora A in human cells is essential for its proper localization to centrosomes and proximal mitotic spindles. Inhibition of Aurora A with the selective small molecule inhibitor MLN8054 in cultured human tumor cells resulted in mislocalization of TACC3 away from mitotic spindles in a concentration-dependent manner. SIGNOR-262655 0.935 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000938 BTO:0000142 19303846 t lperfetto GSK3β regulates β-catenin stability by phosphorylating serine and threonine residues (Ser33/37 and Thr41) important for targeting β-catenin for ubiquitin-dependent proteasomal degradation SIGNOR-227874 0.893 GSK3B protein P49841 UNIPROT DCX protein O43602 UNIPROT up-regulates activity phosphorylation Ser332 STPKSKQsPISTPTS 9606 21159948 t lperfetto Gsk3b phosphorylates dcx at the distinct site of ser327 and thereby contributes to dcx function in the restriction of axon branching. Together, our data define a jip3-regulated gsk3_/dcx signaling pathway that restricts axon branching in the mammalian brain.Gsk3_ induces the phosphorylation of dcx at ser327, which contributes to dcx function in the inhibition of axon branching and self-contact. SIGNOR-170755 0.274 GATA4 protein P43694 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 t miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter SIGNOR-265815 0.252 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser115 PAPSSFSsTSVSSLE 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164629 0.568 PLK2 protein Q9NYY3 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates phosphorylation Ser595 ISFSSNSsFVLKILE 9606 20531387 t lperfetto Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap SIGNOR-166003 0.568 DTL protein Q9NZJ0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR up-regulates binding 9606 BTO:0000567 27906959 t miannu Here, we identify human SDE2 as a new genome surveillance factor regulated by PCNA interaction. The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner, and failure to degrade SDE2 impairs S phase progression and cellular survival. SIGNOR-272808 0.688 PTPN1 protein P18031 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 15632081 t gcesareni Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs SIGNOR-132959 0.737 CS protein O75390 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266239 0.8 RAB1A protein P62820 UNIPROT USO1 protein O60763 UNIPROT up-regulates activity binding -1 10903204 t Giulio Here, the tethering factor p115 was shown to be a Rab1 effector that binds directly to activated Rab1. SIGNOR-261287 0.793 GLI2 protein P10070 UNIPROT PPARG protein P37231 UNIPROT down-regulates BTO:0004300 29205155 f areggio Molecularly, Gli2 is the principle transcription factor in the Gli family to mediate the anti-adipogenic and anti-lipogenic effects of Hh signaling SIGNOR-256224 0.276 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249640 0.746 NR3C1 protein P04150 UNIPROT KLF9 protein Q13886 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 t We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα SIGNOR-256119 0.325 VRK2 protein Q86Y07 UNIPROT DCX DET1-COP1 complex SIGNOR-C24 SIGNOR up-regulates activity binding 9606 BTO:0000007 24298020 t miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme SIGNOR-272874 0.329 AKT proteinfamily SIGNOR-PF24 SIGNOR HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue. SIGNOR-186772 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR E2 conjugating enzyme proteinfamily SIGNOR-PF105 SIGNOR up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-270841 0.2 RYK protein P34925 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 15454084 t gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled. SIGNOR-129571 0.426 PPBP protein P02775 UNIPROT OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258412 0.368 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 BTO:0000782 15280374 t gcesareni Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2. SIGNOR-127198 0.298 STAT5A protein P42229 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates transcriptional regulation 9606 12540601 f fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. SIGNOR-210146 0.7 NR3C1 protein P04150 UNIPROT IRAK3 protein Q9Y616 UNIPROT up-regulates quantity transcriptional regulation 9606 25585690 t We show that glucocorticoids and non-typeable Haemophilus influenzae synergistically upregulate IRAK-M expression via mutually and synergistically enhancing p65 and glucocorticoid receptor binding to the IRAK-M promoter SIGNOR-259287 0.366 AKT proteinfamily SIGNOR-PF24 SIGNOR TERT protein O14746 UNIPROT up-regulates phosphorylation Ser824 AVRIRGKsYVQCQGI 9606 10224060 t lperfetto Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins. SIGNOR-244357 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD1 protein Q15139 UNIPROT up-regulates activity phosphorylation Ser742 GEKSFRRsVVGTPAY 18692497 t lperfetto The results presented in this study indicate that during mitosis, PKD3 and PKD are phosphorylated at Ser(731) and Ser(744) within their activation loop by a mechanism that requires protein kinase C. Mitosis-associated PKD3 Ser(731) and PKD Ser(744) phosphorylation is related to the catalytic activation of these kinases as evidenced by in vivo phosphorylation of histone deacetylase 5, a substrate of PKD and PKD3. SIGNOR-275925 0.2 acetyl-CoA smallmolecule CHEBI:15351 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates activity 9606 10893421 f Acetyl-CoA carboxylase (ACC) catalyzes the first committed step of the fatty acid synthetic pathway. Although ACC has often been proposed to be a major rate-controlling enzyme of this pathway, no direct tests of this proposal in vivo SIGNOR-267383 0.7 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12950161 t lperfetto C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases SIGNOR-86684 0.343 pazopanib hydrochloride chemical CHEBI:71217 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-201250 0.8 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser44 KPTFGKLsINKPTSE 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165558 0.845 DZIP3 protein Q86Y13 UNIPROT H2AC7 protein P20671 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271753 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA4 protein Q9Y5G9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265697 0.2 FOXO1 protein Q12778 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-270251 0.325 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRA protein P01903 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys244 FIIKGLRkSNAAERR 9606 19117940 t miannu Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination. SIGNOR-271412 0.2 Myog/SWI/SNF complex complex SIGNOR-C94 SIGNOR MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 17194702 t miannu Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle SIGNOR-151697 0.639 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR CEBPB protein P17676 UNIPROT down-regulates activity transcriptional regulation 9606 17139329 t fferrentino Phosphorylation of receptor-regulated SMADs (for example, SMAD1 or SMAD3) stimulates dimer formation with SMAD4 and translocation to the nucleus, where the SMADs regulate the transcription of target gene SMAD3 binds to C/EBPs and inhibits their transcriptional activity, including their ability to transactivate the Pparg2 promoter SIGNOR-253538 0.568 ABT-737 chemical CID:11228183 PUBCHEM BCL2L1 protein Q07817 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271;BTO:0000776;BTO:0000785 17200714 t gcesareni A cell-permeant compound, abt-737, binds with high affinity to bcl2, bcl2l1, and bcl2l2, antagonizes their antiapoptotic function, and induces apoptosis in select human tumor cell lines, primary patient-derived cells. SIGNOR-151784 0.8 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 21460634 t lperfetto Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition. SIGNOR-216464 0.477 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t gcesareni Erk2-mediated c-terminal serine phosphorylation of p300 (ser-2279, ser-2315, and ser-2366) is vital to the regulation of epidermal growth factor-induced keratin 16 gene expression. SIGNOR-156891 0.473 NUP153 protein P49790 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262069 0.733 AP1 complex SIGNOR-C154 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 9878062 f lperfetto AP‐1 proteins, including c‐Fos and c‐Jun, are prominent nuclear targets of growth factor induced signaling, making AP‐1 a candidate nuclear effector of growth factor induced proliferation. SIGNOR-252356 0.7 amitriptyline chemical CHEBI:2666 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258702 0.8 CSNK2A2 protein P19784 UNIPROT HSPH1 protein Q92598 UNIPROT down-regulates activity phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 t llicata Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro. SIGNOR-251008 0.33 PRCP protein P42785 UNIPROT POMC protein P01189 UNIPROT down-regulates activity 10090 20694162 f miannu Prolylcarboxypeptidase (PRCP) was found to be responsible for the control of food intake and energy expenditure at a central level. The molecular mechanisms underlying the suppression of food intake in PRCP-deficient mice or by the inhibitor of PRCP clearly provide physiological evidence that PRCP is an inactivator of α-MSH SIGNOR-252372 0.302 NFIX protein Q14938 UNIPROT WNT5A protein P41221 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268889 0.2 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120024 0.784 MDM2 protein Q00987 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates ubiquitination 9606 23252402 t gcesareni Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1. SIGNOR-200197 0.484 TSSK1B protein Q9BXA7 UNIPROT TSSK1B protein Q9BXA7 UNIPROT up-regulates activity phosphorylation Thr174 GRMALSKtFCGSPAY -1 15733851 t Manara Electrospray Q‐TOF2 mass spectroscopy analysis of a trypsin digested TSSK1 purified from E. coli, revealed that it was phosphorylated at its T‐loop residue (Fig. 2D), indicating that TSSK1 as was previously shown for MELK [18], can autophosphorylate its T‐loop Thr residue. SIGNOR-260823 0.2 ZMYND11 protein Q15326 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity binding 24675531 t miannu We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription. SIGNOR-265353 0.2 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-252961 0.588 MARK1 protein Q9P0L2 UNIPROT MAP2 protein P11137 UNIPROT down-regulates activity phosphorylation Ser1799 RRLSNVSsSGSINLL -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250167 0.424 canertinib chemical CHEBI:61399 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258200 0.8 linagliptin chemical CHEBI:68610 ChEBI DPP4 protein P27487 UNIPROT down-regulates activity chemical inhibition 9606 18052023 t Luana Herein, we report the discovery of the novel, potent, and selective DPP-4 inhibitor 1 (BI 1356)9 originating from the class of xanthines (Chart 1) SIGNOR-257764 0.8 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr904 EEEGRDEyDEVAMPV -1 10942405 t Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport. SIGNOR-251414 0.341 MAPK1 protein P28482 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser282 VGKQAPLsPGLPAMG 9606 20230789 t lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity SIGNOR-164227 0.329 BDKRB2 protein P30411 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257090 0.444 PTPRB protein P23467 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni When cells are stimulated with various ligands such as growth factors, hormones, neurotransmitters, or tumor promoters, erk1/2 is activated through dualphosphorylation at the -ptepy-motif. Subsequently, p-erk1/2 translocates into the nucleus and phosphorylates elk-1, thereby acting as a transcription factor for cell proliferationthese data indicate that sa-p-erk1/2 might not only be regulated by mkp such as rvhr, but also by pp1 and ptp as well SIGNOR-269911 0.2 ETS1 protein P14921 UNIPROT CD8A protein P01732 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8413295 f miannu Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. SIGNOR-254078 0.258 MUL1 protein Q969V5 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity sumoylation Lys608 LLAEEKSKPIPIMPA 9606 BTO:0000007 19638400 t Barakat Through detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. SIGNOR-274130 0.544 SLBP protein Q14493 UNIPROT H2BC9 protein Q93079 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265391 0.2 STUB1 protein Q9UNE7 UNIPROT S100P protein P25815 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 23344957 t miannu S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway. SIGNOR-272919 0.294 CCR1 protein P32246 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 25230753 f CCL3, an eosinophil precursor-produced chemokine that signals through CCR1, promotes terminal differentiation of CCR1-positive eosinophil precursors in the absence of IL-5, highlighting an autocrine loop capable of sustaining eosinophil differentiation SIGNOR-254369 0.7 SALL4 protein Q9UJQ4 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16840789 t Luana We conclude that the Nanog enhancer activity is regulated by both Sall4 and Nanog.  SIGNOR-266079 0.788 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr34 KDQFPEVyVPTVFEN 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271700 0.2 STAT3 protein P40763 UNIPROT SALL4 protein Q9UJQ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 19151334 f miannu We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. SIGNOR-255244 0.573 CAMK2A protein Q9UQM7 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275770 0.388 EXOC8 protein Q8IYI6 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270791 0.94 DUSP26 protein Q9BV47 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates activity dephosphorylation 9606 28701747 t miannu NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells SIGNOR-277104 0.2 THBS1 protein P07996 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252271 0.7 TACR1 protein P25103 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257423 0.418 MAPK1 protein P28482 UNIPROT GIGYF2 protein Q6Y7W6 UNIPROT unknown phosphorylation Ser30 SITSPPLsPALPKYK 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262775 0.2 TEAD4 protein Q15561 UNIPROT CCN2 protein P29279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33358571 t miannu The multifunctional cytokine TGF-β has been identified as a potent inducer of CTGF expression, activating CTGF transcription through the canonical Smad signaling pathway. It is worth noting that TGF-β synergizes with Hippo–Yes-associated protein (YAP) signaling, a key regulator of tumorigenesis, to induce the expression of CTGF by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter SIGNOR-277686 0.2 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser146 RPSQRHGsKYLATAS -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 SIGNOR-250011 0.35 SYNGAP1 protein Q96PV0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 26356309 t miannu The reversible removal of AIDA-1 from the PSD core under excitatory conditions is similar to the redistribution of another abundant PSD protein, SynGAP. Both SynGAP-alpha1 and AIDA-1 are known to bind PSD-95. SIGNOR-264229 0.608 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182967 0.737 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248371 0.604 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276100 0.266 RXRB protein P28702 UNIPROT THRA protein P10827 UNIPROT up-regulates binding 9606 10976919 t gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-81452 0.641 RNF146 protein Q9NTX7 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. SIGNOR-259997 0.663 RAB7A protein P51149 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity binding 10116 16040606 t Sara Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments SIGNOR-261304 0.279 PRKCB protein P05771 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity phosphorylation Ser582 LWHFRYEsLKHPKAY 9606 BTO:0000007 23824069 t miannu  Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ. SIGNOR-276496 0.51 ARHGEF4 protein Q9NR80 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260531 0.658 NRXN1 protein Q9ULB1 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites. SIGNOR-265452 0.822 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr66 DTAGQEDyDRLRPLS 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271699 0.2 homocysteine smallmolecule CHEBI:17230 ChEBI methionine smallmolecule CHEBI:16811 ChEBI up-regulates quantity precursor of 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253140 0.8 RINT1 protein Q6NUQ1 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR down-regulates 9606 BTO:0004784 16600870 f lperfetto We propose that p130, forming a complex with Rad50 through RINT-1, blocks telomerase-independent telomere lengthening in normal cells.  SIGNOR-265031 0.7 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT unknown phosphorylation Ser752 KMKKTSTsTETRSSS 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. ser-750, ser-752 and ser-758 are phosphorylated by the n-terminal kinase domain;however, their function is not known. SIGNOR-131403 0.2 CREB1 protein P16220 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 20660310 f amattioni beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state SIGNOR-229777 0.7 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264732 0.2 TGM2 protein P21980 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16407273 t gcesareni Tg2 is able to phosphorylate purified histone proteins, and h3 and h1 in chromatin preparations, and it is associated with chromatin in breast cancer cells. SIGNOR-265369 0.2 SLC24A5 protein Q71RS6 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264398 0.8 TP53 protein P04637 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23506862 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267462 0.357 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10330170 f gcesareni Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. SIGNOR-67535 0.496 PRKAA1 protein Q13131 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 17900900 t gcesareni The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation SIGNOR-157947 0.361 ROBO3 protein Q96MS0 UNIPROT CFL1 protein P23528 UNIPROT up-regulates quantity by expression post transcriptional regulation -1 16226035 t miannu Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268379 0.2 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Thr509 LKRKRRPtSGLHPED 9606 BTO:0000150 17428466 t lperfetto Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation SIGNOR-154312 0.515 ANXA1 protein P04083 UNIPROT FPR2 protein P25090 UNIPROT up-regulates activity binding 9606 BTO:0000007 15187149 t We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2. SIGNOR-259437 0.636 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 23263282 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-200206 0.2 EXOC6 protein Q8TAG9 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270789 0.941 GATA3 protein P23771 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 16386358 t Experimental data indeed supports the existence of a positive circuit involvingGATA-3 that excludes IL-4 and STAT-6, specifically in mouse cells SIGNOR-254297 0.2 lofexidine chemical CHEBI:51368 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 t Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  SIGNOR-258331 0.8 SF3a complex SIGNOR-C345 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 8349644 f miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263950 0.7 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2409 LHGDDQDsEDEVLTI 9606 8318012 t lperfetto The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157. SIGNOR-37831 0.481 GALR1 protein P47211 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256687 0.457 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-217344 0.692 PHF20 protein Q9BVI0 UNIPROT NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR form complex binding 9606 BTO:0000007 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. Two of its subunits, WD repeat domain 5 (WDR5) and host cell factor 1 (HCF1), are shared with members of the MLL/SET family of histone H3 lysine 4 (H3K4) methyltransferase complexes, and a third subunit, MCRS1, is shared with the human INO80 chromatin-remodeling complex. SIGNOR-267159 0.675 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 22252525 t gcesareni The mechanism by which pak1 induced cancer growth might involve activation of jnk in the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor. SIGNOR-195414 0.651 EDN1 protein P05305 UNIPROT EDNRB protein P24530 UNIPROT up-regulates binding 9606 16597412 t gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145762 0.946 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-216322 0.7 TYK2 protein P29597 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 7657660 t lperfetto Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity. SIGNOR-246943 0.77 selumetinib chemical CHEBI:90227 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190191 0.8 UBE2I protein P63279 UNIPROT ETV5 protein P41161 UNIPROT down-regulates sumoylation 9606 15857832 t miannu Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription. SIGNOR-135850 0.268 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000586 16293724 t lperfetto Because phosphorylation of β-catenin by GSK-3β leads to its rapid ubiquitination and subsequent degradation in the proteosome, inactivation of GSK-3β is often a prerequisite for stimulating the accumulation, nuclear translocation, and functional activity of β-catenin SIGNOR-227893 0.893 CDK1 protein P06493 UNIPROT APLP2 protein Q06481 UNIPROT unknown phosphorylation Thr736 VEVDPMLtPEERHLN 9606 BTO:0000142 9109675 t lperfetto A cytoplasmic domain peptide from aplp2 is phosphorylated in vitro by protein kinase c and cdc2 kinase. Aplp2 is phosphorylated by cdc2 kinase at a site homologous to the cdc2 kinase site phosphorylated in app. SIGNOR-47483 0.336 NMDA receptor_2D complex SIGNOR-C350 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264135 0.7 PARP1 protein P09874 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 11907276 f amattioni Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process SIGNOR-111680 0.7 NCBP1 protein Q09161 UNIPROT IRF8 protein Q02556 UNIPROT up-regulates activity binding 9606 BTO:0001413 11483597 t miannu we found that tyrosine phosphorylated ICSBP activates CYBB and NCF2 transcription, during late myeloid differentiation, by interacting with PU.1, IRF1 and CBP. SIGNOR-222939 0.2 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser447 YHRSIRHsSIQE 9606 BTO:0000782 20697158 t miannu Carock2 phosphorylated irf4 at either of 2 distinct phosphorylation sites, s446 and s447 / rock2-mediated phosphorylation of irf4 regulated the synthesis of il-17 and il-21 and the differentiation of th17 cells. SIGNOR-167467 0.424 RPS6KA4 protein O75676 UNIPROT H3-4 protein Q16695 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12773393 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 SIGNOR-249211 0.2 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10209155 t gcesareni Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4. SIGNOR-67003 0.741 N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide chemical CHEBI:94793 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189933 0.8 EZR protein P15311 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 BTO:0000132 35267019 f miannu Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies. Taken together, these results suggest that Rev-erbα potentiates platelet activation via an OPHN-1-mediated RhoA/ERM signalling pathway. SIGNOR-268432 0.7 MBOAT7 protein Q96N66 UNIPROT 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 ChEBI up-regulates quantity chemical modification -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267248 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252830 0.909 PRKAA1 protein Q13131 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates phosphorylation Ser351 HVISRDQsTPIIEVE 9606 SIGNOR-C15 21478464 t gcesareni Tr4 transactivation is inhibited via phosphorylation bymetformin-induced amp-activated protein kinase (ampk) at the amino acid serine 351, which results in the suppression of scd1 gene expression SIGNOR-173118 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser353 DSAIDTWsPSEWQMA 9606 11259409 t lperfetto When subjected to phosphorylation by erk, the most efficient decrease in erk phosphorylation was observed with the s353a mutantamong the mechanisms underlying k protein ability to confer increased transcriptional output are interconversion of duplex and single-stranded dna (59) and association with the c/ebp_ (60), each of which could be better affected by the phosphorylated form of the k protein, which may increase affinity to associated proteins or dna. SIGNOR-105754 0.2 CASP7 protein P55210 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261757 0.346 E2F1 protein Q01094 UNIPROT MT1G protein P13640 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000394 15735762 f lperfetto The E2F transcription factors induce the expression of many genes in response to specific extracellular stimuli. Here, we show that human metallothionein 1G (hMT1G) promoter is upregulated by E2F1 upon VEGF stimulation of human aortic endothelial cells. SIGNOR-254132 0.337 sorafenib tosylate chemical CHEBI:50928 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259226 0.8 ixabepilone chemical CHEBI:63605 ChEBI TUBB3 protein Q13509 UNIPROT down-regulates activity chemical inhibition 9606 18945860 t miannu Ixabepilone, the first drug in a new class of microtubule-stabilizing agents called epothilones, offers a new treatment option for patients with metastatic or locally advanced breast cancer who are refractory to standard chemotherapy. SIGNOR-259349 0.8 ECM stimulus SIGNOR-ST20 SIGNOR A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259035 0.7 SKIL protein P12757 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 SIGNOR-C85 12419246 t gcesareni Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 SIGNOR-195636 0.49 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT down-regulates activity phosphorylation Thr495 LLSLFEDtLDPT -1 12738781 t miannu Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site. SIGNOR-263097 0.712 dactolisib chemical CHEBI:71952 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 t ATP-competitive inhibitor of PI3K and mTOR gcesareni While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines SIGNOR-175712 0.8 risperidone chemical CHEBI:8871 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258530 0.8 MRE11 protein P49959 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. SIGNOR-181628 0.2 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257986 0.8 CSNK2B protein P67870 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser230 VTPSKSTsASAIMNG 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275745 0.272 TP53 protein P04637 UNIPROT FNTB protein P49356 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26469958 f lperfetto In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. SIGNOR-242353 0.2 TAF10 protein Q12962 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269581 0.77 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 17190791 t gcesareni We finally establish that full-length wnk1, wnk2 and wnk3, but not wnk4, are capable of directly phosphorylating ser382 of wnk1 in vitro. This supports the notion that t-loop phosphorylation of wnk isoforms is controlled by trans-autophosphorylation. SIGNOR-151675 0.2 GTF2B protein Q00403 UNIPROT FOXF2 protein Q12947 UNIPROT up-regulates activity binding 9534 BTO:0004055 9722567 t miannu The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. FREAC-2 dependent activation of transcription by TFIIB. SIGNOR-220317 0.5 SATB1 protein Q01826 UNIPROT TAF11 protein Q15544 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255130 0.2 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser196 EKSPSVCsPLNMTSS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276107 0.289 RNF7 protein Q9UBF6 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271450 0.2 REST protein Q13127 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 17453016 f NRSF represses neuronal differentiation by binding to conserved NRS elements (NRSEs) in gene promoters in non-neuronal cells, where it associates with one of several large repressor complexes, including the transcriptional co-repressor mSIN3a/b, nuclear receptor co-repressor 1 (N-CoR1), and coREST/histone deacetylase 2 (HDAC2). In this way, NRSF keeps neural-specific genes turned off in non-neuronal cells. SIGNOR-268622 0.7 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser567 SSSRRRRsSSTAPPT 9606 16513649 t llicata Mutagenesis and mass spectrometry studies identified four pka phosphorylation sites: ser465 (minor site) and three amino acid residues ser568, ser569, and ser570 (major sites) within the carboxyl-terminal region. pka activation decreased sk2 surface localization SIGNOR-145032 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 9840932 t lperfetto The cell-cycle regulated transcription factor b-myb is phosphorylated by cyclin a/cdk2 at sites that enhance its transactivation properties. we show that b-myb is phosphorylated at thr447, thr490, thr497 and ser581 by cyclin a/cdk5 SIGNOR-217252 0.711 BRD4 protein O60885 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR up-regulates activity binding 9606 16109377 t miannu Binding of Brd4 to Core P-TEFb Is Essential for Transcription. SIGNOR-266411 0.612 CDKL5 protein O76039 UNIPROT AMPH protein P49418 UNIPROT down-regulates activity phosphorylation Ser293 PAPARPRsPSQTRKG 10090 23651931 t gcesareni This 120-kDa protein was identified as amphiphysin 1 (Amph1) by LC-MS/MS analysis, and the site of phosphorylation by CDKL5 was determined to be Ser-293.| The phosphorylation mimic mutants, Amph1(S293E) and Amph1(S293D), showed significantly reduced affinity for endophilin, a protein involved in synaptic vesicle endocytosis SIGNOR-245881 0.366 Exon junction complex complex SIGNOR-C369 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 11532962 t lperfetto The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay SIGNOR-268315 0.8 RBBP4 protein Q09028 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 t miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. SIGNOR-268816 0.678 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr981 DNCSEEMyRLMLQCW 9606 14711813 t lperfetto Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesthe results suggest that phosphorylation of tyr981 is not obligatorily required for the catalytic activity but plays a supplementary role in initiating autophosphorylation of tyr905, which brings about the overall kinase activity. SIGNOR-121169 0.2 CYSLTR1 protein Q9Y271 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256883 0.2 STK3 protein Q13188 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser438 EKNYQLKsRQILGMR 9606 21076410 t lperfetto Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins SIGNOR-169539 0.245 CALM1 protein P0DP23 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-114101 0.695 bisphenol A chemical CHEBI:33216 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268732 0.8 MAPK8IP3 protein Q9UPT6 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10629060 t gcesareni These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3 SIGNOR-73906 0.695 IKBKE protein Q14164 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates phosphorylation Ser472 TQREGVSsLDSSSLS 9606 10893229 t gcesareni In response to a viral infection, phosphorylated on ser-477 and ser-479 by tbk1 and ikbke1. Phosphorylation, and subsequent activation is inhibited by vaccinia virus protein e3. SIGNOR-79143 0.68 POMT2 protein Q9UKY4 UNIPROT POMT complex SIGNOR-C372 SIGNOR form complex binding 9606 BTO:0000007 16698797 t miannu  Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex. SIGNOR-265429 0.593 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity transcriptional regulation 10090 BTO:0000165 10066785 t gcesareni Notch signaling up-regulated HES1 mRNA expression within 1 h and subsequently reduced expression of MyoD mRNA SIGNOR-243181 0.297 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183608 0.2 PBX1 protein P40424 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 15149596 t Pbx is constitutively bound close to the Myogenin promoter and can recruit MyoD lperfetto These domains are necessary for the stable binding of myod to the myogenin promoter through an interaction with an adjacent protein complex containing the homeodomain protein pbx, which appears to be constitutively bound at this site SIGNOR-124834 0.416 DHX9 protein Q08211 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 f miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. SIGNOR-260948 0.7 SLC12A1 protein Q13621 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264635 0.8 ATOH1 protein Q92858 UNIPROT HES6 protein Q96HZ4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17826772 f miannu Electrophoretic mobility shift assays and luciferase assays show that ATOH1 activates HES6 transcription through binding to three clustered E boxes of its promoter. SIGNOR-253754 0.448 SDC4 protein P31431 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 23151663 t gcesareni Like other wnt co receptors, syndecan 4 directly interacts with dvl during pcp. SIGNOR-199635 0.259 dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity precursor of 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268259 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0002181 11726515 t irozzo However, direct binding of Grb2 to Bcr/Abl also facilitates its tyrosine phosphorylation, which we propose reflects activation of a physiological negative regulatory mechanism by this oncogenic tyrosine kinase.Direct binding of Grb2 to Bcr/Abl facilitates Grb2 phosphorylation. SIGNOR-255820 0.2 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000938 26136660 t miannu The raise in the intracellular bicarbonate concentration may augment the depolarizing efflux of bicarbonate upon activation of GABAA receptors; however, both transporters also extrude chloride and thereby increase the gradient for a hyperpolarizing chloride current. SIGNOR-264920 0.8 AKT1 protein P31749 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 t esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. SIGNOR-252586 0.57 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Thr151 RSYSRLEtLGSASTS -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276117 0.62 CEBPD protein P49716 UNIPROT KLF5 protein Q13887 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16054042 f fspada Klf5 expression is induced by c/ebpbeta and delta. KLF5, in turn, acts in concert with c/ebpbeta/delta to activate the ppargamma2 promoter. SIGNOR-210007 0.512 MRPS35 protein P82673 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261442 0.67 PTPN1 protein P18031 UNIPROT STAM2 protein O75886 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr291 KSEPEPVyIDEDKMD 9606 20504764 t Together, the results presented here demonstrate that PTP1B can influence RTK signaling in a previously unrecognized manner. We show that PTP1B directly targets STAM2, part of the ESCRT-0 endosomal sorting complex, and we provide the first evidence that tyrosine phosphorylation affects STAM localization and function. This regulatory mechanism could impact signaling downstream of numerous cell surface receptors that are ubiquitinated and recognized by this conserved sorting machinery. SIGNOR-248406 0.48 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258714 0.8 morphine chemical CHEBI:17303 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258932 0.8 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Thr145 AGNKRLStIDESGSI 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250589 0.775 WWP2 protein O00308 UNIPROT TP73 protein O15350 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25071155 t miannu WWP2 ubiquitinates p73 and controls its protein stability. In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  SIGNOR-272233 0.285 CSNK2A1 protein P68400 UNIPROT STX1A protein Q16623 UNIPROT up-regulates phosphorylation Ser14 ELRTAKDsDDDDDVA 9606 11846792 t lperfetto In this report, we show that syntaxin-1a is phosphorylated in vitro by cki on thr21. Casein kinase ii (ckii) has been shown previously to phosphorylate syntaxin-1a in vitro and we have identified ser14 as the ckii phosphorylation site. the phosphorylation of syntaxin-1a by ckii enhances its capacity to associate with synaptotagmin [21]. Therefore, phosphorylation of ser14 by ckii suggests an important role for this residue in regulating the interaction between syntaxin-1a and synaptotagmin SIGNOR-114840 0.371 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation 9606 8381049 t inferred from 70% family members gcesareni Activated map kinase phosphorylates cpla2 at ser-505, causing increased enzymatic activity of cpla2, which is only realized upon translocation of cpla2 to the membrane. SIGNOR-270192 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR E2F5 protein Q15329 UNIPROT up-regulates activity phosphorylation Thr261 SQSLTPVtPQKSSMA 9606 10783242 t miannu Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. SIGNOR-262732 0.633 cis-(z)-Flupenthixol chemical CHEBI:10454 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258715 0.8 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 10090 BTO:0004831 11896587 t lperfetto Serine 20 phosphorylation of p53 has been shown to be required for the activation of p53 following UV radiation. we determined the role of map kinases in uvb-induced phosphorylation and found that jnks are directly involved in the phosphorylation of p53 at serine 20 SIGNOR-106538 0.793 MYT1L protein Q9UL68 UNIPROT SIN3B protein O75182 UNIPROT up-regulates activity binding 10090 BTO:0002572 28379941 t miannu We found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. SIGNOR-266774 0.458 RELA protein Q04206 UNIPROT NPPB protein P16860 UNIPROT unknown transcriptional regulation 15837525 f In comparison to the ANF gene, less is known about BNP promoter consensus elements that regulate gene expression by mechanical or neurohumoral agonists. A number of cis-acting elements for GATA, Nkx2.5, NF-kappaB and TEF transcription factors have recently been identified within the BNP promoter that regulate BNP expression in response to specific agonists. This review focuses on the information available regarding cis-acting determinants responsible for inducible BNP transcription. SIGNOR-253651 0.2 CPT1C protein Q8TCG5 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267134 0.8 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 12242151 t gcesareni We find short peptides representing the alpha-helical bh3 domains of bid or bim are capable of inducing oligomerization of bak and bax to release cytochrome cthe first alfa helix of bax plays a necessary role in its ligand-induced activation by the bh3-only proteins bid and puma SIGNOR-92945 0.821 CDK1 protein P06493 UNIPROT SAMHD1 protein Q9Y3Z3 UNIPROT down-regulates phosphorylation Thr592 DVIAPLItPQKKEWN 9606 23602554 t llicata Cyclin a2/cdk1 phosphorylates samhd1 at the threonine 592 residue both in vitro and in vivo. Phosphorylation of samhd1 thr592 correlates with loss of its ability to restrict hiv-1. SIGNOR-201913 0.501 perifosine chemical CHEBI:67272 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 22090271 t Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine is an alkylphospholipid that targets the pleckstrin homology domain of akt and blocks its membrane translocation, hence preventing akt phosphorylation and activation SIGNOR-252630 0.8 TGFBR1 protein P36897 UNIPROT SPTBN1 protein Q01082 UNIPROT up-regulates phosphorylation 9606 12543979 t gcesareni This suggests that, upon stimulation with tgf-beta1, phosphorylation of elf could induce a conformational change that reduces its affinity for ankyrin and tropomyosin and facilitates an association with smad3 and smad4 instead. SIGNOR-97626 0.509 TPH1 protein P17752 UNIPROT 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity chemical modification 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264010 0.8 STAT1 protein P42224 UNIPROT NOS2 protein P35228 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19029990 t lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249497 0.436 IL10RA protein Q13651 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity binding 9606 BTO:0000801;BTO:0000776 10347215 t miannu Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5. SIGNOR-68010 0.804 BCL2L11 protein O43521 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000972 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260426 0.7 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr529 TPGSRSRtPSLPTPP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249323 0.758 LRFN5 protein Q96NI6 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264098 0.7 PTPRJ protein Q12913 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity dephosphorylation 9606 25386896 t lperfetto Our data demonstrate that CD148 promotes E-cadherin cell adhesion by regulating Rac1 activity, concomitant with modulation of p120, \u03b2-catenin, and Src tyrosine phosphorylation, and that this effect requires E-cadherin and p120 association.|Taken together, it is likely that CD148 dephosphorylation of \u03b2-catenin enhances the cadherin cell adhesion independent of Rho family GTPases. SIGNOR-276992 0.505 MFGE8 protein Q08431 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 10116 31958465 t miannu Milk fat globule-EGF factor 8 (MFGE8), a protein known as lactadherin in humans, contains C domains interacting with extracellular matrices and epidermal growth factor–like domains with an RGD motif binding to integrins αvβ3 and αvβ5. SIGNOR-260644 0.514 NUMB protein P49757 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000150 18492217 t gcesareni Numb can actually interact in vivo with endogenous mdm2 and p53, resulting in a trimeric complex between the three proteins [10]. This interaction appears to regulate the stability of p53, as reduction of numb levels by rna interference (rnai) causes a decrease in the half-life of p53 and consequently a reduction in steady-state levels of the protein. Consistent with this observation, overexpression of numb increases the level of p53 in both unstressed and stressed cells. SIGNOR-178668 0.525 SBDS protein Q9Y3A5 UNIPROT EIF6 protein P56537 UNIPROT up-regulates 9606 BTO:0001271 21536732 f miannu Human sbds is an essential cofactor for the efl1 gtpase, and together they cooperate to directly catalyze the release of eif6 from mammalian pre-60s ribosomal subunits SIGNOR-173536 0.526 DUSP9 protein Q99956 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates binding 9606 21908610 t inferred from 70% of family members gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-269902 0.2 CRP protein P02741 UNIPROT CCL2 protein P13500 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004910 26961257 f miannu In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the “risk” His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. SIGNOR-252144 0.449 MEN1 protein O00255 UNIPROT MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t irozzo We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity[...]. SIGNOR-255867 0.2 ROCK1 protein Q13464 UNIPROT FHOD1 protein Q9Y613 UNIPROT up-regulates phosphorylation Ser1131 AARERKRsRGNRKSL 9606 18239683 t lperfetto Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres. SIGNOR-160544 0.313 ATR protein Q13535 UNIPROT ATRIP protein Q8WXE1 UNIPROT up-regulates phosphorylation Ser68 EELDTLAsQALSQCP 9606 15451423 t lperfetto When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro. SIGNOR-129469 0.875 NFAT5 protein O94916 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000815 22266867 t done miannu  As expected, the depletion of NFAT5 decreased the S100A4 and LCN2 mRNA levels (Figure 3a). In addition, chromatin immunoprecipitation (ChIP) assay using NFAT5 antibody indicated that NFAT5 was bound to the S100A4 and LCN2 promoters (Figure 3b, Supplementary Figure S3), as expected (Chen et al., 2009). SIGNOR-274115 0.486 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275983 0.379 KAT5 protein Q92993 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys21 GGAKRHRkVLRDNIQ 9606 12776177 t lperfetto Thus, the TIP60 HAT complex is recruited to MYC-target genes and, probably with other other HATs, contributes to histone acetylation in response to mitogenic signals. SIGNOR-262061 0.2 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser698 PEWPRRAsCTSSTSG -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250883 0.332 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma IGF-I binding to its receptor activates the kinase activity of the receptor, which then recruits the insulin response substrate-1, causing activation of phosphatidyl-inositol-3 kinase (PI3K) to phosphorylate Akt. SIGNOR-255104 0.866 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates activity phosphorylation Ser99 KNKGKGFsVVADTPE -1 12432067 t miannu Lasp-1 binds to non-muscle filamentous (F) actin in vitro in a phosphorylation-dependent manner. Phosphorylation of recombinant lasp-1 with recombinant PKA increased the Kd and decreased the Bmax for lasp-1 binding to F-actin. PKA-dependent phosphorylation sites in rabbit lasp-1 to S99 and S146 SIGNOR-250075 0.309 STK3 protein Q13188 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t Two of these, S909 and T1079, were required for Lats1 activation. milica Since the N-terminal half of Lats1 (residues 1–588) was dispensable for the activation of Lats1 by Mst2, mass spectrometry was used to identify phosphorylation sites within the C-terminal domain of Lats1. SIGNOR-133544 0.61 IGF1R protein P08069 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 18595745 t gcesareni Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively) SIGNOR-252690 0.69 GSK3B protein P49841 UNIPROT TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0003492 21254166 t miannu  This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361. SIGNOR-276301 0.352 FLT3 protein P36888 UNIPROT PTPRJ protein Q12913 UNIPROT down-regulates activity 10090 22438257 f Taken together, the described findings supported the notion that FLT3 ITD causes reduced DEP-1 activity compared with cells expressing WT FLT3 rather than alterations in mRNA or protein levels. SIGNOR-261553 0.498 RNF146 protein Q9NTX7 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity ubiquitination 9606 BTO:0000007 21799911 t By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a positive regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. SIGNOR-259998 0.516 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr255 ITTPELTtPCGSAEY 9606 20927323 t gcesareni Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e. SIGNOR-168314 0.501 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207603 0.8 FPR1 protein P21462 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256961 0.251 AVPR2 protein P30518 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256897 0.271 FANCE protein Q9HB96 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263247 0.839 ITGA3 protein P26006 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253173 0.8 SGK3 protein Q96BR1 UNIPROT FLII protein Q13045 UNIPROT up-regulates phosphorylation Ser436 RLRRRKDsAQDDQAK 9606 19293151 t lperfetto Here we show that flii is an in vivo substrate of cisk that functions downstream of pi 3-kinase. Cisk can associate with flii and phosphorylate flii at residues ser(436) and thr(818).We demonstrate here that cisk can enhance er transcription, which is dependent on its kinase activity, and mutation of cisk phosphorylation sites on flii attenuates its activity as an er co-activator. SIGNOR-184688 0.361 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser410 RKDSLDDsGSCLSGS 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248988 0.395 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;VIRAL ABL gcesareni SIGNOR-193372 0.8 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni Protein kinase c isoforms differentially phosphorylate human choline acetyltransferase regulating its catalytic activity. SIGNOR-129280 0.288 AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR RABGEF1 protein Q9UJ41 UNIPROT up-regulates activity relocalization 10090 27411398 t lperfetto AP-1/sigma1A-ArfGAP1-Rabex-5 complex formation leads to more endosomal Rabex-5 and enhanced, Rab5GTP-stimulated Vps34 PI3-kinase activity, which is essential for multivesicular body endosome formation. SIGNOR-260706 0.326 PLCG2 protein P16885 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates quantity chemical modification 9606 23000145 t scontino Upon stimulation with various immune receptors, PLCγ2 cleaves the membrane-bound phospholipid phosphatidyl inositol-4, 5-biphosphate (PIP2) into the second messenger molecules inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). SIGNOR-268454 0.8 HDAC1 protein Q13547 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 t lperfetto ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.|These data further suggest that HDAC1 is involved in the SNAI1P-mediated repression of the human CLDN7 gene promoter. SIGNOR-254106 0.2 MRPS28 protein Q9Y2Q9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-267732 0.627 IFNG protein P01579 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 20525234 f miannu Pro-inflammatory cytokines like interferon-γ (IFN-γ) induce expression of GTP-cyclohydrolase I in various brain cells. SIGNOR-252223 0.253 SLC24A5 protein Q71RS6 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264403 0.8 FAM83H protein Q6ZRV2 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273755 0.2 SKP1 protein P63208 UNIPROT SCF-SKP2 complex SIGNOR-C136 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243554 0.94 CDC14A protein Q9UNH5 UNIPROT KMT5A protein Q9NQR1 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t The dephosphorylation of S29 during late mitosis by the Cdc14 phosphatases was required for APC(cdh1)-mediated ubiquitination of PR-Set7 and subsequent proteolysis. SIGNOR-248835 0.2 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Ser226 LNPQWNEsFTFKLKP 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277177 0.2 PRKAA2 protein P54646 UNIPROT PAK2 protein Q13177 UNIPROT unknown phosphorylation Ser20 APPVRMSsTIFSTGG 9606 SIGNOR-C15 22137581 t llicata Together, these results indicate that ampk phosphorylates endogenous ppp1r12c at s452 and pak2 at s20 in human cells. SIGNOR-195110 0.243 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-188916 0.527 Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 20498094 f miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263728 0.7 GPR183 protein P32249 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257202 0.262 RAPGEF5 protein Q92565 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183735 0.423 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr53 PPGSLSStPLSTPCS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159394 0.2 PRKD1 protein Q15139 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser154 STLYRTQsSSNLAEL 9606 BTO:0000738 23129748 t miannu  PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration.  SIGNOR-276426 0.2 CAMK2A protein Q9UQM7 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 7822264 t llicata On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II. SIGNOR-250626 0.434 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161585 0.613 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 21349850 t gcesareni Using a mass spectrometry-based assay, we show that egf induces phosphorylation of iqgap1 ser(1443), a residue known to be phosphorylated by pkcthe nonphosphorylatable iqgap1 s1441a/s1443a had no effect. In contrast, the s1441e/s1443d mutation markedly enhanced the ability of iqgap1 to induce neurite outgrowth. SIGNOR-172239 0.2 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser151 VLPSSKRsPSTATLS 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276779 0.634 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Leu433 REYHTEKlVTSKGDK -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain SIGNOR-263624 0.2 E2F5 protein Q15329 UNIPROT CBX5 protein P45973 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 21374739 t Luana We identified for E2F5 a repressor function for HP1a expression. SIGNOR-261591 0.2 SRC protein P12931 UNIPROT CLTC protein Q00610 UNIPROT up-regulates phosphorylation Tyr1477 LFITEEDyQALRTSI 9606 10089883 t gcesareni Egf-mediated clathrin phosphorylation is followed by clathrin redistribution to the cell periphery and is the product of downstream activation of src kinase by egf receptor (egfr) signaling SIGNOR-65714 0.412 AKT1 protein P31749 UNIPROT CCDC88A protein Q3V6T2 UNIPROT unknown phosphorylation Ser1417 INRERQKsLTLTPTR 9606 16139227 t llicata Akt phosphorylates serine at position 1416 in girdin, and phosphorylated girdin accumulates at the leading edge of migrating cells. SIGNOR-252482 0.608 EGFR protein P00533 UNIPROT IKBKE protein Q14164 UNIPROT up-regulates activity phosphorylation Tyr179 SVYGTEEyLHPDMYE 9606 27287717 t miannu EGFRL858R/T790M phosphorylates IKBKE at tyrosine residues. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.  SIGNOR-277243 0.259 FUS protein P35637 UNIPROT GEMIN6 protein Q8WXD5 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 23022481 t lperfetto Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells SIGNOR-262106 0.2 SERPINA1 protein P01009 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 t lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). SIGNOR-263515 0.334 AMPK complex SIGNOR-C15 SIGNOR CSNK1E protein P49674 UNIPROT up-regulates activity phosphorylation Ser389 RGAPANVsSSDLTGR -1 17525164 t miannu AMPK enhances mPer2 degradation and CKIɛ activity by phosphorylating Ser-389 of CKIɛ. One of the regulators of the period length is casein kinase Iepsilon (CKIepsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKIepsilon, resulting in increased CKIepsilon activity and degradation of mPer2.  SIGNOR-276064 0.265 CSNK1D protein P48730 UNIPROT MTSS1 protein O43312 UNIPROT down-regulates quantity by destabilization phosphorylation Ser322 SSVSSHDsGFISQDA 9606 BTO:0000567 24318128 t miannu Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.  SIGNOR-276611 0.33 DNMT1 protein P26358 UNIPROT BAG4 protein O95429 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 18413740 f lperfetto In contrast, an increase in BAG-1, BAG-3, and BAG-4 gene expression was observed in HCT116 cells overexpressing either DNMT1 (DNMT1+) or DNMT3B (DNMT3B+) SIGNOR-254112 0.2 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 16146838 t lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-249622 0.417 DLL3 protein Q9NYJ7 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209738 0.478 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr293 QSAQSLAtPVVSVAT 9606 9069290 t The effect has been demonstrated using Q06413-3 lperfetto We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation. SIGNOR-47136 0.688 pemetrexed chemical CHEBI:63616 ChEBI TYMS protein P04818 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205933 0.8 CDK1 protein P06493 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser48 KLDPVFDsPRMSRRS 9606 BTO:0000567 25482198 t miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. SIGNOR-263099 0.363 CRYAB protein P02511 UNIPROT CRYGS protein P22914 UNIPROT up-regulates activity binding -1 20621668 t miannu Human gamma-crystallins are long-lived, unusually stable proteins of the eye lens exhibiting duplicated, double Greek key domains. The lens also contains high concentrations of the small heat shock chaperone alpha-crystallin, which suppresses aggregation of model substrates in vitro. Mature-onset cataract is believed to represent an aggregated state of partially unfolded and covalently damaged crystallins. The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. These in vitro results provide support for protein unfolding/protein aggregation models for cataract, with alpha-crystallin suppressing aggregation of damaged or unfolded proteins through early adulthood but becoming saturated with advancing age. SIGNOR-253623 0.549 U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR RNA_splicing phenotype SIGNOR-PH201 SIGNOR up-regulates 9606 30765414 f lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270651 0.7 Caspase 3 complex complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT down-regulates activity cleavage Asp1405 CPGYPETdHGLFEDP 9606 12907805 t lperfetto Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain. SIGNOR-256438 0.325 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000596 24942200 t flangone During neural fate specification, nuclear translocation of ERK1/2 is critical for its activation of Sox2 transcription. More-over, melatonin-induced Sox2 expression, through ERK1/ 2 activation, could locate between base pairs2719 and 1708 in the mouse Sox2 gene. SIGNOR-241977 0.2 GSK3B protein P49841 UNIPROT EIF2B2 protein P49770 UNIPROT down-regulates binding 9606 21798082 t gcesareni Akt also promotes protein synthesis by phosphorylating and inactivating gsk3b, thus releasing the gsk3b-dependent inhibition of the eukariotic translation initiation factor 2b (eif2b). SIGNOR-175475 0.2 CDK1 protein P06493 UNIPROT SYN3 protein O14994 UNIPROT up-regulates phosphorylation Ser470 PQGQQPLsPQSGSPQ 9606 14732590 t lperfetto A rare, missense polymorphism, s470n, was identified in the synapsin iii gene and appeared more frequently in individuals with schizophrenia than in controls. Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. SIGNOR-121398 0.2 ATXN7 protein O15265 UNIPROT CRX protein O43186 UNIPROT down-regulates activity binding 10090 11580893 t miannu We found that ataxin-7 and CRX colocalize and coimmunoprecipitate. We observed that polyglutamine-expanded ataxin-7 can dramatically suppress CRX transactivation. SIGNOR-223226 0.619 CSNK2A1 protein P68400 UNIPROT CACNA1S protein Q13698 UNIPROT up-regulates activity phosphorylation Ser1575 PEICRTVsGDLAAEE -1 20937870 t miannu To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2. SIGNOR-263114 0.2 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT up-regulates activity phosphorylation Ser64 KPKTGKKsKQQAFIK -1 14608379 t lperfetto Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.  SIGNOR-249241 0.675 G6PD protein P11413 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267050 0.8 ABL1 protein P00519 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation 9606 BTO:0000567;BTO:0001271 12944467 t gcesareni We thus hypothesized that wrn may interact with the abl tyrosine kinase in the dna damage response. Here, we provide evidence for a functional and physical interaction between wrn and c-abl, including wrn relocalization in response to dna damage, suggesting that this protein-protein interaction participates in a shared pathway of genome surveillance. SIGNOR-86497 0.418 3-phenanthryl hydrogen sulfate chemical CHEBI:37459 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. SIGNOR-258439 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR TTC3 protein P53804 UNIPROT up-regulates phosphorylation Ser378 AYTPRSLsAPIFTTS 9606 20059950 t llicata Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context SIGNOR-162984 0.2 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates activity phosphorylation Ser25 KRRSARLsAKPPAKV 9606 11438671 t lperfetto We report here that the NBD of the HMGN1 and -N2 protein family is highly and specifically phosphorylated during mitosis and that this phosphorylation has a major functional consequence: it abolishes the interaction of the proteins with its chromatin targets. SIGNOR-249101 0.368 TWIST1 protein Q15672 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20646316 f miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. SIGNOR-255524 0.485 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR Cell_shape phenotype SIGNOR-PH182 SIGNOR up-regulates 9606 24302288 f lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266033 0.7 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268704 0.605 DZIP3 protein Q86Y13 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHK 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271757 0.2 ULK1 protein O75385 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19211835 t gcesareni Ulks directly phosphorylate atg13 SIGNOR-183957 0.916 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PAK1 protein Q13153 UNIPROT down-regulates phosphorylation 9606 14993270 t inferred from 70% family members gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. SIGNOR-270186 0.2 SYN1 protein P17600 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269184 0.302 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser407 DSQGRNCsTNDSLL -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251197 0.687 CSF1R protein P07333 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24890514 f apalma The Erk1/2 pathway has a central role in CSF-1R-regulated myeloid differentiation. CSF-1 induces early (peaking at ‚àº5 min) and persistent (starting at 1 h) waves of MEK/Erk1/2 phosphorylation SIGNOR-255572 0.289 VAMP8 protein Q9BV40 UNIPROT STX11-VAMP8 SNARE complex complex SIGNOR-C273 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  SIGNOR-261896 0.566 GUCY1B2 protein O75343 UNIPROT GUCY1A2-B2 complex SIGNOR-C137 SIGNOR form complex binding 9606 10977868 t gcesareni This enzyme is a heterodimeric protein consisting of - and ²-subunits, and expression of both subunits is required for catalytic activity SIGNOR-243974 0.2 WNT4 protein P56705 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 9753670 f gcesareni Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm. SIGNOR-60370 0.297 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10090 BTO:0002572 20670887 t lperfetto Specifically as part of mTORC1, mTOR directly phosphorylates the ribosomal protein S6 kinases (S6K1 and S6K2) and the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP1 and 4E-BP2)phosphorylation of the 4E-BPs leads to their inhibition and release from eIF4E at the 5_ cap of mRNAs SIGNOR-235745 0.754 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys122 SPVEDNEkDLVKLAK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272743 0.471 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAMAC protein Q9BTL3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 YLKRPPEsPPIVEEW 9606 BTO:0001581 27452456 t miannu ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency. SIGNOR-277819 0.2 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258452 0.8 CSNK2A1 protein P68400 UNIPROT NR1H3 protein Q13133 UNIPROT down-regulates phosphorylation Ser198 SLPPRASsPPQILPQ 9606 BTO:0000801 18250151 t llicata Ck2? Also phosphorylated lxr? At s198 in vitro, suggesting that ck2 may be a bona fide s198 kinase. our results show that macrophage lxr? Phosphorylation at s198 affects the transcriptional activity of the receptor in a gene-specific manner (fig. ?(Fig.3a)3a) and restricts the repertoire of genes regulated by lxr? SIGNOR-160640 0.2 WNT3A protein P56704 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity 9606 18772438 f gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. SIGNOR-180803 0.682 INSR protein P06213 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr427 ELFDDPSyVNVQNLD 11075717 t Insulin predominantly phosphorylates the Shc Tyr-317 residue. Phosphorylated Shc binds to Grb2 which forms a complex with Sos guanine nucleotide exchange factor for p21ras.  SIGNOR-251325 0.703 GDNF protein P39905 UNIPROT Neural_tissue_regeneration phenotype SIGNOR-PH68 SIGNOR up-regulates 10116 15212950 f miannu The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. In normal development, GDNF promotes survival of sympathetic, parasympathetic, and spinal motorneurons. It even promotes regeneration of spinal motor neurons after spinal cord injury. SIGNOR-252170 0.7 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269237 0.767 SREBF2 protein Q12772 UNIPROT HMGCR protein P04035 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000759 31848472 t miannu The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription SIGNOR-265161 0.503 PKA proteinfamily SIGNOR-PF17 SIGNOR ENAH protein Q8N8S7 UNIPROT up-regulates activity phosphorylation 9606 15066263 t miannu  Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts SIGNOR-268285 0.2 PK proteinfamily SIGNOR-PF80 SIGNOR phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266539 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PALLD protein Q8WX93 UNIPROT unknown phosphorylation Ser1118 VRRPRSRsRDSGDEN 9606 20471940 t llicata Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling. SIGNOR-165497 0.2 PRKACA protein P17612 UNIPROT KCNJ2 protein P63252 UNIPROT down-regulates activity phosphorylation Ser425 PRPLRREsEI -1 19843922 t miannu PKA consensus site S425 required for PKA-mediated effects on Kir2.1 channels. PKA activation reduced outward IK1 for heteromeric Kir2.1 WT+V227F channels after 2 hours of PKA activation. SIGNOR-276267 0.2 SRPK1 protein Q96SB4 UNIPROT SRPK1 protein Q96SB4 UNIPROT up-regulates phosphorylation Ser309 RPNKQEEsESPVERP 9606 22727668 t llicata We found that activated akt binds and induces srpk1 autophosphorylation because akt-mediated phosphorylation depends on the kinase activity of srpk1 SIGNOR-197985 0.2 SRC protein P12931 UNIPROT INPPL1 protein O15357 UNIPROT up-regulates phosphorylation Tyr986 NSFNNPAyYVLEGVP 9606 12235291 t lperfetto Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo. SIGNOR-92931 0.545 FYN protein P06241 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Tyr1105 CSEVERTyLKTKSSS -1 10195142 t lperfetto To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain. SIGNOR-247151 0.728 AKT1 protein P31749 UNIPROT BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-252559 0.445 PRKCE protein Q02156 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0001253 16418226 t gcesareni Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation. SIGNOR-143832 0.405 FOXS1 protein O43638 UNIPROT FASLG protein P48023 UNIPROT down-regulates quantity by repression transcriptional regulation 9913 BTO:0004577 18288644 t Luana As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells SIGNOR-261612 0.2 GSK3B protein P49841 UNIPROT FOXM1 protein Q08050 UNIPROT down-regulates quantity by destabilization phosphorylation Ser474 S-->A 9606 BTO:0002181 26912724 t miannu GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. SIGNOR-277208 0.359 PPP5C protein P53041 UNIPROT CDC37 protein Q16543 UNIPROT down-regulates activity dephosphorylation Ser13 VWDHIEVsDDEDETH 9606 18922470 t Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37. SIGNOR-248539 0.664 FADS3 protein Q9Y5Q0 UNIPROT arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267913 0.8 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT up-regulates activity phosphorylation Tyr487 DNSSDSDyDLHGAQR 9606 BTO:0000782 11298344 t lperfetto Tyrosine phosphorylation of cd5 requires lck activity. We propose that t cell activation mediates cd5 tyrosine phosphorylation at residues y429 and y463 mainly through the activation of lck SIGNOR-106803 0.552 SNAP23 protein O00161 UNIPROT STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR form complex binding 9606 BTO:0000132 22767500 t lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23.  SIGNOR-261895 0.734 POMT complex SIGNOR-C372 SIGNOR DGC complex SIGNOR-C217 SIGNOR up-regulates activity glycosylation 9606 BTO:0000007 14699049 t miannu we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O-mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O-mannosylation is complex. Further, protein O-mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain. SIGNOR-265431 0.411 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT down-regulates activity phosphorylation Thr14 PAKAANRtPPKSPGD -1 17693641 t miannu Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. The phosphorylation sites Thr(14), Ser(18), Ser(160) for Cdk5; Ser(18), Ser(160) for ERK2, and Ser(32) for PKA were identified by mass spectrometry. The phosphorylation by ERK2 or Cdk5 resulted in the loss of microtubule-assembling activity of TPPP. SIGNOR-262933 0.41 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 15169778 t gcesareni Stabilization of mdm2 via decreased ubiquitination is mediated by protein kinase b/akt-dependent phosphorylation. SIGNOR-124949 0.807 CSNK2A2 protein P19784 UNIPROT IL16 protein Q14005 UNIPROT up-regulates activity phosphorylation Ser743 MPLQPNAsLNEEEGT -1 12450396 t llicata We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation. SIGNOR-251009 0.329 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176841 0.778 MAPK3 protein P27361 UNIPROT STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 25846811 t lperfetto Directly and/or through the activation of p90RSK, ERK phosphorylates LKB-1 at Ser325 and Ser428. The phosphorylation of LKB-1 causes the dissociation of LKB-1 from AMPK, resulting in the impaired activation of AMPK. SIGNOR-209880 0.395 sertindole chemical CHEBI:9122 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258549 0.8 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser239 WRSPGRGsWFVQALC 9606 BTO:0000150 21555521 t gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. SIGNOR-173655 0.355 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser247 GALSNSEsIPTIDGL 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250599 0.292 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation 9606 21902831 t lperfetto As a permissive environment is created at these loci, p38 further stimulates gene expression through the phosphorylation of additional myogenic transcription factors, including mef2c and e47. SIGNOR-176551 0.688 HSPA2 protein P54652 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 12391142 t gcesareni Coimmunoprecipitation analysis revealed a physical interaction between endogenous hsp72 and ask1 in nih 3t3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ask1 and ask1-dependent apoptosis. SIGNOR-94565 0.2 THR proteinfamily SIGNOR-PF84 SIGNOR RARG protein P13631 UNIPROT up-regulates binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-270315 0.2 ACE2 protein Q9BYF1 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates activity cleavage His42 RVYIHPFhLVIHNES -1 11815627 t miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. SIGNOR-260221 0.2 ME2 protein P23368 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu The major NADPH-producing enzymes in the cell are glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) in the pentose phosphate pathway (PPP), malic enzyme (ME) in the pyruvate cycling pathway, and isocitrate dehydrogenase (IDH) in the tricarboxylic acid (TCA) cycle SIGNOR-267054 0.8 SRC protein P12931 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Tyr289 MELQTYRyHGHSMSD 9606 BTO:0000007 26848621 t miannu Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1).  SIGNOR-277204 0.354 Immunoglobulin lambda-1 light chain protein P0DOX8 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323265 t scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. SIGNOR-268190 0.2 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161565 0.323 ASF1A protein Q9Y294 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates activity binding 9606 BTO:0002181 33503415 t miannu Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks. SIGNOR-277621 0.315 RPS27L protein Q71UM5 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262445 0.789 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126736 0.737 IL1R1 protein P14778 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity 9606 BTO:0000007 14625308 f lperfetto Formation of the signaling il-1 receptor complex results in the activation and hyperphosphorylation of irak-1. SIGNOR-119208 0.913 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1721 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273048 0.55 5-[6-[(4-methyl-1-piperazinyl)methyl]-1-benzimidazolyl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]-2-thiophenecarboxamide chemical CHEBI:91333 ChEBI PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192991 0.8 LPAR3 protein Q9UBY5 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257357 0.486 ARID5B protein Q14865 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu We also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). SIGNOR-256159 0.2 NEK9 protein Q8TD19 UNIPROT NEK9 protein Q8TD19 UNIPROT up-regulates phosphorylation Ser944 GQQVGMHsKGTQTAK 9606 21454704 t lperfetto We find that the interaction of lc8 with nek9 depends on a (k/r)xtqt motif adjacent to the nek9 c-terminal coiled coil motif, results in nek9 multimerization, and increases the rate of nek9 autoactivation. Lc8 binding to nek9 is regulated by nek9 activity through the autophosphorylation of ser(944), a residue immediately n-terminal to the (k/r)xtqt motif. SIGNOR-173026 0.2 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207833 0.8 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12471034 t gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). SIGNOR-96250 0.967 MAP4K2 protein Q12851 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 9712898 t gcesareni The mekk1 associated with the gck carboxyl terminus is catalytically active. SIGNOR-59682 0.553 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation 22848740 t When AMPK is stimulated, pre-existing FOXO3 becomes reverted toward an active form. SIGNOR-255755 0.513 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity precursor of 9606 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268246 0.8 CHD8 protein Q9HCK8 UNIPROT SOX11 protein P35716 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268923 0.2 AMP smallmolecule CHEBI:456215 ChEBI MLXIPL protein Q9NP71 UNIPROT down-regulates activity chemical inhibition 10116 26984404 t We discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. SIGNOR-255668 0.8 tiotropium chemical CHEBI:90960 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition -1 8441333 t miannu A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by KD-values in the 10(-10) M concentration range.he drug showed "kinetic receptor subtype selectivity" by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors. SIGNOR-258485 0.8 CHUK protein O15111 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275508 0.327 STUB1 protein Q9UNE7 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 21454478 t gcesareni In addition, some proteins (e.g. Chip, carboxyl terminus of hsc70-interacting protein) inhibit the signaling activities of smad1/5 by recruiting smad1/5 from the functional r/co-smad complex and further promoting the ubiquitination and degradation of smad1/5 in a chaperone-independent manner SIGNOR-172996 0.347 monobenzyl phthalate chemical CHEBI:132612 ChEBI SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression 10116 16257484 f miannu DIDP, BBP and DOP stimulate NIS mRNA expression. Here, hNIS promoter construct (N3) was up-regulated 2.5-fold by DIDP, 2.6-fold by BBP and 2.4-fold by DOP in the presence of TSH. Likewise, these phthalates also enhanced rNIS endogenous mRNA expression, which increased ca. 2-fold after 48 h of treatment compared with the expression level generated by TSH only. At 72 h, mRNA content was unchanged. SIGNOR-268743 0.8 UBR5 protein O95071 UNIPROT RNF168 protein Q8IYW5 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0001938 22884692 t miannu Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1. SIGNOR-266782 0.449 DZIP3 protein Q86Y13 UNIPROT H2AZ1 protein P0C0S5 UNIPROT up-regulates activity monoubiquitination Lys121 IHKSLIGkKGQQKTV 9606 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271748 0.2 LPAR2 protein Q9HBW0 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257169 0.454 ERG protein P11308 UNIPROT EZH2 protein Q15910 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25277175 f miannu Increased expression of ERG or other ETS factors under control of androgen responsive promoter (TMPRSS2) is an inevitable consequence of the fusion events, and it activates transcriptional program that contributes to oncogenesis by upregulating expression of, among others, MYC, EZH2 and SOX9 and repressing NKX3. SIGNOR-251555 0.348 testosterone smallmolecule CHEBI:17347 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 15861399 t miannu Testosterone is the predominant circulating androgen in mammals and is converted to dihydrotestosterone (DHT) by 5α-reductase in certain tissues of the male urogenital tract, skin, and other target cells. DHT binds with highest affinity to AR and together with testosterone promotes AR transcriptional activity thereby ensuring the development and maintenance of male reproductive functions. SIGNOR-251553 0.8 PIK3R4 protein Q99570 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260321 0.883 PLK1 protein P53350 UNIPROT NUDC protein Q9Y266 UNIPROT up-regulates activity phosphorylation Ser274 KKINPENsKLSDLDS 9606 BTO:0000567 12852857 t lperfetto Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites. SIGNOR-103403 0.724 TGFB1 protein P01137 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 19114990 t lperfetto While association of the TGF_RI receptor with p85 requires TGF-_ stimulation. SIGNOR-252729 0.265 AXIN2 protein Q9Y2T1 UNIPROT APC protein P25054 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. SIGNOR-79944 0.836 EEF1A1P5 protein Q5VTE0 UNIPROT Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269544 0.8 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR GSK3B protein P49841 UNIPROT up-regulates activity dephosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 20080667 t miannu DAB2IP interacts via its C2 domain with GSK3β, recruiting phosphatase PP2A for S9 de-phosphorylation and leading to GSK3β activation. SIGNOR-254754 0.427 DRAM2 protein Q6UX65 UNIPROT RHOC protein P08134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259143 0.2 TLN1 protein Q9Y490 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 10090 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257625 0.787 PAX6 protein P26367 UNIPROT CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR form complex binding 9606 10506141 t lperfetto In the present study, we investigated the interaction of cdx-2 and pax-6 with p300, a co-activator coupled to the basal transcription machinery. In transient transfection-expression experiments, we found that the transactivating effects of cdx-2 and pax-6 on the glucagon gene were greatly enhanced by the additional expression of p300. SIGNOR-70963 0.478 DRD5 protein P21918 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257311 0.409 IRF3 protein Q14653 UNIPROT ABCC2 protein Q92887 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15185298 f miannu Expression of recombinant human IRF3 increased MRP2 promoter activity.  SIGNOR-254533 0.2 PPP2CA protein P67775 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. SIGNOR-248650 0.312 KAR proteinfamily SIGNOR-PF57 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264940 0.8 PRKCZ protein Q05513 UNIPROT TRAF2 protein Q12933 UNIPROT unknown phosphorylation Ser55 QCGHRYCsFCLASIL 9606 BTO:0000785 19336568 t llicata Here, we report that protein kinase czeta phosphorylates traf2 at ser(55), within the ring domain of the protein, after tnfalpha stimulation SIGNOR-184941 0.42 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates 9606 BTO:0000671 9335553 f gcesareni These results indicate that activation of protein kinase c stimulates a kinase which can phosphorylate insulin receptor substrate-1 at serine 612, resulting in an inhibition of insulin signaling in the cell these data suggest that: 1) activation of pkctheta contributes to ikk and jnk activation by ffas;2) ikk and jnk mediate pkctheta signals for irs-1 serine phosphorylation and degradation; ser-302 phosphorylation is dependent on pi 3-kinase/mtor, whereas ser-307 depends on c-jun nh2-terminal kinase to inhibit irs1 tyrosine phosphorylation. Ser-636 is located around the pi 3-kinase binding site and, therefore, thought to inhibit pi 3-kinase signaling. SIGNOR-52707 0.637 RUNX3 protein Q13761 UNIPROT CAPN10 protein Q9HC96 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255091 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1717 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269384 0.721 Neuromedin B smallmolecule CHEBI:80139 ChEBI NMBR protein P28336 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257547 0.8 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation 9606 21232017 t lperfetto Tak1 become activated and then phosphorilates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation SIGNOR-216396 0.886 GABRB1 protein P18505 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263763 0.606 APOA1 protein P02647 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates quantity by stabilization binding 9606 12869555 t miannu ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1. SIGNOR-252101 0.786 MAP4K1 protein Q92918 UNIPROT CARD11 protein Q9BXL7 UNIPROT up-regulates activity phosphorylation Ser559 QPPRSRSsIMSITAE -1 19706536 t miannu HPK1 interacts with CARMA1 in a TCR stimulation-dependent manner and phosphorylates the linker region of CARMA1. Interestingly, the putative HPK1 phosphorylation sites in CARMA1 are different from known PKC consensus sites. Mutations of residues S549, S551, and S552 in CARMA1 abrogated phosphorylation of a CARMA1-linker construct by HPK1 in vitro. SIGNOR-276258 0.502 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates activity phosphorylation Tyr602 TYVDPFTyEDPNQAV -1 8622893 t Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry. Complimentary approaches of in vitro binding assays and BIAcore analysis revealed a high affinity association between the Y602 Sek autophosphorylation site and the cytoplasmic tyrosine kinase p59fyn, an interaction mediated through the SH2 domain of this intracellular signalling molecule. SIGNOR-251119 0.2 pirenzepine chemical CHEBI:8247 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258394 0.8 AKT1 protein P31749 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24743741 f Activation of PDGFRα stimulates proliferation of PDGFRα(+) cells through PI3K-Akt and MEK2-MAPK signaling pathways, and aberrant accumulation of PDGFRα(+) cells was conspicuous in muscles of patients with both genetic and non-genetic muscle diseases. SIGNOR-254372 0.7 LMAN2 protein Q12907 UNIPROT SERPINA1 protein P01009 UNIPROT up-regulates quantity by stabilization binding 9606 20477988 t miannu Identification of α1‐antitrypsin as interaction partner of VIP36. The complex formed by VIP36 and alpha1-AT in the Golgi recycled back to the ER. The combined data are most consistent with a function of VIP36 in post-ER quality control of alpha1-AT. We propose that VIP36 acts in post‐ER quality control in the Golgi by binding incompletely folded α1‐AT, which inadvertently escaped ER quality control, and by recycling it back to the ER for an additional round of quality control. SIGNOR-261356 0.419 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270427 0.8 CSNK2A3 protein Q8NEV1 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1112 VPIAVGEsDFENLNT 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275751 0.2 ATM protein Q13315 UNIPROT USP28 protein Q96RU2 UNIPROT down-regulates activity phosphorylation Ser714 ESSTNSSsQDYSTSQ 31938050 t lperfetto Once all the three conservative SQ sites (S67, S495, and S714), in USP28, were mutated to alanine, the pS/TQ antibody completely could not recognize the immunoprecipitated Flag-USP28-3S/A (Figure ​Figure55D), suggesting that in response to 5'-AZA-induced stress, ATM phosphorylates USP28 at all these three sites.|We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. SIGNOR-275853 0.315 TGFB1 protein P01137 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8142649 f Regulation miannu Basic fibroblast growth factor (bFGF) and transforming growth factor-beta 1 (TGF-beta) have both been shown to act on hematopoietic progenitor cells. bFGF antagonized the TGF-beta-mediated induction of hemoglobin in a dose-dependent manner, with 0.1 ng/mL bFGF inhibiting hemoglobin induction by 40% and 10 ng/mL bFGF completely abrogating hemoglobin production. SIGNOR-251797 0.264 BRCA2 protein P51587 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates SIGNOR-204538 0.541 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 14585074 f amattioni Activation of the nf-kb pathway regulates a variety of ant-apoptotic factors SIGNOR-96834 0.7 MLLT1 protein Q03111 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 t 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. SIGNOR-239228 0.678 TFEB protein P19484 UNIPROT HPS4 protein Q9NQG7 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276795 0.295 Caspase 3 complex complex SIGNOR-C221 SIGNOR Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-256481 0.7 SRC protein P12931 UNIPROT SPRY2 protein O43597 UNIPROT up-regulates phosphorylation Tyr55 AIRNTNEyTEGPTVV 9606 15564375 t lperfetto Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway. SIGNOR-131189 0.555 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269377 0.721 SP1 protein P08047 UNIPROT MAOB protein P27338 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11259630 f miannu Cotransfection experiments show that Sp1 and its closely related family member Sp4 can trans-activate MAO B promoter activity through the proximal cluster of Sp1 sites and its activation can be repressed by the over-expression of Sp3 and a related family member BTEB2. SIGNOR-253868 0.276 MAPK1 protein P28482 UNIPROT RGS19 protein P49795 UNIPROT up-regulates phosphorylation Ser151 EDYVSILsPKEVSLD 9606 10993892 t gcesareni Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation. SIGNOR-82083 0.483 Naloxone benzoylhydrazone chemical CID:9601084 PUBCHEM OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258423 0.8 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser835 ELKATLPsPDKLPGF 9606 BTO:0000567 7724583 t lperfetto Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Thus, the serine at position 835 is a phosphorylation site. Taking these findings into consideration, we consider that cyclin b might be one of the substrates targeted by the specific ubiquitin conjugation pathway activated by the phosphorylation of e1 with cdc2 kinase. SIGNOR-32225 0.41 PDGFRA protein P16234 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 BTO:0000567 20802513 t miannu Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. SIGNOR-259400 0.416 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 9736715 t acerquone Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation. SIGNOR-252597 0.775 FYN protein P06241 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 15537652 t gcesareni Here we provide evidence that fyn kinase, a member of the src kinase family, is involved in the uvb-induced phosphorylation of histone h3 at serine 10 SIGNOR-265330 0.2 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation 9606 18243099 t amattioni Direct phosphorylation of the aurora b regulator borealin by mps1 enhances aurora b activity and is essential for chromosome alignment SIGNOR-160604 0.468 PPP2R5D protein Q14738 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity binding 9606 BTO:0000007 16239230 t gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. SIGNOR-243420 0.434 MTNR1A protein P48039 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256849 0.483 PRKCH protein P24723 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser738 ARIIGEKsFRRSVVG 9606 10197446 t llicata These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748. SIGNOR-66730 0.359 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 23431053 t milica MST1/2 directly phosphorylate Lats1/2 at the hydrophobic motif (Lats1 T1079 and Lats2 T1041), and this phosphorylation is required for Lats1/2 activation SIGNOR-201298 0.626 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr162 SFDAILYyYQSGGRI 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. SIGNOR-183519 0.383 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser77 PTAGALYsGSEGDSE -1 2046671 t llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. SIGNOR-250955 0.54 TNKS protein O95271 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19759537 t lperfetto Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-187972 0.77 F2R protein P25116 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254850 0.306 VRK3 protein Q8IV63 UNIPROT DUSP3 protein P51452 UNIPROT up-regulates activity binding 27346674 t lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding SIGNOR-275546 0.698 SMG1 protein Q96Q15 UNIPROT UPF1 protein Q92900 UNIPROT up-regulates phosphorylation Ser1089 GLSQPELsQDSYLGD 9606 23356578 t lperfetto Smg-1 directly phosphorylates upf1 helicase, another key component of nmd, upon recognition of ptc on postspliced mrna during the initial round of translation. Phosphorylated-upf1 recruits the smg-5/smg-7 complex to induce ribosome dissociation and decapping-mediated decay. T28 and s1096 are responsible for phospho-specific recruitment of smg-6 to the n-terminal conserved region, and the smg-5/smg-7 heterodimer complex to the c-terminal sq-rich region of upf1, respectively SIGNOR-200785 0.971 SREBF1 protein P36956 UNIPROT FASN protein P49327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20373869 t lperfetto Ultimately, both the AKT and MAPK transduction pathways regulate FASN expression through the modulation of expression of sterol regulatory element-binding protein (SREBP)-1c, which binds to regulatory elements in the FASN promoter. Proto-oncogene FBI-1 (Pokemon), a transcription factor of the bric--brac tramtrack broad complex/pox viruses and zinc fingers (BTB/POZ) domain family, interacts directly with SREBP-1c through its DNA-binding domain to synergistically activate the transcription of FASN SIGNOR-242884 0.505 TMC2 protein Q8TDI7 UNIPROT Hair cells mechanotransduction channel complex SIGNOR-C290 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The pore forming subunits of the hair cells mechanotransduction channel still need to be identified, but some candidates have emerged including TMC-1,TMC-2 (Kawashima et al., 2011), Piezo1 and Piezo2 (Coste et al., 2010; Coste et al., 2012). SIGNOR-262570 0.4 CDK2 protein P24941 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Ser399 GLLTPPQsGKKQSSG 9606 14536078 t amattioni Phosphorylation-triggered ubiquitination has been proposed to be the major pathway regulating cyclin e protein abundance. Cdk2 activity is required for cyclin e turnover in vivo because it phosphorylates s384. Mutation of ser384 to alanine also rendered cyclin e resistant to degradation SIGNOR-118555 0.954 LYN protein P07948 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268215 0.701 MAPK1 protein P28482 UNIPROT PITPNM1 protein O00562 UNIPROT up-regulates phosphorylation Thr794 LEMLVPStPTSTSGA 9606 15125835 t lperfetto Both cdk1 and erk2 induced phosphorylation of the wild-type nir2. Substitution of t794 by alanine reduced the phosphorylation by erk2, whereas the double mutations t794/1223a completely abolished it. The requirement of multiple nir2 phosphorylation sites for plk1 binding may provide a mechanism that sets a threshold for the nir2-plk1 interaction during mitosis. SIGNOR-124650 0.2 STYK1 protein Q6J9G0 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 BTO:0000007 31696776 t lperfetto We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. |The results indicated that the level of BECN1 S90 phosphorylation significantly increased after STYK1 overexpression, but not STYK1K147R mutant.|STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I SIGNOR-264568 0.2 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR NUP98 protein P52948 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16036565 f miannu Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein SIGNOR-260870 0.2 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT up-regulates activity dephosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10195903 t Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. SIGNOR-248383 0.349 PPP2R2A protein P63151 UNIPROT WEE1 protein P30291 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 BTO:0000018 33108758 t miannu Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. SIGNOR-266381 0.39 TAB2 protein Q9NYJ8 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 14633987 t lperfetto These results suggest that TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction. SIGNOR-119370 0.935 INCENP protein Q9NQS7 UNIPROT AURKB protein Q96GD4 UNIPROT up-regulates binding 9606 12925766 t gcesareni Using recombinant proteins, we found that aurora b kinase activity was stimulated by incenp and that the c-terminal region of incenp was sufficient for activation. SIGNOR-86218 0.973 LRP1B protein Q9NZR2 UNIPROT DVL2 protein O14641 UNIPROT down-regulates activity binding 9606 28408316 t irozzo In this study, we have shown that LRP1B inhibited the activity of beta-catenin/TCF signaling possibly by interacting with DVL2. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling. SIGNOR-259090 0.391 PPP3CB protein P16298 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 11062529 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-84047 0.716 cortisol smallmolecule CHEBI:17650 ChEBI NR3C2 protein P08235 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258707 0.8 BMP7 protein P18075 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 7644468 t lperfetto In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7. SIGNOR-217520 0.774 2'-deoxyguanosine smallmolecule CHEBI:17172 ChEBI 2'-deoxyguanosine 5'-monophosphate(2-) smallmolecule CHEBI:57673 ChEBI up-regulates quantity precursor of 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275812 0.8 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser529 KGAKVFGsLERGLDK 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141018 0.2 TFAP2B protein Q92481 UNIPROT ADIPOQ protein Q15848 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19325541 f miannu A transcription factor, TFAP2B, has been shown to participate in the regulation of adipocyte metabolism, by facilitating glucose uptake and lipid accumulation, while simultaneously reducing insulin sensitivity, and recently a direct function for TFAP2B as an inhibitor of adiponectin expression was observed. SIGNOR-255421 0.37 PTPN9 protein P43378 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22394684 t lperfetto Results are presented as mean \u00b1 SD from three independent experiments. (B) PTPMeg2 inhibits STAT3-mediated transcriptional activity in a dose dependent manner.|These results indicate that PTPMeg2 inhibits STAT3 activation with certain specificity.|In this study, we demonstrated that PTPMeg2 dephosphorylates STAT3 at the Tyr705 residue by a direct interaction. SIGNOR-276976 0.44 TUBA3E protein Q6PEY2 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269726 0.7 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser321 SKPSGNDsCELRNLK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276213 0.2 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB2 protein Q9Y5G2 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265688 0.2 UNC13A protein Q9UPW8 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 t miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. SIGNOR-263971 0.464 IFNG protein P01579 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-270238 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 t llicata Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis. SIGNOR-177019 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ERF protein P50548 UNIPROT down-regulates phosphorylation 9606 7588608 t lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf SIGNOR-216852 0.372 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser19 KLQYYYSsSEDEDSD 9606 16717095 t lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. SIGNOR-146829 0.37 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser439 SIGHSPLsLSAQSVM 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204732 0.537 DAB2IP protein Q5VWQ8 UNIPROT HRAS protein P01112 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 t miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. SIGNOR-254745 0.589 AKT proteinfamily SIGNOR-PF24 SIGNOR DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. SIGNOR-173976 0.2 TLK1 protein Q9UKI8 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity phosphorylation -1 11314006 t The effect has been demonstrated using Q9UKI8-2 lperfetto Purified tlk1b phosphorylated histone h3 at s(10) with high specificity both in a mix of core histones and in isolated chromatin, suggesting that histone h3 is a physiological substrate for tlk1b. Phosphorylation of H3 has been linked to the activation of the immediate-early genes upon mitogenic stimulation, and to chromatin condensation during mitotic/meiotic events. SIGNOR-265370 0.2 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22470139 f miannu Efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. SIGNOR-255607 0.543 MAPK3 protein P27361 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188151 0.2 NAE complex SIGNOR-C131 SIGNOR ANAPC2 protein Q9UJX6 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243175 0.389 HARS1 protein P12081 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270488 0.8 EZH2 protein Q15910 UNIPROT SSTR1 protein P30872 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 f miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. SIGNOR-254143 0.2 MYD88 protein Q99836 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity binding 9606 12297423 t Signaling between MyD88 and TRAF6 is mediated by members of the IL-1R-associated kinase (IRAK) family; however, the exact function of each IRAK protein remains controversial. IRAK-1 is required for the optimal transduction of IL-1R- and TLR-mediated signals, but IRAK-1 can be replaced by other IRAKs. Surprisingly, gene targeting studies show that the newest IRAK protein, IRAK-4, has an essential role in mediating signals initiated by IL-1R and TLR engagement. SIGNOR-252097 0.945 CSNK2A1 protein P68400 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser162 DDIDLFGsDNEEEDK 9606 BTO:0000567 21936567 t lperfetto Direct phosphorylation of eef1d by ck2 was shown by performing ck2 assays with eef1d -flag from hela cells. Dramatic increases in eef1d phosphorylation following _-phosphatase treatment and phospho- eef1d antibody recognizing eef1d ps162 indicated phosphorylation at the ck2 site in cells. SIGNOR-176632 0.331 Caspase 3 complex complex SIGNOR-C221 SIGNOR NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization cleavage -1 9367996 t lperfetto The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues. SIGNOR-256456 0.429 Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity binding 9606 30205058 t miannu The exocyst is a multisubunit protein complex that was first identified and characterized in budding yeast. This complex mediates the tethering of secretory vesicles to the plasma membrane prior to fusion mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Sec3 interacts with PI(4,5)P2 (red dots) in the plasma membrane. Its interaction with the t-SNARE protein Sso promotes the assembly of the Sso–Sec9 binary t-SNARE complex. SIGNOR-270792 0.427 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268652 0.8 PPARD protein Q03181 UNIPROT TXN protein P10599 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001950 18048767 f miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. SIGNOR-255052 0.2 SKA2 protein Q8WVK7 UNIPROT SKA complex complex SIGNOR-C364 SIGNOR form complex binding -1 22483620 t lperfetto We show that the structure of the Ska core complex is a W-shaped dimer of coiled coils, formed by intertwined interactions between Ska1, Ska2, and Ska3. SIGNOR-265195 0.9 magnesium(2+) chemical CHEBI:18420 ChEBI Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-267755 0.8 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270737 0.846 BAG3 protein O95817 UNIPROT HSPA8 protein P11142 UNIPROT up-regulates activity binding -1 27474740 t lperfetto Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. SIGNOR-254116 0.784 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT up-regulates phosphorylation Ser29 ATPAARAsKKILLPE 9606 11042191 t acerquone Phosphorylation of grk2 by protein kinase c abolishes its inhibition by calmodulinin vitro, grk2 was preferentially phosphorylated by pkc isoforms alpha, gamma, and delta SIGNOR-83231 0.2 AMPK complex SIGNOR-C15 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser94 RLRKLPDsFFKPPEP 9606 BTO:0002181 25751140 t miannu Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. SIGNOR-277638 0.301 AKT proteinfamily SIGNOR-PF24 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 t lperfetto Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity. SIGNOR-244176 0.2 WNT3 protein P56703 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131823 0.641 NDUFB11 protein Q9NX14 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262164 0.743 ARRB2 protein P32121 UNIPROT INPP5D protein Q92835 UNIPROT up-regulates activity binding 9606 24817116 t lperfetto We identified a new adaptor beta-arrestin 2 that associates with phosphorylated TIGIT and mediates recruitment of inositol phosphatase SHIP1 through the ITT-like motif (Fig. 7). Finally, SHIP1 impairs TRAF6 autoubiquitination to abolish NF-kappaB activation, leading to inhibition of IFN- gamma production in NK cells. SIGNOR-261428 0.2 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1404 EEIKSQNsQESTADE 9606 12086603 t lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint SIGNOR-90113 0.785 GPR119 protein Q8TDV5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257241 0.251 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248885 0.287 PKC proteinfamily SIGNOR-PF53 SIGNOR NOXO1 protein Q8NFA2 UNIPROT up-regulates activity phosphorylation Ser159 SRAAGRLsIHSLEAQ 9606 28336130 t lperfetto Importantly, the constitutive activity of NoxO1 can be modulated. NoxO1 phosphorylation by PKC at Ser154 doubles its binding ability to NoxA1, which in turn acts as a molecular switch, allowing optimal interaction of NoxO1 with p22phox SIGNOR-264728 0.2 HDLBP protein Q00341 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 9925647 f miannu HBP/vigilin binds HDL and apoA-I on ligand blots; conceivably therefore apoA-I may interact with cytoplasmic vigilin promoting changes in cholesterol flux. SIGNOR-266692 0.7 ATR protein Q13535 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Ser33 GFGSPAPsQAEKKSR 9606 19843584 t llicata Atr phosphorylates s33 in response to replication stress SIGNOR-188666 0.751 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser552 QDTQRRTsMGGTQQQ 9606 17287208 t lperfetto Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activitywe have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo. SIGNOR-152958 0.559 TLN1 protein Q9Y490 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257630 0.579 TFIIH complex SIGNOR-C457 SIGNOR AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 21157430 t acerquone Here, we show that the transcription factor tfiih, via its cdk7 kinase, phosphorylates the androgen receptor (ar) at position ar/s515. Strikingly, this phosphorylation is a key step for an accurate transactivation that includes the cyclic recruitment of the transcription machinery, the mdm2 e3 ligase, the subsequent ubiquitination of ar at the promoter of target genes and its degradation by the proteasome machinery SIGNOR-269331 0.322 Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR RAE1 protein P78406 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16036565 f miannu Nup98/Nup96 (41) and Rae1 (17)are up regulated by interferons, which revert the mRNAexport block induced by VSV M protein SIGNOR-260869 0.2 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Thr218 TAANSRDtIFQKERF 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. SIGNOR-185303 0.2 CHEK1 protein O14757 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr182 SHFVRVStAQKSKKG 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. SIGNOR-276909 0.776 MAPK14 protein Q16539 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation 9606 20626350 t gcesareni Jnk and p38 mapk activation have antagonistic effects in many cases. From a mechanicistic point of view, the p38 mapk pathway can negatively regulate jnk activity at the level of map3ks, either by phosphorylating mlk3 or the tak1 regulatory subunit tab2 SIGNOR-166605 0.308 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser365 RLDRTGSsPTQGIVN 9606 15767678 t gcesareni Identification of rock1 as an upstream activator of the jip-3 to jnk signaling axis in response to uvb damage. phosphorylation of jip-3 by rock1 was crucial for the recruitment of jnk. Inhibition of the activity of rock1 in keratinocytes resulted in decreased activation of the jnk pathway and thus a reduction in apoptosis. SIGNOR-134588 0.336 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr336 AKGNLQEyLTRHVIS -1 9169454 t lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. SIGNOR-48863 0.2 MC4R protein P32245 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257336 0.251 NFATC2 protein Q13469 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 t miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. SIGNOR-264021 0.36 CAMK2A protein Q9UQM7 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 t llicata By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons. SIGNOR-250630 0.692 AURKB protein Q96GD4 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates phosphorylation Ser265 QKVAERRsSPLLRRK 9606 22865920 t lperfetto We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions SIGNOR-198646 0.267 NDUFS4 protein O43181 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262178 0.843 MAST3 protein O60307 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation 9606 15951562 t gcesareni Furthermore, binding of PTEN to the PDZ domains from microtubule-associated serine/threonine kinases facilitated PTEN phosphorylation at its C terminus by these kinases. SIGNOR-138080 0.579 Shikonin chemical CHEBI:81068 ChEBI PK proteinfamily SIGNOR-PF80 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000093;BTO:0000018 21516121 t inferred from family member lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. SIGNOR-270289 0.8 EEF1A1P5 protein Q5VTE0 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269555 0.8 PRKCA protein P17252 UNIPROT MYL9 protein P24844 UNIPROT down-regulates phosphorylation Ser2 sSKRAKAK 9606 22136066 t lperfetto Rlc can also be phosphorylated at ser1/ser2/thr9 by protein kinase c (pkc). Biophysical studies show that phosphorylation at these sites leads to an increase in the km of myosin light chain kinase (mlck) for rlc, thereby indirectly inhibiting myosin ii activity. SIGNOR-177940 0.281 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr648 DVHNLDYyKKTTNGR 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3. SIGNOR-106734 0.2 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 19108785 t irozzo Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Nilotinib binds to inactive configuration of the abl kinase, thus preventing the tyrosine phosphorylation of proteins involved in bcr-abl signal transduction. Nilotinib binds to the inactive (unphosphorylated) configuration of the abl TK, with the P-Ioop folding over, disrupting the ATP binding site and catalytic activity of the enzyme. SIGNOR-255818 0.8 ibuprofen chemical CHEBI:5855 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9057869 t miannu Naproxen had similar activity against both COX-1 and COX-2 enzymes (IC50s of 3.2 and 2.5 μM, respectively), whereas ibuprofen was approximately 100-fold more potent for COX-2 (IC50 = 0.1 μM) than for COX-1 (IC50 = 11 μM), and indomethacin was about 50-fold more potent for COX-1 (IC50 = 0.012 μM) than for COX-2 (IC50 = 0.56 μM). SIGNOR-258604 0.8 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 16440056 f lperfetto Axonemal dyneins are responsible for the movement of cilia and flagella. SIGNOR-265021 0.7 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation -1 16326050 t miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SIGNOR-268749 0.8 PKI-587 chemical CID:44516953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205992 0.8 SEC13 protein P55735 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR form complex binding 9606 23723239 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255305 0.859 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249121 0.345 SLBP protein Q14493 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265374 0.2 PAX8 protein Q06710 UNIPROT TG protein P01266 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11786384 t miannu The transcription factor Pax8 plays an important role in the expression of the differentiated phenotype of thyroid follicular cells. It has recently been shown that Pax8 is necessary for thyroglobulin (Tg) gene expression. SIGNOR-251998 0.467 CDC26 protein Q8NHZ8 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252011 0.847 FAM83H protein Q6ZRV2 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273768 0.329 PRKCA protein P17252 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates activity phosphorylation Thr193 KKRAKTItFSKNAVI -1 22139477 t miannu The giant patch clamp together with site direct mutagenesis revealed that Thr-193 is the phosphorylation site on PKC that regulates the pH(i) sensitivity of ROMK1 channels. Mutation of PKC-induced phosphorylation sites (T193A) decreases the pH(i) sensitivity and increases the interaction of channel-PIP(2).  SIGNOR-276389 0.2 SERPINE1 protein P05121 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR down-regulates 9606 10368279 f gcesareni Pai-1 is the physiological inhibitor of the fibrinolytic pathway SIGNOR-68481 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 17311928 t inferred from 70% family members llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-270154 0.2 H2AZ2 protein Q71UI9 UNIPROT Nucleosome_H2A.Z.2 variant complex SIGNOR-C323 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263709 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17960585 f miannu Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells. SIGNOR-260425 0.486 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 12145304 t gcesareni Oxidative stress-responsive kinase-1 (osr1) is a known upstream regulator of n(k)ccs. these results suggest that, globally, osr1 is involved in the regulation of bp and renal tubular na(+) reabsorption mainly via the activation of nkcc1 and nkcc2. SIGNOR-90931 0.534 CDR2 protein Q01850 UNIPROT NUF2 protein Q9BZD4 UNIPROT up-regulates quantity by expression transcriptional regulation 20383333 f lperfetto Additionally, cdr2 knockdown lead to a decrease (Table 3) in four other transcripts (AURKA, CENPE, SPC25 and TTK), which are involved in kinetochore and spindle biology SIGNOR-252022 0.2 OXTR protein P30559 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 30739093 t miannu OT binds to its cognate G protein‚Äìcoupled receptor (OTR) and exerts diverse effects, including stimulation (Gs) or inhibition (Gi/o) of adenylyl cyclase, stimulation of potassium channel currents (Gi), and activation of phospholipase C (Gq). SIGNOR-270331 0.417 IGF1 protein P05019 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity binding 9606 21798082 t lperfetto Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor. SIGNOR-175662 0.956 FOXO proteinfamily SIGNOR-PF27 SIGNOR IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260088 0.2 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 10090 BTO:0002572 10988287 t amattioni The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis. SIGNOR-81808 0.718 PPP2CA protein P67775 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity dephosphorylation Ser129 NEAYEMPsEEGYQDY 9606 21562258 t α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylates α-Syn at serine 129 SIGNOR-248635 0.336 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000304 30519351 t miannu The results showed that TNC induced the cytoplasmic translocation of pFOXO1 via regulation of AKT activation. As shown in Fig. 3C, stimulation of PANC-1 cells with exogenous TNC markedly increased the phosphorylation of AKT and FOXO1. Our study showed that pFOXO1 translocates from the nucleus to the cell cytoplasm after exogenous TNC treatment, which indicates that its transcriptional activity was inhibited. SIGNOR-277740 0.2 CUDC-101 chemical CID:24756910 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262264 0.8 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269245 0.622 leuprolide chemical CHEBI:6427 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257499 0.8 CDK1 protein P06493 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 t phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. SIGNOR-272968 0.2 GH1 protein P01241 UNIPROT GHR protein P10912 UNIPROT up-regulates binding 9606 7862673 t gcesareni The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh. SIGNOR-34129 0.856 PPP3CC protein P48454 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates 9606 BTO:0001103 11062529 f gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-83740 0.441 drospirenone chemical CHEBI:50838 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000671 1493716 t miannu Dihydrospirorenone is a potent aldosterone antagonist 8 times as potent as spironolactone and antiandrogenic (0.3 times cyproterone acetate). The high binding affinity of dihydrospirorenone to the binding sites of the mineralocorticoid receptor of rat kidney with an RBA value of 230% compared to aldosterone is remarkable. This reflects the strong antimineralocorticoid activity of this compound which was evaluated in adrenalectomized rats. SIGNOR-258349 0.8 MAPK11 protein Q15759 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-114063 0.412 MAPK14 protein Q16539 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 10806218 t gcesareni More importantly, incubation of active erk2 or p38 kinase with h3 protein resulted in phosphorylation of h3 at serine 10 in vitro. These results suggest that erk and p38 kinase are at least two important mediators of phosphorylation of h3 at serine 10. SIGNOR-265338 0.2 JMY protein Q8N9B5 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261005 0.313 QRICH1 protein Q2TAL8 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269413 0.2 TGFB1 protein P01137 UNIPROT ITGA2 protein P17301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001596 1744142 f lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. SIGNOR-253354 0.288 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252348 0.2 PRKCB protein P05771 UNIPROT OCLN protein Q16625 UNIPROT up-regulates activity phosphorylation Ser340 DKRFYPEsSYKSTPV 9615 BTO:0000837 11502742 t lperfetto Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X. SIGNOR-249106 0.462 BCL2L1 protein Q07817 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003328 9393856 f fcortellessa Bcl-xL Expression Prevents Cytochrome c Redistribution and Subsequent Mitochondrial Depolarization during Apoptosis. Bcl-xL expression prevented both cytochrome c redistribution and mitochondrial membrane depolarization. In contrast, zVAD treatment could not prevent either cytochrome c redistribution or mitochondrial membrane depolarization in control transfectants withdrawn from IL-3. Thus, cytochrome c redistribution from mitochondria is an early apoptotic event that precedes mitochondrial membrane depolarization. Bcl-xL expression functions to inhibit both of these events. In at least some forms of cell death, the ability of Bcl-xL to regulate these mitochondrial events cannot be mimicked by caspase inhibition SIGNOR-261683 0.7 HDAC1 protein Q13547 UNIPROT FSHR protein P23945 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23086931 f miannu Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. SIGNOR-254225 0.2 HOXD1 protein Q9GZZ0 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001949 21501586 t Luana Consistently, ITGB1 promoter activity was decreased by HOXD1 knockdown in ECs. Furthermore, we identified the putative HOXD1-binding sites in the promoter region of ITGB1. Together, these findings suggest that HOXD1 plays a significant role in EC functions by regulating the expression of ITGB1. SIGNOR-261648 0.2 NMS protein Q5H8A3 UNIPROT NMUR1 protein Q9HB89 UNIPROT up-regulates binding 9606 BTO:0000142 15635449 t gcesareni Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus. SIGNOR-133074 0.723 E2F1 protein Q01094 UNIPROT NOX4 protein Q9NPH5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002195 18554521 f lperfetto Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F SIGNOR-254134 0.2 SYK protein P43405 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates activity phosphorylation Tyr227 AVSLLACyLKSRQTP 9606 BTO:0001154 11714793 t lperfetto Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells SIGNOR-246556 0.332 RITA1 protein Q96K30 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 21102556 t gcesareni Thus, we propose that rita acts as a negative modulator of the notch signalling pathway, controlling the level of nuclear rbp-j/cbf-1, where its amounts are limiting. SIGNOR-170089 0.424 RHOH protein Q15669 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity relocalization 10090 BTO:0004850 18089848 t irozzo Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs SIGNOR-259085 0.394 ADRA2A protein P08913 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256841 0.455 RPS6KA1 protein Q15418 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9606 BTO:0000007 20048145 t lperfetto Herein, we demonstrate that the n-terminal kinase domain (ntk) of rsk1 is necessary for interactions with pkarialpha. Substitution of the activation loop phosphorylation site (ser-221) in the ntk with the negatively charged asp residue abrogated the association between rsk1 and pkarialpha. SIGNOR-162681 0.2 PIGBOS1 protein A0A0B4J2F0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0002181 31653868 f miannu Here, we characterize a microprotein called PIGBOS and reveal a role for a mitochondrial protein in UPR signaling. Together, these results showed that loss of PIGBOS increases cellular sensitivity to ER stress, which in turn increases apoptosis and links PIGBOS levels to the ability of cells to survive stress. SIGNOR-261042 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-183616 0.2 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Ser-15, ser-78, and ser-82 in hsp27 (ser-15 and ser-86 in hsp25) are part of the rxxs motif, a known recognition site for p70rsk. SIGNOR-186955 0.313 AKT2 protein P31751 UNIPROT PPIF protein P30405 UNIPROT up-regulates activity phosphorylation Ser31 LPAARACsKGSGDPS 9606 BTO:0002004 25650317 t miannu In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy. SIGNOR-276875 0.2 CENPM protein Q9NSP4 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265211 0.695 TFAP2C protein Q92754 UNIPROT SULT1E1 protein P49888 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255399 0.2 DSCAM protein O60469 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 10116 BTO:0000938 18585357 f miannu DSCAM is required for commissural axon guidance in vivo. DSCAM promotes axonal growth but is dispensable for cell body migration and for axon turning toward a local source of netrin-1 in whole spinal cord turning assays. SIGNOR-268401 0.7 HMGA2 protein P52926 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14645522 f miannu Transcriptional activation of the cyclin a gene by the architectural transcription factor hmga2 SIGNOR-119496 0.315 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263426 0.668 RPS6KA5 protein O75582 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000567 9687510 t lperfetto Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. SIGNOR-59458 0.725 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75009 0.787 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Thr383 HYRYSDTtDSDPENE 9606 18321849 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-161126 0.616 Silmitasertib chemical CID:24748573 PUBCHEM CSNK2A2 protein P19784 UNIPROT down-regulates activity chemical inhibition 9606 21159648 t Federica In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. SIGNOR-261130 0.8 GNAT1 protein P11488 UNIPROT PDE6G protein P18545 UNIPROT down-regulates activity binding 10090 30962282 t In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis. SIGNOR-260008 0.759 PRKACA protein P17612 UNIPROT RGS13 protein O14921 UNIPROT up-regulates quantity by stabilization phosphorylation Thr41 SFENLMAtKYGPVVY 20974683 t miannu Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation.we show that PKA activation also leads to increased steady-state RGS13 expression through RGS13 phosphorylation, which inhibits RGS13 protein degradation. RGS13 phosphorylation was diminished by mutation of an N-terminal Thr residue (T41) identified as a phosphorylation site by mass spectrometry. SIGNOR-259835 0.338 FBXO11 protein Q86XK2 UNIPROT BCL6 protein P41182 UNIPROT down-regulates binding 9606 BTO:0000785 22113614 t miannu Fbxo11 targets bcl6 for degradation SIGNOR-177652 0.499 HSD17B11 protein Q8NBQ5 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 16166196 t lperfetto A novel 17beta-hydroxysteroid dehydrogenase (17beta-HSD) chronologically named type 12 17beta-HSD (17beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17beta-HSD (17beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. SIGNOR-268664 0.8 NLRC4 inflammasome complex SIGNOR-C223 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-263122 0.7 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270605 0.833 DIP2A protein Q14689 UNIPROT SOD2 protein P04179 UNIPROT up-regulates activity binding 10090 BTO:0000142 33781892 t miannu DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. SIGNOR-266592 0.2 PCDHA1 protein Q9Y5I3 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265663 0.2 1-phosphatidyl-1D-myo-inositol 4-phosphate(3-) smallmolecule CHEBI:58178 ChEBI 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity precursor of 9606 9367159 t miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities SIGNOR-277288 0.8 SPRY2 protein O43597 UNIPROT CBLB protein Q13191 UNIPROT down-regulates binding 9606 11053437 t gcesareni One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis. SIGNOR-83507 0.493 FASTKD5 protein Q7L8L6 UNIPROT COX4I1 protein P13073 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25683715 f miannu FASTKD5 is required for maturing precursor mRNAs that are not flanked by tRNAs and that therefore cannot be processed by the canonical mRNA maturation pathway. Silencing FASTKD5 rendered mature COX I mRNA almost undetectable, which severely reduced the synthesis of COX I, resulting in a complex IV assembly defect. SIGNOR-261223 0.2 ATF4 protein P18848 UNIPROT LARS2 protein Q15031 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269421 0.253 PRKACA protein P17612 UNIPROT NOS1 protein P29475 UNIPROT unknown phosphorylation -1 1375933 t miannu NOS is stoichiometrically phosphorylated by PKA, PKC, and CaMK, with each enzyme predominantly phosphorylating a distinct serine. CPT-CAMP has no effect on NOS activity SIGNOR-250021 0.324 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser139 RRGLLYDsDEEDEER 9606 16899510 t Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. SIGNOR-259850 0.303 MSL1 protein Q68DK7 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271977 0.2 MEF2C protein Q06413 UNIPROT JUN protein P05412 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9069290 f gcesareni One consequence of mef2c activation is increased c-jun gene transcription. Our results show that p38 may influence host defence and inflammation by maintaining the balance of c-jun protein consumed during infection SIGNOR-47139 0.611 PRKAA2 protein P54646 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 t miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. SIGNOR-277608 0.2 OPA1 protein O60313 UNIPROT Mitochondrial_fusion phenotype SIGNOR-PH218 SIGNOR up-regulates 9606 25486875 f lperfetto OPA1, MFN1 and MFN2 are essential mediators of the sequential fusion of the outer and inner membranes of adjacent mitochondria SIGNOR-272987 0.7 WNT3A protein P56704 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates activity binding 9606 BTO:0000222 10601008 t gcesareni Here we focus on the role of Wnts, their putative receptors Frizzled and the soluble antagonist Frzb1 in regulating mammalian myogenesis. Although it is becoming evident that the signaling downstream of Frizzled receptors is much more complex than anticipated, it is conceivable that it may lead to transcriptional activation of Myf5 and MyoD and to initiation of myogenesis. SIGNOR-73039 0.631 TRAF3 protein Q13114 UNIPROT MAP3K14 protein Q99558 UNIPROT down-regulates quantity by destabilization binding 10090 15084608 t lperfetto Traf3 is physically associated with nik via a specific sequence motif located in the n-terminal region of nik; this molecular interaction appears to target nik for degradation by the proteasome. SIGNOR-124236 0.659 FYN protein P06241 UNIPROT MAG protein P20916 UNIPROT up-regulates activity phosphorylation Tyr620 LTEELAEyAEIRVK 10090 BTO:0000142 7525550 t Fyn constitutively binds to MAG in a latent form. Ligand stimulation of L-MAG would result in activation of Fyn kinase and phosphorylation of Tyr-620. Binding and activation of PLC y through this phosphotyrosine residue would contribute to the signaling pathway involved in the regulation of myelination. SIGNOR-251178 0.432 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser326 PPKMWKTsPDPSPVS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252335 0.641 CDK1 protein P06493 UNIPROT CDC16 protein Q13042 UNIPROT up-regulates phosphorylation Ser560 KTLKNIIsPPWDFRE 9606 14657031 t lperfetto Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation SIGNOR-119762 0.629 tRNA(Glu) smallmolecule CHEBI:29175 ChEBI Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270385 0.8 AKAP8L protein Q9ULX6 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 f miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. SIGNOR-260949 0.7 BAK1 protein Q16611 UNIPROT AIFM1 protein O95831 UNIPROT up-regulates relocalization 9606 23003569 t gcesareni First, bax/bak-mediated momp leads to the release of a significant part of the cyt c, smac/diablo and htra2/omi proteins. in a third step, cyt c, smac/diablo and htra2/omi, which were released into the cytosol, trigger caspase activation. This is necessary to alter the physical association of aif and endog with the im to enable their relocation to the cytosol. SIGNOR-192092 0.301 CTSB protein P07858 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg95 GFQEAYRrFYGPV -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256320 0.333 KIF3B protein O15066 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272537 0.7 POLR2H protein P52434 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266140 0.865 PHF2 protein O75151 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264517 0.2 SP1 protein P08047 UNIPROT UGT1A4 protein P22310 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 19546240 f miannu our data indicate that up-regulation of UGT1A4 expression by E(2) is mediated by both ER alpha and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy. SIGNOR-254076 0.2 PAK4 protein O96013 UNIPROT FH protein P07954 UNIPROT down-regulates quantity phosphorylation Ser46 PNAARMAsQNSFRIE 9606 BTO:0002058 30683654 t miannu  FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation.  SIGNOR-266315 0.2 CDK8 protein P49336 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 t miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. SIGNOR-266686 0.9 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 17299140 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-153031 0.928 MTOR protein P42345 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C3 21659604 t gcesareni The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase. SIGNOR-174071 0.42 3,5-dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]-2-hydroxy-6-methoxybenzamide chemical CHEBI:92070 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258856 0.8 CSNK2A1 protein P68400 UNIPROT MYB protein P10242 UNIPROT down-regulates activity phosphorylation Ser11 RPRHSIYsSDEDDED -1 7735324 t llicata For c-Myb mutational analysis of the CKII phosphorylation sites showed altered steady state DNA binding. Replacing Ser-11/12 by alanine residues resulted in increased DNA binding compared to wt c-Myb or Myb Asp-11/12 as demonstrated by up to 10-fold differences in the dissociation constants.  SIGNOR-250918 0.343 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 t miannu  We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A). SIGNOR-276308 0.589 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-184573 0.588 CDK1 protein P06493 UNIPROT REPS2 protein Q8NFH8 UNIPROT down-regulates activity phosphorylation Ser463 RPRSRSYsSTSIEEA 10029 10764745 t miannu Phosphorylation of POB1 and Epsin by p34cdc2 kinase. Their phosphorylation sites (Ser411 of POB1 and Ser357 of Epsin) were determined. Phosphorylated Epsin and EpsinS357D formed a complex with α-adaptin less efficiently than wild type Epsin. SIGNOR-262724 0.344 PTPRH protein Q9HD43 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase SIGNOR-76084 0.272 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 9606 BTO:0000007 11544529 t gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. SIGNOR-252064 0.775 bexarotene chemical CHEBI:50859 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259231 0.8 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr149 SVTAPSPyAQPSSTF 9606 19783996 t Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. SIGNOR-260934 0.532 anthraflavic acid chemical CHEBI:34250 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258156 0.8 MAFA protein Q8NHW3 UNIPROT SLC2A2 protein P11168 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254565 0.378 TFE3 protein P19532 UNIPROT CTSF protein Q9UBX1 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276817 0.2 CASP6 protein P55212 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Asp616 EISEVKMdAEFRHDS -1 10438520 t lperfetto Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons SIGNOR-261762 0.717 AMHR2 protein Q16671 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 14746809 t gcesareni See table2 SIGNOR-121596 0.435 GRIA4 protein P48058 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 30825796 f miannu In the mammalian brain the majority of fast excitatory neurotransmission is carried out by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses SIGNOR-264614 0.7 PRKCA protein P17252 UNIPROT PLCB3 protein Q01970 UNIPROT down-regulates phosphorylation Ser1105 LDRKRHNsISEAKMR 9606 9660757 t gcesareni These data establish that direct phosphorylation by pka of ser1105 in the putative g-box of plcbeta3 inhibits galphaq-stimulated plcbeta3 activity. SIGNOR-58859 0.467 CTBP1 protein Q13363 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21681822 t irozzo Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. SIGNOR-259196 0.592 RB1 protein P06400 UNIPROT ANP32A protein P39687 UNIPROT down-regulates activity binding 9606 phosphorylation:Thr826 LPTPTKMtPRSRILV 15716273 t We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation. SIGNOR-259083 0.2 LTB4R protein Q15722 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256834 0.251 ERG protein P11308 UNIPROT VWF protein P04275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 9444957 f miannu Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells. SIGNOR-253914 0.249 PRKACA protein P17612 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser236 IDKNRRKsCQACRLR 9606 9891036 t lperfetto Phosphorylation of human estrogen receptor alpha by protein kinase a regulates dimerizationeralpha is phosphorylated by protein kinase a (pka) on serine-236 within the dna binding domain. Mutation of serine-236 to glutamic acid prevents dna binding by inhibiting dimerization by eralpha SIGNOR-63984 0.474 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser467 IDLTIDSsSDEEEEE 9606 19217413 t llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. SIGNOR-184043 0.335 GEMIN2 protein O14893 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253116 0.869 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser138 SLQLGAVsPGTLTPT 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276589 0.432 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233526 0.2 LYN protein P07948 UNIPROT RGS16 protein O15492 UNIPROT up-regulates activity phosphorylation Tyr168 TLMEKDSyPRFLKSP -1 12588871 t Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes. SIGNOR-251410 0.35 WNT5A protein P41221 UNIPROT FZD4 protein Q9ULV1 UNIPROT up-regulates activity binding 9606 16602827 t areggio We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. SIGNOR-258954 0.732 GDC-0879 chemical CHEBI:83405 ChEBI BRAF protein P15056 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192592 0.8 Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 25195934 f miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270741 0.7 CUDC-907 chemical CID:54575456 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252661 0.8 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 11717410 f Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases SIGNOR-255344 0.7 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of -1 30553771 t PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species SIGNOR-267274 0.8 LYN protein P07948 UNIPROT PAG1 protein Q9NWQ8 UNIPROT up-regulates activity phosphorylation Tyr317 EEEISAMySSVNKPG 9534 16920712 t miannu Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn. SIGNOR-262898 0.719 PIN1 protein Q13526 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16699525 t lperfetto To investigate the temporal regulation of IRF3-dependent transcription by Pin1, we used a rapid-response luciferase reporter gene. Real-time reporter gene assays showed that suppression of endogenous Pin1 expression substantially prolonged both IRF3-dependent transcription and IFN-beta promoter activation after poly(I)dotpoly(C) stimulation (Fig. 4c,d). Consistent with the inhibitory effects of Pin1 on the IFN-beta promoter SIGNOR-252289 0.2 ADRA2A protein P08913 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256698 0.543 CREBBP protein Q92793 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 t lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. SIGNOR-170262 0.645 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity phosphorylation Tyr153 LAYILSMePCGHCLI 9606 15657060 t Manara We show that ABL1 phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. ! Moreover, inhibition of ABL1 with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3. SIGNOR-260792 0.522 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-251477 0.2 JAK3 protein P52333 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Tyr371 ADFAPEDySSFQHIR 9606 BTO:0001372 23263556 t miannu  Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1.  SIGNOR-276435 0.388 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 14585074 t lperfetto Tradd mediates recruitment of the traf2 adaptor protein SIGNOR-118770 0.867 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-175805 0.846 MFGE8 protein Q08431 UNIPROT GRK2 protein P25098 UNIPROT up-regulates quantity by expression 10090 BTO:0000763 22634615 f Giorgia Our findings showed MFG-E8–mediated upregulation of GRK2, which can be correlated with reduction of surface CXCR2. The MFG-E8 effect is mediated by αvβ3 integrin to upregulate GRK2 expression and results in downregulation of surface CXCR2 levels in neutrophils, leading to decrease of neutrophil migration SIGNOR-260648 0.2 ABL1 protein P00519 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Tyr394 QSQESEDySQPSTSS 9606 12110584 t gcesareni C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2. SIGNOR-90512 0.709 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t Expression of GRK4α drastically increased the basal level of32P incorporation into B2R. GRK4α elevated the basal phosphorylation of Ser339 and Ser346/Ser348. phosphorylation of specific residues was correlated with the initiation of receptor internalization and the regulation of its desensitization. SIGNOR-251193 0.29 NDUFB9 protein Q9Y6M9 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262172 0.806 PTPN1 protein P18031 UNIPROT STAT5B protein P51692 UNIPROT down-regulates dephosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000149 10993888 t gcesareni A cytosolic protein-tyrosine phosphatase ptp1b specifically dephosphorylates and deactivates prolactin-activated stat5a and stat5b. SIGNOR-82042 0.667 DMTF1 protein Q9Y222 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261582 0.2 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257925 0.8 AKT1 protein P31749 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. SIGNOR-149698 0.837 RERE protein Q9P2R6 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity relocalization 9606 BTO:0000932 11331249 t miannu We detected RERE protein mainly in the nucleus, where it colocalizes with the promyelocytic leukemia protein in promyelocytic leukemia oncogenic domains (PODs). Overexpression of RERE recruits a fraction of the proapoptotic protein BAX to PODS: This observation correlates with RERE-induced apoptosis, which occurs in a caspase-dependent manner. SIGNOR-264485 0.2 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1090 TNTGFPRyPNDSVYA 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. SIGNOR-121145 0.2 RNF146 protein Q9NTX7 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263339 0.265 CDC42 protein P60953 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 9606 BTO:0000452 11696321 t miannu We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia. SIGNOR-268424 0.86 SRC protein P12931 UNIPROT PROM1 protein O43490 UNIPROT unknown phosphorylation Tyr852 GYHKDHVyGIHNPVM 9606 19296573 t llicata Cd133 (prominin-1) is phosphorylated on cytoplasmic tyrosine-828 and tyrosine-852 by src SIGNOR-184776 0.509 creatine smallmolecule CHEBI:16919 ChEBI CKB protein P12277 UNIPROT up-regulates activity chemical activation 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265783 0.8 CSK protein P41240 UNIPROT SRC protein P12931 UNIPROT down-regulates phosphorylation Tyr530 FTSTEPQyQPGENL 9606 18614016 t gcesareni The catalytic activity of the src family of tyrosine kinases is suppressed by phosphorylation on a tyrosine residue located near the c terminus (tyr 527 in c-src), which is catalyzed by c-terminal src kinase (csk). SIGNOR-179417 0.557 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr12 DLSGRELtIDSIMNK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276203 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EPCAM protein P16422 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11505407 f miannu The current results provide the first insights into the regulation of EpCAM expression, which is regulated negatively by TNFalpha and TPA through the activation of NF-kappaB. The repression may rely on the competition of NF-kappaB for p300/CBP histone acetyl transferase activity, because the overexpression of p300 reverts TNFalpha effects. SIGNOR-254790 0.286 ABL2 protein P42684 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 t lperfetto The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization SIGNOR-134400 0.2 glycine smallmolecule CHEBI:15428 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267297 0.8 ANK2 protein Q01484 UNIPROT CACNA1B protein Q00975 UNIPROT up-regulates quantity binding 10090 BTO:0000142 24394417 t miannu Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo. SIGNOR-266707 0.265 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12161428 f miannu A homeodomain and a forkhead transcription factor, NKX2.1 and HNF-3, respectively, are known activators of Sp-B transcription SIGNOR-254181 0.286 FAM83H protein Q6ZRV2 UNIPROT CSNK1E protein P49674 UNIPROT up-regulates quantity binding 9606 BTO:0000007 29789297 t miannu We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates. SIGNOR-273764 0.334 STAT3 protein P40763 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates 9606 18156621 f Our results demonstrate that IL-27 inhibits the acquisition of the Treg phenotype at the level of Foxp3. The inhibitory effect of IL-27 on Treg generation was at least partially signal transducer and activator of transcription 3 (STAT3) dependent as examined by targeted STAT3 protein inhibition using small interfering RNA (siRNA) SIGNOR-254364 0.585 NCAPH2 protein Q6IBW4 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263910 0.901 CID 132010322 chemical CID:132010322 PUBCHEM BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition 9606 31969702 t Luana ABBV-744 potently inhibited the BD2 domain of BET family proteins with more than 290× selectivity relative to the BD1 domains of BRD2, BRD3 and BRD4 SIGNOR-261103 0.8 UBE2D1 protein P51668 UNIPROT ZSWIM2 protein Q8NEG5 UNIPROT up-regulates activity binding 9606 BTO:0000007 16522193 t miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  SIGNOR-271554 0.323 PPARG protein P37231 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 20553736 f lperfetto Pigment epithelium-derived factor induces interleukin-10 expression in human macrophages by induction of PPAR gamma. SIGNOR-271688 0.375 Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270713 0.7 CUL3 protein Q13618 UNIPROT TBCB protein Q99426 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 t miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. SIGNOR-268945 0.247 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252484 0.758 UBE2D3 protein P61077 UNIPROT UBR5 protein O95071 UNIPROT up-regulates activity ubiquitination -1 11714696 t miannu Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks. SIGNOR-272669 0.47 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni Hpk1 binds and phosphorylates mekk1 directly SIGNOR-44040 0.546 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser139 DARDLEMsKKVRRSY -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276125 0.704 SGK3 protein Q96BR1 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249135 0.442 PRKAA1 protein Q13131 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser92 VAELTSLsDEDSGKG 9606 19923321 t lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. SIGNOR-161783 0.2 CDK5 protein Q00535 UNIPROT VRK3 protein Q8IV63 UNIPROT up-regulates activity phosphorylation Ser108 RPPTPKSsPQKTRKS 27346674 t lperfetto Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding|Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation| SIGNOR-275544 0.361 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176809 0.778 POLR1D protein P0DPB5 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266158 0.892 MYOD1 protein P15172 UNIPROT ITGA7 protein Q13683 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8798472 t lperfetto Only myogenin and MyoD were able to efficiently trans-activate the alpha7 promoter-CAT construct (Fig. 7). Myogenin trans-activated the promoter by _2-fold whereas MyoD was able to trans-activate by nearly 4-fold, indicating that both of these factors may play a role in alpha7 gene expression during muscle development. SIGNOR-241518 0.29 CTLA4 protein P16410 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 BTO:0000782 16227604 f Barakat Akt phosphorylation in cells stimulated by CD3/CD28/CTLA-4 or CD3/CD28/PD-1 aAPCs did not have detectable phosphorylated Akt at any time point, indicating that CTLA-4 and PD-1 signaling blocked rather than delayed Akt activation. SIGNOR-275409 0.596 MAP2K1 protein Q02750 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity phosphorylation Tyr216 RGEPNVSyICSRYYR 9606 BTO:0001253 15020233 t lperfetto In vitro kinase assay was carried out using a recombinant human active mek1 and we found that gsk-3beta was phosphorylated on tyr(216) by this kinase in a dose- and time-dependent manner. Further, the pretreatment of fibroblasts with u0126 inhibited serum-induced nuclear translocation of gsk-3beta. These results suggested that mek1/2 induces tyrosine phosphorylation of gsk-3beta and this cellular event might induce nuclear translocation of gsk-3beta. SIGNOR-236622 0.347 PPARG protein P37231 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 15356291 f miannu Mutation analysis indicated that the MEF2 site contributed to the activation of the CPT1beta promoter by PPAR in C2C12 cells. The reporter construct containing the PPRE and the MEF2C site was synergistically activated by co-expression of PPAR, retinoid X receptor (RXR) and MEF2C in non-muscle cells. Moreover, protein-binding assays demonstrated that MEF2C and PPAR specifically bound to one another in vitro. Also for the synergistic activation of the CPT1beta gene promoter by MEF2C and PPARalpha-RXRalpha, a precise arrangement of its binding sites was essential. SIGNOR-254581 0.392 E2F2 protein Q14209 UNIPROT TFDP1 protein Q14186 UNIPROT up-regulates activity binding 10029 BTO:0000246 8832394 t 2 miannu The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3. SIGNOR-240550 0.731 PRKACA protein P17612 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates phosphorylation Ser119 YGPPSRRsENRVVVS 9606 22393468 t llicata Here, we show that pka phosphorylates srsf1 on serine 119 in vitro. Phosphorylation of srsf1 on this site enhanced the rna binding capacity of srsf1 in vivo SIGNOR-196397 0.2 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT unknown phosphorylation Tyr691 PKGTQADyAEVKFQ 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. however, it is not clear whether y691 is capable of binding sap or a similar protein. Future studies will attempt to elucidate the signaling activities associated with y691 SIGNOR-112487 0.2 EIF3C protein Q99613 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266398 0.931 GART protein P22102 UNIPROT N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity chemical modification 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267300 0.8 SIN3A protein Q96ST3 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 16254079 t Chromatin immunoprecipitation (ChIP) and DNA affinity precipitation analysis demonstrated that Ebp1 and Sin3A associate at the PSA and E2F1 promoters. Functionally, Sin3A enhanced the ability of Ebp1 to repress transcription of androgen receptor (AR) and E2F1 regulated genes. SIGNOR-253663 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t lperfetto Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis. SIGNOR-244373 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser247 KYQCKNCsKTFSRMS 9606 BTO:0001950 37596321 t miannu  PKA-dependent phosphorylation is pivotal for FBXO28-mediated SNAI2 degradation.  SIGNOR-277905 0.2 BTK protein Q06187 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT -1 11524430 t llicata We present a number of lines of evidence that in vivo, Src-type tyrosine kinases are responsible for the phosphorylation of tyrosine 139 in DAPP-1. | Although Btk appears to phosphorylate DAPP-1 relatively efficiently both in Sf9 cells and in vitro, we find no evidence that in either B cells or PAE cells Btk family kinases phosphorylate DAPP-1. SIGNOR-250602 0.664 ATM protein Q13315 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 20068082 t gcesareni Atr (predominantly) or atm (to a lesser extent) phosphorylates chk1 at ser317/345, directly leading to activation. SIGNOR-163110 0.842 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257915 0.8 LTF protein P02788 UNIPROT ITLN1 protein Q8WWA0 UNIPROT up-regulates activity binding 9606 23921499 t Intelectin 1 (IntL) is known as a lectin expressed in intestinal epithelia and also as a receptor for an iron-binding protein, lactoferrin (LF).  SIGNOR-272500 0.366 HACD proteinfamily SIGNOR-PF86 SIGNOR FASN protein P49327 UNIPROT up-regulates activity chemical activation 9606 18554506 t Very long-chain fatty acids are produced through a four-step cycle. However, the 3-hydroxyacyl-CoA dehydratase catalyzing the third step in mammals has remained unidentified. Mammals have four candidates, HACD1-4, based on sequence similarities to the recently identified yeast Phs1, although HACD3 and HACD4 share relatively weak similarity. We demonstrate that all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases, SIGNOR-267764 0.2 RLN2 protein P04090 UNIPROT RXFP1 protein Q9HBX9 UNIPROT up-regulates binding 9606 BTO:0000142 11809971 t gcesareni Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway SIGNOR-114549 0.756 LCK protein P06239 UNIPROT PRDX2 protein P32119 UNIPROT down-regulates activity phosphorylation Tyr193 NVDDSKEyFSKHN -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276279 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr134 LKFYDSNtVKQKYLS 9606 BTO:0004828 32483448 t lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway SIGNOR-273111 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120248 0.319 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 9712898 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-59689 0.892 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Ser328 ERALTEDsTQTSDTA -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-247763 0.2 PCSK7 protein Q16549 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation 9606 12435397 t gcesareni In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site SIGNOR-95622 0.2 trichostatin A chemical CHEBI:46024 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258013 0.8 letrozole chemical CHEBI:6413 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193651 0.8 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207938 0.8 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 10581361 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-72728 0.516 INTS13 protein Q9NVM9 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261469 0.2 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249154 0.2 GGNBP2 protein Q9H3C7 UNIPROT ESR1 protein P03372 UNIPROT down-regulates activity binding 9606 BTO:0001248 27357812 t miannu We further demonstrate that GGNBP2 protein physically interacts with ERα, inhibits E2-induced activation of estrogen response element-driven reporter activity, and attenuates ER target gene expression in T47D cells. SIGNOR-269076 0.2 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates activity binding 9606 14963330 t lperfetto Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program SIGNOR-178690 0.747 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 23336025 t gcesareni Bcl-2 inhibitors physically antagonize their anti-apoptotic actions to create a synergistic effect. Numerous compounds have been specifically developed or identified as bcl-2 inhibitors. These compounds include abt-737 and abt-263, obatoclax, gossypol. SIGNOR-200460 0.8 PRKAA1 protein Q13131 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Ser385 RRRKKRTsIETNIRV 9606 1684878 t lperfetto Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites. SIGNOR-20971 0.2 PRKCA protein P17252 UNIPROT HLA-A protein P04439 UNIPROT unknown phosphorylation Ser359 SAQGSDVsLTACKV 2941417 t lperfetto As shown in Fig. 6A, the HLA heavy chain was phosphorylated by kinase C. | The major site of in vivo phosphorylation of the HLA-B7 heavy chain was localized to Ser-335 which is conserved in all specificitie SIGNOR-248891 0.326 UQCR11 protein O14957 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262196 0.839 DNMT3A protein Q9Y6K1 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR form complex binding 9606 12145218 t miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation SIGNOR-90842 0.779 NFKBIE protein O00221 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates binding 9606 BTO:0001271 SIGNOR-C13 12835716 t gcesareni Nf-kb is normally sequestered in the cell cytoplasm by binding to ikbx, ikbb, ikbe SIGNOR-102774 0.528 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10090 BTO:0000011 11279134 t lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-250566 0.467 CBX5 protein P45973 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264490 0.2 PI4K2B protein Q8TCG2 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269099 0.8 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity binding -1 12408824 t llicata The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. SIGNOR-238012 0.811 WDFY3 protein Q8IZQ1 UNIPROT GABARAP protein O95166 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 24668264 t miannu Here, we show that ALFY binds selectively to LC3C and the GABARAPs through a LIR in its WD40 domain. Binding of ALFY to GABARAP is indispensable for its recruitment to LC3B-positive structures and, thus, for the clearance of certain p62 structures by autophagy. SIGNOR-266796 0.674 PTPRJ protein Q12913 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 12771128 t inferred from 70% of family members gcesareni A dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-269919 0.466 ADORA2A protein P29274 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257151 0.264 KATNA1 protein O75449 UNIPROT KATNB1 protein Q9BVA0 UNIPROT up-regulates activity binding 9606 BTO:0000567 10751153 t miannu In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer SIGNOR-267174 0.769 CMA1 protein P23946 UNIPROT EDN3 protein P14138 UNIPROT up-regulates activity cleavage Tyr127 TPEQTVPyGLSNYRG 9606 BTO:0000830 9257865 t miannu Chymase from human mast cells selectively cleaved big endothelins (ETs) at the Tyr31-Gly32 bond and produced novel trachea-constricting 31-amino acid-length endothelins, ETs(1-31), without any further degradation products. SIGNOR-256355 0.379 ATM protein Q13315 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates phosphorylation Ser564 LEEESPVsQLFELEI 9606 23405218 t gcesareni The main phosphorylation site of daxx is identified to be ser564, which is a direct target of atm. Phosphorylation of endogenous daxx at ser564 occurs rapidly during the dna damage response and precedes p53 activation. Blockage of this phosphorylation event prevents the separation of daxx from mdm2, stabilizes mdm2, and inhibits dna damage-induced p53 activation. SIGNOR-200889 0.508 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1948 SPTSPGYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273036 0.55 FASN protein P49327 UNIPROT Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 9356448 f miannu Our model of the native fatty acid synthase (FAS) depicts it as a dimer of two identical multifunctional proteins (Mr approximately 272,000) arranged in an antiparallel configuration so that the active Cys-SH of the beta-ketoacyl synthase of one subunit (where the acyl group is attached) is juxtaposed within 2 A of the pantetheinyl-SH of the second subunit (where the malonyl group is bound). This arrangement generates two active centers for fatty acid synthesis and predicts that if we have two appropriate halves of the monomer, we should be able to reconstitute an active fatty acid-synthesizing site SIGNOR-270536 0.7 PRKCA protein P17252 UNIPROT EIF6 protein P56537 UNIPROT unknown phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 t llicata Pkc stimulation led to eif6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eif6 impaired rack1/pkc-mediated translational rescue. SIGNOR-119600 0.32 SP1 protein P08047 UNIPROT CHGA protein P10645 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12456801 t Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation. SIGNOR-254273 0.2 POLD2 protein P49005 UNIPROT DNA polymerase delta complex SIGNOR-C376 SIGNOR form complex binding -1 12403614 t lperfetto Reconstitution and characterization of the human DNA polymerase delta four-subunit holoenzyme. SIGNOR-265516 0.922 bremazocine chemical CHEBI:3171 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258778 0.8 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120116 0.314 MYC protein P01106 UNIPROT MYCT1 protein Q8N699 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11909865 t miannu MT-MC1 is a widely expressed nuclear protein whose overexpression, unlike that of c-Myc targets reported previously, recapitulates multiple c-Myc phenotypes. These include promotion of apoptosis, alteration of morphology, enhancement of anchorage-independent growth, tumorigenic conversion, promotion of genomic instability, and inhibition of hematopoietic differentiation. The MT-MC1 promoter is a direct c-Myc target; it contains two consensus E-box elements, both of which bind c-Myc. SIGNOR-261736 0.301 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates activity phosphorylation 9606 23616010 t lperfetto Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1. SIGNOR-233520 0.2 PRKAA2 protein P54646 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000007 11069105 t miannu AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells.  activation of PFK-2 was due to the phosphorylation of Ser466 SIGNOR-250323 0.435 COPS3 protein Q9UNS2 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates quantity by stabilization binding 9606 30631038 t miannu Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1. SIGNOR-256217 0.2 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258899 0.8 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser201 PLQRQPSsPGPTPRN 9606 BTO:0001103 10212242 t lperfetto Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates. SIGNOR-67065 0.66 CAMK2D protein Q13557 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates 9606 19725819 f areggio In response toincreases in intracellular Ca2+ levels, activated CaMKII translocates into the nucleus where it phosphorylates and deactivates HDAC4 which, as a result, dissociates from theDNA-binding domain of MEF2. This dissociation allows MEF2 to bind to its DNA-binding domain to activate transcription of the MEF2-dependent target gene products MyoD and myogenin SIGNOR-255956 0.44 ERBB4 protein Q15303 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146879 0.6 PTPN1 protein P18031 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 17197020 t llicata In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of Ca2+ influx through TRPV6 Ca2+ channels in HEK293 cells. SIGNOR-248433 0.621 SH2B2 protein O14492 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 10029 BTO:0000977 10854852 t lperfetto APS-mediated recruitment of c-Cbl to the insulin receptor led to rapid ubiquitination of the insulin receptor beta-subunit in CHO. T-APS but not in parental CHO.T cells. These results suggest that the function of APS is to facilitate coupling of the insulin receptor to c-Cbl in order to catalyse the ubiquitination of the receptor and initiation of internalisation or degradation. SIGNOR-78337 0.637 STK4 protein Q13043 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. SIGNOR-175841 0.848 RPS6KA5 protein O75582 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser40 GQGAPGPsLTGSPWP 9606 12421349 t The effect has been demonstrated using P07101-3 gcesareni Recombinant human tyrosine hydroxylase (hth1) was found to be phosphorylated by mitogen and stress-activated protein kinase 1 (msk1) at ser40 and by p38 regulated/activated kinase (prak) on ser19. Phosphorylation by msk1 induced an increase in vmax. studies on th from several species suggest that ser40 is the main site involved in direct activation of th SIGNOR-95491 0.341 STK4 protein Q13043 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181060 0.346 STAT5A protein P42229 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21261500 f miannu STAT5 binds directly to the promoter region and potently mediates repression of MEF2C, probably via HDAC recruitment. SIGNOR-254207 0.281 mTORC1 complex SIGNOR-C3 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256172 0.347 PPP4C protein P60510 UNIPROT TRIM28 protein Q13263 UNIPROT down-regulates activity dephosphorylation 9606 22732494 t miannu PP4 dephosphorylated pKAP1 in vitro. SIGNOR-277163 0.362 GSK3B protein P49841 UNIPROT APC protein P25054 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 10698523 t lperfetto Gsk-3beta-dependent phosphorylation of apc. SIGNOR-75366 0.752 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 15546612 t gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-130640 0.541 CYP19A1 protein P11511 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268669 0.8 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78420 0.855 CDK1 protein P06493 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Thr92 EVPDVTAtPARLLFF 9606 SIGNOR-C17 20526282 t gcesareni Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons. SIGNOR-165867 0.47 ICAM3 protein P32942 UNIPROT AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 8777714 t lperfetto A novel leukointegrin, alpha d beta 2, binds preferentially to ICAM-3. SIGNOR-253371 0.603 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates binding 9606 BTO:0001253 9625767 t gcesareni Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab). SIGNOR-58122 0.904 EGLN3 protein Q9H6Z9 UNIPROT PKM protein P14618 UNIPROT up-regulates activity hydroxylation Pro408 LAPITSDpTEATAVG 9606 BTO:0000567 21620138 t Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. SIGNOR-267477 0.443 CXCL1 protein P09341 UNIPROT GLI3 protein P10071 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16885213 f gcesareni The data suggest that smo is in fact the source of two signals relevant to the activation of gli: one involving g(i) and the other involving events at smo's c-tail independent of g(i). SIGNOR-148460 0.2 DNAH17 protein Q9UFH2 UNIPROT Cilium_movement phenotype SIGNOR-PH171 SIGNOR up-regulates 9606 BTO:0001277 31178125 f miannu Our study provides a comprehensive analysis of ODA heavy chain distribution in human spermatozoa and demonstrates the importance of DNAH17 (β-HC) in sperm flagellum structure and motility. We demonstrate that DNAH17 (β-HC) mutations are associated with a loss of ODAs and male infertility but not with PCD. SIGNOR-265549 0.7 MAPK8 protein P45983 UNIPROT PKMYT1 protein Q99640 UNIPROT up-regulates phosphorylation 9606 BTO:0001286 19204086 t The results showed that residues 140 to 205 of JNK1 have the ability to interact with Myt1. gcesareni A kinase assay using gst-myt1 revealed that active jnk1 or jnk3, but not jnk2, phosphorylated myt1 in vitro. SIGNOR-183899 0.339 MAPK3 protein P27361 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser616 DDGYMPMsPGVAPVP 9606 15001544 t lperfetto Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation. SIGNOR-123177 0.7 TFE3 protein P19532 UNIPROT UVRAG protein Q9P2Y5 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto The most significantly up-regulated genes encode proteins that play an essential role in formation of autophagosomes (ATG16L1, ATG9B, GABARAPL1, and WIPI1), as well as their degradation (UVRAG). Analysis of the LC3II/LC3I ratio upon TFE3, TFEB, or MITF1 overexpression confirmed autophagy induction (Fig. 4, B and C). Accordingly, we observed an accumulation of autophagosomes in TFE3-expressing cells SIGNOR-276829 0.266 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MEF2C protein Q06413 UNIPROT down-regulates activity phosphorylation Ser396 NIKSEPVsPPRDRTT BTO:0003166 16478538 t llicata Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity. | Intriguingly, we show that phosphorylation of S396 in MEF2C, a residue in close proximity to the major sumoylation site (K391) and known to be phosphorylated in vivo, enhances sumoylation of delta- N2-MEF2C in vitro. The S396A mutation reduces sumoylation of MEF2C in vivo and enhances the transcription activity of MEF2C in reporter assays. | CDK1/Cyclin B1 phosphorylated GST-MEF2C-ΔN2-WT to a greater extent than the MEF2C-ΔN2-S396A mutant, suggesting that Cdk1/Cyclin B1 can phosphorylate MEF2C at S396. SIGNOR-250719 0.366 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 BTO:0000150 21316371 t gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) SIGNOR-171907 0.344 EIF2AK2 protein P19525 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263121 0.312 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248293 0.409 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR -1 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-250080 0.682 codeine chemical CHEBI:16714 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258933 0.8 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120204 0.319 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser276 PLPSPTAsPNHTLAP 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126847 0.402 lipopolysaccharide smallmolecule CHEBI:16412 ChEBI TLR4 protein O00206 UNIPROT up-regulates activity chemical activation 10090 9851930 t The mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. SIGNOR-252075 0.8 CAMK4 protein Q16566 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates activity phosphorylation Ser302 PQLASKQsMVNSLPT BTO:0000938 11970865 t llicata Ser301 of CBP was identified as a major target of CaMKIV phosphorylation in vitro and in vivo. CaM kinase inhibitors attenuated phosphorylation at Ser301 and blocked CBP-dependent transcription. Additionally, mutation of Ser301 impaired NMDA- and CaMKIV-stimulated transcription. These findings demonstrate that activity-induced CaMKIV signaling contributes to CREB/CBP-dependent transcription by phosphorylating CBP at Ser301. SIGNOR-250710 0.628 rRNA_transcription phenotype SIGNOR-PH145 SIGNOR 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR up-regulates 25901680 f lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262601 0.7 SRC protein P12931 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-246377 0.668 TNFSF12 protein O43508 UNIPROT MYH3 protein P11055 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000165 17314137 t miannu TWEAK induces ubiquitination of MyHCf and expression of atrogin-1 and MuRF1 in myotubes. our data show that TWEAK rapidly increases the conjugation of ubiquitin to MyHCf (Fig. 3A) and ubiquitination preceded the degradation of MyHCf (Fig. 2C and Fig. 3A). SIGNOR-272628 0.2 KIF5B protein P33176 UNIPROT GABBR1 protein Q9UBS5 UNIPROT up-regulates activity relocalization 10090 17532644 t SARA GABABR1 co-immunoprecipitated with Marlin-1 and kinesin-I, providing evidence for the existence of a complex between these proteins. Kinesin-I modulates GABAB receptor transport. SIGNOR-260990 0.257 PTPRB protein P23467 UNIPROT CDH5 protein P33151 UNIPROT up-regulates activity dephosphorylation 9606 19015309 t miannu Because we had shown previously that VE-PTP supports VE-cadherin function when exogenously expressed in transfected cells, we expected it to be expressed at endothelial cell contacts.|Indeed, tyrosine phosphorylation of VE-cadherin is reduced by VE-PTP in COS-7 and CHO cells. SIGNOR-277131 0.593 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262219 0.8 PRDM1 protein O75626 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12052884 f miannu Blimp-1-dependent repression of pax-5 is required for differentiation of b cells to immunoglobulin m-secreting plasma cells SIGNOR-89032 0.512 WWTR1 protein Q9GZV5 UNIPROT TEAD3 protein Q99594 UNIPROT up-regulates binding 9606 23431053 t YAP/TAZ mainly bind to the transcription factors TEAD1??4 to regulate genes involved in cell proliferation and cell death. gcesareni When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14. SIGNOR-201415 0.691 SMC4 protein Q9NTJ3 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263904 0.936 JAK1 protein P23458 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity phosphorylation Tyr585 NDIKNSGyISRYLTD 10090 BTO:0000099 25113558 t miannu JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3. SIGNOR-276676 0.2 Fluocinonide chemical CHEBI:5109 ChEBI SMO protein Q99835 UNIPROT up-regulates activity chemical activation 10090 20439738 t gcesareni We identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. SIGNOR-248218 0.8 TFDP1 protein Q14186 UNIPROT DHFR protein P00374 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253860 0.425 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS 9606 10931940 t lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. SIGNOR-261773 0.555 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation 9606 19188143 t lperfetto Phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression SIGNOR-183695 0.687 CNR1 protein P21554 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates activity binding 9606 29751001 t miannu Another example is the heteromer between CB1 and orexin 1 receptor (OX1R). The CB1 activation potentiated the OX1R signaling (218), suggesting the interaction of these two receptors. Interaction of their surface distribution was also reported.  SIGNOR-264269 0.393 ADAM17 protein P78536 UNIPROT AREG protein P15514 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259842 0.456 phosphatidic acid smallmolecule CHEBI:16337 ChEBI PIP5K1A protein Q99755 UNIPROT up-regulates chemical activation 9606 17245604 t gcesareni All pip5k isoforms are stimulated by pa. SIGNOR-152542 0.8 FBP2 protein O00757 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267613 0.8 IL21R protein Q9HBE5 UNIPROT JAK3 protein P52333 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 t gcesareni Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5 SIGNOR-90269 0.547 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 9545235 t lperfetto IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspasesThese findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis SIGNOR-56484 0.921 RPS6KA1 protein Q15418 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser173 PGKRRTQsLSALPKE 9606 BTO:0000848 21087211 t gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3) SIGNOR-169883 0.2 MYCT1 protein Q8N699 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity 9606 30283340 f miannu Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways. SIGNOR-261943 0.2 TLK1 protein Q9UKI8 UNIPROT NEK1 protein Q96PY6 UNIPROT up-regulates activity phosphorylation Thr141 IFLTKDGtVQLGDFG 28426283 t lperfetto TLK1 phosphorylated NEK1 at T141, which lies in the kinase domain, and caused an increase in its activity.  SIGNOR-275840 0.294 ETS1 protein P14921 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22270366 f miannu VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. SIGNOR-254083 0.383 TRADD protein Q15628 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates binding 9606 10629108 t amattioni Tradd mediates recruitment of traf1/2 SIGNOR-73913 0.687 SETDB2 protein Q96T68 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity methylation Lys 10 RTKQTARkSTGGKAP 9606 BTO:0000007 20404330 t miannu Here, we have characterized a previously undescribed member of the histone H3K9 methyltransferase family named CLLD8 (or SETDB2 or KMT1F). This protein contributes to the trimethylation of both interspersed repetitive elements and centromere-associated repeats and participates in the recruitment of heterochromatin protein 1 to centromeres. Methylation of histone H3 at lysine 9 (H3K9) has emerged as an important player in the formation of heterochromatin, chromatin condensation, and transcriptional repression. SIGNOR-263896 0.2 TNFRSF11A protein Q9Y6Q6 UNIPROT Osteoclast_differentiation phenotype SIGNOR-PH76 SIGNOR up-regulates 9606 17572386 f miannu Osteoclasts are fully differentiated, multi-nucleated cells originating from the hematopoietic monocyte-macrophage linage. RANKL, a member of the tumor necrosis factor (TNF) superfamily, and its receptor RANK are essential regulators of osteoclast maturation and activation SIGNOR-253043 0.7 BRCA2 protein P51587 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 17515904 t We suggest that interactions of the BRCA2 C-terminal region with RAD51 may facilitate efficient nucleation of RAD51 multimers on DNA and thereby stimulate recombination-mediated repair. SIGNOR-259905 0.946 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). SIGNOR-59643 0.757 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BHMT protein Q93088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16953798 f miannu SAM and MTA down-regulate BHMT expression in HepG2 cells in part by inducing NF-kappaB, which acts as a repressor for the human BHMT gene. While SAM's mechanism is NF-kappaB-dependent, MTA has both NF-kappaB-dependent and -independent mechanisms. SIGNOR-254659 0.2 CDK4 protein P11802 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176524 0.282 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-268077 0.8 CLK1 protein P49759 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 t llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. SIGNOR-250774 0.35 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr52 DGFIPKNyIEMKPHP 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246293 0.2 CYP11B2 protein P19099 UNIPROT corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268680 0.8 GNA12 protein Q03113 UNIPROT RFFL protein Q8WZ73 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 22609986 f miannu LPA and Gα12 may upregulate the expression of an E3 ubiquitin ligase that catalyzes the polyubiquitination of PRR5L. SIGNOR-271496 0.2 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT up-regulates activity binding 9606 BTO:0001073 29407449 t scontino T3 binds its receptor (TR) in the nucleus. TRs are ligand-dependent transcription factors belonging to the type II group of NHRs. TRs are encoded by two genes, Thra and Thrb. SIGNOR-267254 0.8 ATR protein Q13535 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser345 LVQGISFsQPTCPDH 9606 15775976 t gcesareni Atr activation typically leads to chk1 phosphorylation and activation. In response to genotoxic stress, chk1 is phosphorylated on serines 317 (s317) and 345 (s345) by the ataxia-telangiectasia-related (atr) protein kinase. SIGNOR-134716 0.924 ENPP1 protein P22413 UNIPROT Bone_mineralization phenotype SIGNOR-PH69 SIGNOR up-regulates 9606 19049325 f miannu PC-1 and Tnap work together to produce normally mineralized bone matrix through the generation and hydrolysis of pyrophosphate. SIGNOR-252195 0.7 CUL3 protein Q13618 UNIPROT MAP1S protein Q66K74 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0000142 18680552 t miannu Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B. SIGNOR-268947 0.244 HTR4 protein Q13639 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257416 0.251 ACTR2 protein P61160 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251512 0.927 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Ser29 WLKDQELsPREPVLP 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275599 0.25 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 18250158 t gcesareni For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated. SIGNOR-160672 0.852 WNT5A protein P41221 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-253129 0.83 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-252868 0.76 PRKAA1 protein Q13131 UNIPROT ACACA protein Q13085 UNIPROT down-regulates activity phosphorylation Ser1201 IPTLNRMsFSSNLNH 10116 7907095 t miannu We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase SIGNOR-250400 0.693 PRKCB protein P05771 UNIPROT TP73 protein O15350 UNIPROT up-regulates activity phosphorylation Ser388 VPQPLVDsYRQQQQL 9606 19158275 t miannu Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.  SIGNOR-276234 0.2 CLIP1 protein P30622 UNIPROT DCTN1 protein Q14203 UNIPROT up-regulates activity binding 9606 15381688 t miannu MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif. SIGNOR-252164 0.776 ATM protein Q13315 UNIPROT RAD17 protein O75943 UNIPROT unknown phosphorylation Ser656 SASELPAsQPQPFSA 9606 10608806 t lperfetto We determined a general phosphorylation consensus sequence for atm and identified putative in vitro targets by using glutathione s-transferase peptides as substrates. Putative atm in vitro targets include p95/nibrin, mre11, brca1, rad17, pts, wrn, and atm (s440) itself. SIGNOR-73524 0.844 PKNOX1 protein P55347 UNIPROT PBX1 protein P40424 UNIPROT up-regulates activity binding -1 9482740 t 2 miannu we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity. SIGNOR-241212 0.738 NR1D1 protein P20393 UNIPROT OPHN1 protein O60890 UNIPROT up-regulates activity binding 9606 BTO:0000132 35267019 t miannu Rev-erbα regulates OPHN-1-mediated RhoA/ERM signalling in platelets., The results of the co-immunoprecipitation revealed that Rev-erbα coimmunoprecipitated with OPHN-1 in both mouse and human platelets and this interaction significantly increased upon stimulation with agonist U46619. SIGNOR-268428 0.2 HNF1A protein P20823 UNIPROT UGT1A9 protein O60656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000195 15044625 t Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter. SIGNOR-253973 0.269 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273069 0.635 GATA1 protein P15976 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates activity relocalization 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275664 0.538 alanine smallmolecule CHEBI:16449 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264746 0.7 ASIP protein P42127 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268713 0.509 Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270890 0.7 CCL2 protein P13500 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261027 0.7 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267588 0.8 suprofen chemical CHEBI:9362 ChEBI PTGS1 protein P23219 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001061 18667313 t Luana Profens, that is, Ketoprofen 1, Suprofen 2 (Fig. 1), were chosen because of their interesting inhibitory activity against cyclooxygenase and of their different selectivity versus the two isoforms COX-1/COX-2.  SIGNOR-257809 0.8 CCR3 protein P51677 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 11591790 f We and others have recently found that eotaxin activates extracellular signal-regulated kinase (ERK)-1/2 and p38 mitogen-activated protein (MAP) kinases in eosinophils, and that these kinases are indispensable for eosinophil chemotaxis and degranulation SIGNOR-254358 0.25 MYC protein P01106 UNIPROT PRODH protein O43272 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22615405 f miannu MYC not only inhibited POX/PRODH, but also markedly increased the enzymes of proline biosynthesis from glutamine, including P5C synthase and P5C reductase 1. SIGNOR-254608 0.2 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268582 0.2 GRIK4 protein Q16099 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264345 0.7 BMPR1A protein P36894 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 10712517 t gcesareni Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors SIGNOR-75649 0.483 IL6ST protein P40189 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 16306329 f mrosina Upon formation of the IL-6/IL-6Ralpha/gp130 hexameric signaling complex, two distinct signaling pathways are activated: 1) Janus kinase (JAK)/signal transducers and activator of transcription (STAT) and 2) the Src homology 2-containing tyrosine phosphatase (SHP-2)/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways SIGNOR-255022 0.28 RPS6KA1 protein Q15418 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-180462 0.557 GNAL protein P38405 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 BTO:0004032 21303898 t miannu D1-class dopamine receptors (D1 and D5) activate the G s/olf family of G proteins to stimulate cAMP produc tion by AC and are found exclusively postsynaptically on dopamine-receptive cells, such as GABA-ergic medium spiny neurons (MSNs) in the striatum. SIGNOR-267852 0.634 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t lperfetto In this study, we showed that mad1 is a substrate of p90 ribosomal kinase (rsk) and p70 s6 kinase (s6k). Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway SIGNOR-252811 0.2 CSNK2A1 protein P68400 UNIPROT GPI protein P06744 UNIPROT down-regulates activity phosphorylation Ser185 GPRVWYVsNIDGTHI 9606 BTO:0000459 15637053 t llicata It is known that human PGI/AMF is phosphorylated at Ser(185) by protein kinase CK2 (CK2) | These results demonstrate that phosphorylation affects the allosteric kinetic properties of the enzyme, resulting in a less active form of PGI, whereas non-phosphorylated protein species retain cytokine activity.  SIGNOR-250869 0.336 tyrphostin B42 chemical CHEBI:131968 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity 9606 11368440 t gcesareni The Janus kinase inhibitor, tyrphostine AG490, inhibits STAT3 activation, STAT3 DNA binding, and IL-2Ralpha mRNA and protein expression in parallel SIGNOR-238293 0.8 MAPK10 protein P53779 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Jnk phosphorylates 14-3-3zetaat ser-184 and 14-3-3sigmaat ser-190 SIGNOR-124009 0.2 RPS6KB1 protein P23443 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser286 LRSCSLGsLGALGPA -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.  SIGNOR-274068 0.326 UBE2K protein P61086 UNIPROT RNF138 protein Q8WVD3 UNIPROT up-regulates activity binding 9606 BTO:0000007 16714285 t miannu NARF exhibits E3 ubiquitin-ligase activity in cooperation with the ubiquitin conjugating enzyme, E2-25K. These data show that the auto-ubiquitylating activity of NARF is coordinated with E2-25K, and that the RING finger domain of NARF is indispensable for this reaction. SIGNOR-271594 0.523 LYN protein P07948 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249381 0.647 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 21159646 t gcesareni In comparison, in the same assay conditions, the previously reported mps1 inhibitor sp600125 (13) was 10-fold less potent than nms-p715 on mps1 and, in addition, it was highly unspecific, being more active on at least 12 kinases including mitotic kinases. SIGNOR-170611 0.8 SRC protein P12931 UNIPROT PLSCR1 protein O15162 UNIPROT up-regulates activity phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 12871937 t lperfetto Plscr1 is phosphorylated by c-src, within the tandem repeat sequence 68vynqpvynqp77.|The EGF-mediated Interaction between PLSCR1 and Shc Requires Phosphorylation of Tyr69 and Tyr74 in PLSCR1 SIGNOR-103773 0.484 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 22945643 t lperfetto Cdk8 regulates e2f1 transcriptional activity through s375 phosphorylation. SIGNOR-198934 0.492 YAP1 protein P46937 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates binding 9606 23431053 t YAP can specifically recognize the phosphorylated SMAD linker sequence containing the PY motif, and its presence is required for efficient transcription of BMP target genes. gcesareni Yap binds to the phosphorylated smad1 to activate gene transcription. SIGNOR-201462 0.565 RDH5 protein Q92781 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity chemical modification 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS11 SIGNOR-265114 0.8 MRPL40 protein Q9NQ50 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262356 0.718 DLL4 protein Q9NR61 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209735 0.634 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser222 TSPARLGsQHSPGRT 9606 21419341 t lperfetto Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex. SIGNOR-172873 0.43 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227897 0.893 TGFBR2 protein P37173 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0001660 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227521 0.454 DAB2IP protein Q5VWQ8 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity gtpase-activating protein 9606 27858941 t miannu The GAP domain of DAB2IP is homologous to other Ras-GAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines. DAB2IP is able to stimulate in vitro and in vivo the GTPase activity of RAS proteins (H-Ras, K-Ras, and N-Ras) facilitating GTP hydrolysis to GDP. SIGNOR-254746 0.505 MAPK8 protein P45983 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264876 0.2 RPL36AL protein Q969Q0 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262493 0.784 STUB1 protein Q9UNE7 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 19940151 t miannu the ubiquitin ligase activity of CHIP regulates HIF-1α degradation. SIGNOR-271426 0.381 ITK protein Q08881 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated SIGNOR-98090 0.391 PIK-75 Hydrochloride chemical CID:45265864 PUBCHEM PRKDC protein P78527 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206214 0.8 AKT3 protein Q9Y243 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-61565 0.505 GNB1 protein P62873 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-252679 0.518 IL7 protein P13232 UNIPROT IL7R protein P16871 UNIPROT up-regulates binding 9606 BTO:0000782 8204885 t fspada Antibody r34.34 was further found to be directed against an epitope interfering with binding of interleukin-7 (il-7) to pre-alp cells. Expression cloning from a pre-alp cdna library showed that r34.34 antigen is cdw127, the 75- to 80-kd il-7 receptor. Proliferation of the b-lineage all cell lines reh and mieliki was inhibited by il-7, and this effect was specifically reverted by moab r34.34. In addition, antibody r34.34 specifically inhibited il-7-dependent proliferation of normal bcp, pre-alp cells, and peripheral t cells. These results imply that both inhibitory and proliferative effects of il-7 can be mediated through the same receptor on various lineages. SIGNOR-37012 0.913 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 11904305 t gcesareni Here we show that p42/p44 mapk directly phosphorylates sp1 on threonines 453 and 739 both in vitro and in vivo. Mutation of these sites to alanines decreases by half the mapk-dependent transcriptional activity of sp1. Phosphorylated extracellular signal-regulated protein kinases 1 and 2 phosphorylate sp1 on serine 59 and regulate cellular senescence via transcription of p21sdi1/cip1/waf1. SIGNOR-116166 0.635 DLGAP5 protein Q15398 UNIPROT SHANK2 protein Q9UPX8 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264599 0.458 sonidegib chemical CHEBI:90863 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21041712 t gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. SIGNOR-169203 0.8 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser204 DSRPRSQsSKAAIPP 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262706 0.321 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys373 SSHLKSKkGQSTSRH 9606 BTO:0000567 11070080 t gcesareni P300 acetylates and activates the tumor suppressor p53 after dna damage. SIGNOR-84070 0.91 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates 9606 22972936 t milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-192042 0.588 MC4R protein P32245 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256797 0.509 HOXD12 protein P35452 UNIPROT MAFK protein O60675 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221929 0.381 MRPL30 protein Q8TCC3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262365 0.665 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser197 APRRRAAsMDSSSKL 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252828 0.909 SRC protein P12931 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates activity phosphorylation Tyr1510 LVKLQQTyAALNSKA 9606 BTO:0000815 33087447 t miannu IQGAP1 was phosphorylated exclusively on Tyr-1510 under conditions with enhanced MET or c-Src signaling, including in human lung cancer cell lines. This phosphorylation was significantly reduced by chemical inhibitors of MET or c-Src or by siRNA-mediated knockdown of MET. SIGNOR-277533 0.688 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser451 NGFYHFGsTSSSPPI 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251245 0.403 CDK2 protein P24941 UNIPROT CROCC protein Q5TZA2 UNIPROT down-regulates phosphorylation Ser1460 APRPVPGsPARDAPA 9606 22610972 t llicata Finally, phosphorylation of tax1bp2 at serine-763 by cyclin-dependent kinase (cdk)2 abolished the tax1bp2-mediated p38 activation and tumor-suppressive activity, indicating that tax1bp2 can adapt cdk2 signaling to the p38/p53/p21 pathway. SIGNOR-197593 0.2 TRRAP protein Q9Y4A5 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269288 0.738 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR CSNK1A1 protein P48729 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000670 26131937 t gcesareni We demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1a) by the E3 ubiquitin ligase CUL4€“RBX1€“DDB1€“CRBN (known as CRL4CRBN) SIGNOR-236907 0.385 LPAR1 protein Q92633 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t milica Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. SIGNOR-236985 0.441 IFNAR complex SIGNOR-C243 SIGNOR Macrophage_activation phenotype SIGNOR-PH126 SIGNOR up-regulates 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260848 0.7 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr165 PSPATDLyQVPPGPG 9606 22084245 t lperfetto Protein-tyrosine kinase 6 promotes peripheral adhesion complex formation and cell migration by phosphorylating p130 crk-associated substrate. Tyrosine residues 165 and 664 of p130cas were both phosphorylated by ptk6 in vitro SIGNOR-177238 0.59 LATS2 protein Q9NRM7 UNIPROT MTF1 protein Q14872 UNIPROT down-regulates activity phosphorylation Ser152 EGCPRTYsTAGNLRT 35027733 t lperfetto The Hippo pathway kinases LATS1 and LATS2 attenuate cellular responses to heavy metals through phosphorylating MTF1|the Hippo pathway kinase LATS phosphorylates and inhibits MTF1|LATS phosphorylates MTF1 at S152 and disrupts its association with the promoters of heavy metal response genes, resulting in the loss of heavy metal response gene expression SIGNOR-275475 0.2 tibolone chemical CHEBI:32223 ChEBI PGR protein P06401 UNIPROT up-regulates activity chemical activation 9606 19464167 t Luana In this study, we have assessed the potential hormonal profile of tibolone and its primary metabolites on all human steroid receptors (PR, AR, GR, MR, ERα and ERβ) using HeLa or PC3 cells stably transfected with a given receptor and a luciferase reporter gene. We show that tibolone and its ∆ 4 -isomer predominantly bind and activate PR and AR whereas 3α and 3β-OH-tibolone predominantly bind and activate ERα (Table 1). SIGNOR-257822 0.8 USP8 protein P40818 UNIPROT STAM protein Q92783 UNIPROT up-regulates quantity binding 9606 BTO:0000567 16520378 t Stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells. SIGNOR-266904 0.545 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 14560030 t Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, SIGNOR-248666 0.867 AKT proteinfamily SIGNOR-PF24 SIGNOR AGAP2 protein Q99490 UNIPROT up-regulates phosphorylation Ser985 THLSRVRsLDLDDWP 9606 BTO:0001130 19176382 t lperfetto In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2. SIGNOR-244132 0.2 AMER1 protein Q5JTC6 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity relocalization 9606 SIGNOR-C110 21304492 t gcesareni Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6. SIGNOR-171886 0.783 NFYC protein Q13952 UNIPROT GFI1B protein Q5VTD9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19965638 f miannu HMGB2 binds to the GFI1B promoter in vivo and up-regulates its trans-activation most likely by enhancing the binding of Oct-1 and, to a lesser extent, of GATA-1 and NF-Y to the GFI1B promoter. SIGNOR-254433 0.303 AIRE protein O43918 UNIPROT ICA1 protein Q05084 UNIPROT down-regulates quantity by repression transcriptional regulation 22447927 t lperfetto Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. SIGNOR-268973 0.367 arginine smallmolecule CHEBI:29016 ChEBI Arg-tRNA(Arg) smallmolecule CHEBI:18366 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270370 0.8 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1197 STAENAEyLRVAPQS 9606 16943190 t lperfetto we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human SIGNOR-149277 0.425 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103 20219869 f apalma Once in the nucleus, NF-kB can induce the transcription of iNOS, TNF-alpha, and IL-1, which may then promote further NF-kB activation, as well as elevate the expression of other inflammatory mediators such as CCL2 and IL-6. SIGNOR-255355 0.576 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000007 14761950 t lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. SIGNOR-121709 0.378 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 20385093 t gcesareni A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution. SIGNOR-164785 0.89 BCL2 protein P10415 UNIPROT BECN1 protein Q14457 UNIPROT down-regulates binding 9606 17643073 t gcesareni In mammalian cells, the antiapoptotic protein, bcl-2, binds to beclin 1 during nonstarvation conditions and inhibits its autophagy function. SIGNOR-156941 0.734 PPM1K protein Q8N3J5 UNIPROT BCKDHA protein P12694 UNIPROT up-regulates activity dephosphorylation Ser337 TYRIGHHsTSDDSSA 10090 19411760 t BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates SIGNOR-248758 0.777 CAMK2B protein Q13554 UNIPROT CAMK2B protein Q13554 UNIPROT up-regulates activity phosphorylation Thr287 SMMHRQEtVECLKKF 2842767 t llicata Ca2+/calmodulin-dependent protein kinase II: identification of threonine-286 as the autophosphorylation site in the alpha subunit associated with the generation of Ca2+-independent activity. SIGNOR-250640 0.2 CSNK2A1 protein P68400 UNIPROT SERINC3 protein Q13530 UNIPROT up-regulates activity phosphorylation Ser380 ILGDTTTsGASDEED -1 30135209 t miannu The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro. SIGNOR-273631 0.2 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT down-regulates quantity by repression transcriptional regulation 16146838 f lperfetto Oncogenic mutations of Flt3 also result in the activation of aberrant signaling pathways, including strong activation of STAT5, induction of STAT target genes, and repression of myeloid transcription factors c/EBP-3 and Pu.1. SIGNOR-249634 0.616 GSK3B protein P49841 UNIPROT CCND1 protein P24385 UNIPROT down-regulates quantity by destabilization phosphorylation Thr286 EEVDLACtPTDVRDV 9606 phosphorylation:Ser9 SGRPRTTsFAESCKP 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245437 0.779 PHF7 protein Q9BWX1 UNIPROT SMARCD3 protein Q6STE5 UNIPROT form complex binding 9606 33941892 t miannu Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, it increases chromatin accessibility and transcription factor binding at these sites. Furthermore, PHF7 recruits cardiac transcription factors to activate a positive transcriptional autoregulatory circuit in reprogramming. PHF7 interacts with SMARCD3 to promote reprogramming. SIGNOR-269816 0.2 F2RL1 protein P55085 UNIPROT AREG protein P15514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254855 0.2 USP1 protein O94782 UNIPROT FANCI protein Q9NVI1 UNIPROT down-regulates activity deubiquitination SIGNOR-C302 18985065 t lperfetto Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2. SIGNOR-263272 0.659 mTORC1 complex SIGNOR-C3 SIGNOR EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser72 KSERYSSsGSPANSF 9606 BTO:0000093 35513296 t miannu Our phosphoproteomics analysis add to this body of knowledge as it indicates that mTORC1 modulates additional phosphorylation sites in eEF2K, such as Y69, S70, S72, and S74, which is consistent with our previous findings SIGNOR-277906 0.347 PCDH19 protein Q8TAB3 UNIPROT GABRA4 protein P48169 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C327,SIGNOR-C326,SIGNOR-C333 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267220 0.2 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser192 PRPDHTKsIYTRSVI -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250225 0.2 LYN protein P07948 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268209 0.701 meloxicam chemical CHEBI:6741 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition -1 9083488 t miannu Meloxicam (5),an NSAID in the enol−carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. This favorable therapeutic index has been confirmed in clinical trials. In subsequent studies we and others discovered that it possessed a selectivity profile for COX-2 superior to several other marketed NSAIDs.1 A comparison of 5 with piroxicam (6) revealed different inhibitory profiles for the two enzymes SIGNOR-258609 0.8 B4GALT1 protein P15291 UNIPROT UDP-D-galactose smallmolecule CHEBI:18307 ChEBI down-regulates quantity chemical modification 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268467 0.8 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser94 QISTIAEsEDSQESV 9606 9931297 t lperfetto Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement. SIGNOR-64250 0.316 TOMM5 protein Q8N4H5 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267675 0.627 Ast-487 chemical CID:11409972 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259693 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MCL1 protein Q07820 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 18676833 t inferred from 70% family members fstefani We then showed that erk could phosphorylate mcl-1 at two consensus residues, thr 92 and 163, which is required for the association of mcl-1 and pin1, resulting in stabilization of mcl-1. SIGNOR-270158 0.2 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 11823427 t lperfetto The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosine“SH2 domain interactions SIGNOR-236373 0.786 PRKD1 protein Q15139 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 22865920 t lperfetto When phosphorylated by camk/pkd, class iia hdacs bind 14-3-3 chaperone proteins, which facilitates their nuclear export, thereby relieving hdac-mediated transcriptional repression. SIGNOR-198662 0.526 OXTR protein P30559 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257266 0.541 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser345 RPASVDGsPVSPSTN -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251295 0.648 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT up-regulates activity phosphorylation Ser360 RKTQTSMsLGTTREK -1 24012422 t gianni MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation.[...]S345, S347, and T349 in the MLKL activation loop were phosphorylated by RIPK3 in in vitro kinase assays SIGNOR-266440 0.746 betrixaban chemical CHEBI:140421 ChEBI F10 protein P00742 UNIPROT down-regulates activity chemical inhibition -1 19297154 t Luana Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. SIGNOR-257817 0.8 MAPK6 protein Q16659 UNIPROT TDP2 protein O95551 UNIPROT up-regulates activity phosphorylation Ser60 EMERALNsYFEPPVE -1 26701725 t miannu In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition.  SIGNOR-277188 0.383 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9534 BTO:0001538 11163210 t miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  SIGNOR-272937 0.867 DYRK2 protein Q92630 UNIPROT PSMC4 protein P43686 UNIPROT down-regulates quantity by destabilization phosphorylation Thr25 LSVSRPQtGLSFLGP 26655835 t lperfetto Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. SIGNOR-275845 0.287 CHEK2 protein O96017 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171026 0.2 ITGA9 protein Q13797 UNIPROT A9/b1 integrin complex SIGNOR-C166 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253183 0.776 KRAS protein P01116 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k. SIGNOR-175207 0.706 dimethyloxalylglycine chemical CHEBI:102218 ChEBI EGLN1 protein Q9GZT9 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000018 28900510 t lperfetto We treated the A549 cells with the following EGLN/PHD inhibitors: dimethyloxalyglycine (DMOG), CoCl2, inhibitors of dioxygenases, and BAY 85-3494 (BAY), a specific inhibitor of EGLNs with highest potency against EGLN1. SIGNOR-261991 0.8 alpha-D-ribose 1-phosphate(2-) smallmolecule CHEBI:57720 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 17804405 t miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. SIGNOR-267074 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MED1 protein Q15648 UNIPROT up-regulates phosphorylation 9606 12356758 t inferred from 70% family members lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase SIGNOR-270199 0.2 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser463 PPISPASsDLSVAGS 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251246 0.403 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation -1 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258442 0.8 PHF12 protein Q96QT6 UNIPROT TLE2 protein Q04725 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266992 0.2 SPOP protein O43791 UNIPROT DAXX protein Q9UER7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0002181 16524876 t Gianni These results suggest that SPOP/Cul3-ubiquitin ligase plays an essential role in the control of Daxx level and, thus, in the regulation of Daxx-mediated cellular processes, including transcriptional regulation and apoptosis. SIGNOR-268858 0.492 TSSK4 protein Q6SA08 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 15964553 t gcesareni Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway. SIGNOR-138289 0.59 TWIST1 protein Q15672 UNIPROT FAP protein Q12884 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20646316 f miannu Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1. SIGNOR-255523 0.243 RAPH1 protein Q70E73 UNIPROT EVL protein Q9UI08 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268427 0.351 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser287 RQRKGTLsVNFVDLY -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274062 0.307 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates activity binding 9606 BTO:0000801 18551128 t lperfetto The GM-CSF receptor (CSF2R) is a heterodimer composed of a specific ligand-binding subunit (CSF2Ralpha) and a common signal-transduction subunit (CSF2Rbeta) SIGNOR-249501 0.854 SF3B2 protein Q13435 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268404 0.922 GSK3A protein P49840 UNIPROT PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation Ser280 FHCCQCTsVETVTEL 10116 BTO:0003324 30745182 t miannu Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). This modification ligand independently enhances transcription of a subset of PPARα targets, selectively stimulating FA uptake and storage, but not oxidation, thereby promoting lipid accumulation.  SIGNOR-277431 0.2 CD2AP protein Q9Y5K6 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 BTO:0000007;BTO:0001938 29175910 t lperfetto One such regulator is the adaptor protein CD2AP, which delivers capping proteins to the barbed ends of polymerizing F-actin. Capping growing filaments can promote the formation of actin branches by increasing the G-actin pool available to form branches SIGNOR-264769 0.7 MZF1 protein P28698 UNIPROT PRKCA protein P17252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26010542 t irozzo The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity. SIGNOR-256337 0.39 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser101 LESFKKQsFVLKEGV 9606 15225553 t lperfetto Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174. SIGNOR-126650 0.602 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser653 PSLSRHSsPHQSEDE -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. SIGNOR-250881 0.332 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192777 0.8 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20817722 t miannu In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding. SIGNOR-267983 0.664 RUNX2 protein Q13950 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast SIGNOR-107169 0.448 Sincalide smallmolecule CID:9833444 PUBCHEM CCKBR protein P32239 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257467 0.8 ULK1 protein O75385 UNIPROT AMPK complex SIGNOR-C15 SIGNOR down-regulates phosphorylation 9606 21460634 t lperfetto Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. SIGNOR-217484 0.477 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation 9606 29920310 t lperfetto It has been reported that the protein tyrosine phosphatase PTP1B could inactivate MET by direct dephosphorylation of Tyr 1234 and 1235 in its activation loop, and that this dephosphorylation takes place in peri-nuclear region of the cell [ xref ]. SIGNOR-277001 0.627 PIM1 protein P11309 UNIPROT HBP1 protein O60381 UNIPROT up-regulates activity phosphorylation Ser372 SAVYVLSsMARQRRA 9606 BTO:0002181 28348080 t miannu  Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. SIGNOR-277346 0.2 TUBA4A protein P68366 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000007 19185337 f miannu We show here that Elongator regulates corticogenesis because an acute disruption of its activity in dorsal progenitors results in radial migration delays and defective terminal branching of projection neurons that come with a reduction in α-tubulin acetylation. Importantly, this complex interacts with the microtubule cytoskeleton, where Elp3 may directly acetylate α-tubulin, a posttranslational modification known to regulate the intracellular trafficking that is critical for cell shape remodeling during migration and terminal branching. SIGNOR-269730 0.7 LPAR2 protein Q9HBW0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257056 0.616 MARCHF5 protein Q9NX47 UNIPROT FIS1 protein Q9Y3D6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 16874301 t Barakat MITOL associates with and ubiquitinates mitochondrial fission protein hFis1. (A) Ubiquitination of hFis1 by MITOL. Thus, MITOL may control the protein expression level of hFis1 through the ubiquitin‚Äìproteasome pathway. SIGNOR-274141 0.2 TOMM20 protein Q15388 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267678 0.697 MASP1 protein P48740 UNIPROT C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263435 0.597 ATG7 protein O95352 UNIPROT ATG12 protein O94817 UNIPROT up-regulates binding 9606 18704115 t gcesareni Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein. SIGNOR-180132 0.936 SOSTDC1 protein Q6X4U4 UNIPROT WNT2B protein Q93097 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242701 0.293 GRM7 protein Q14831 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264350 0.7 RXRB protein P28702 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site SIGNOR-79449 0.276 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT up-regulates activity phosphorylation Tyr281 EKKSLTIyAQVQKPG 9534 BTO:0000298 11806999 t All 3 tyrosines of CD150 (Tyr281, Tyr307, Tyr327) are phosphorylated by the src kinase Fyn. CD150 is unique among its homologues in the immunoglobulin superfamily in that it is able to bind SAP, a floating SH2 domain, in the absence of tyrosine phosphorylation. In this study, using a detailed mutagenesis mapping approach we have shown that SAP binding to CD150 is in fact bimodal. Prior to tyrosine phosphorylation, SAP binds the membrane-proximal motif surrounding Tyr281. Following tyrosine phosphorylation by tyrosine kinases such as Fyn, SAP binds additionally to the distal motif surrounding Tyr327. SIGNOR-251181 0.651 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser484 KRRKRMSsGTEECGE 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275767 0.278 ZEB1 protein P37275 UNIPROT FBP1 protein P09467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000762 30616754 t lperfetto Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells. SIGNOR-267596 0.2 E2F1 protein Q01094 UNIPROT RASGEF1B protein Q0VAM2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18396012 f miannu We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. SIGNOR-253851 0.2 EFNA1 protein P20827 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity SIGNOR-56962 0.807 p38 proteinfamily SIGNOR-PF16 SIGNOR TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK SIGNOR-264445 0.2 RAB8A protein P61006 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 9606 18694559 f miannu CEP290 cooperates with Rab8a to promote ciliogenesis and this function is antagonized by CP110 SIGNOR-252148 0.7 AKT1 protein P31749 UNIPROT DLX5 protein P56178 UNIPROT up-regulates phosphorylation 9606 22298955 t gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5. akt interacts with and phosphorylates dlx5. In addition, we provide evidences that akt kinase activity is important for akt to enhance the protein stability and transcriptional activity of dlx5. SIGNOR-195546 0.266 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. SIGNOR-236010 0.787 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr391 PFLNSGTyHSRDEST 9606 BTO:0002035 35723276 t miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  SIGNOR-275455 0.277 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9606 17158707 t lperfetto The JNK-mediated phosphorylation of both Ser63 and Ser73 within the transactivation domain of c-Jun (Table _(Table1)1) potentiates its transcriptional activity SIGNOR-36466 0.2 nimodipine chemical CHEBI:7575 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 t Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  SIGNOR-257765 0.8 TRIM27 protein P14373 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38. SIGNOR-102031 0.273 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu65 MEETCSYeEAREVFE -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263670 0.605 MTHFR protein P42898 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity chemical modification 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-268229 0.8 PRPF8 protein Q6P2Q9 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270641 0.775 panobinostat chemical CHEBI:85990 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257749 0.8 DEK protein P35659 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268823 0.437 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t gcesareni These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis. SIGNOR-252617 0.463 FZR1 protein Q9UM11 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization binding 9534 BTO:0004055 12023018 t miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. SIGNOR-272610 0.549 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr310 VPPLPKVtPTKELQQ 9606 BTO:0000142 16733250 t lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. SIGNOR-146910 0.402 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser183 CPHHERCsDSDGLAP 9606 22611192 t gcesareni We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma). SIGNOR-197598 0.713 CSNK2A1 protein P68400 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Ser102 NLNENQAsEEEDELG -1 2557337 t llicata Study of [Plphosphate release during manual Edman degradation confirmed that the phosphorylated residues in rat DARPP-32 were Ser45 and Ser102. | Phosphorylation by casein kinase II did not affect the potency of DARPP-32 as an inhibitor of protein phosphatase-1, which depended only on phosphorylation of Thr34 by cAMP-dependent protein kinase. However, phosphorylation of DARPP-32 by casein kinase II facilitated phosphorylation of Thr34 by cAMP-dependent protein kinase SIGNOR-250927 0.344 HRH3 protein Q9Y5N1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256689 0.421 LSM-1231 chemical CHEBI:91471 ChEBI NTRK2 protein Q16620 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258239 0.8 PRKACA protein P17612 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity phosphorylation YES 9606 12536214 t inferred from family member gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-267784 0.494 Hexocyclium chemical CHEBI:5707 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258398 0.8 NADPH(4-) smallmolecule CHEBI:57783 ChEBI FASN protein P49327 UNIPROT up-regulates activity binding 9606 34765544 t miannu We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. SIGNOR-267371 0.8 BTK protein Q06187 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr216 SSTSLAQyDSNSKKI 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. SIGNOR-98028 0.338 PTK2B protein Q14289 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Tyr657 FGLGSRAyPHFCAFA 9606 BTO:0000007 18483407 t gcesareni We found that fluid shear stress induces the association of enos with the proline-rich tyrosine kinase 2 (pyk2) in endothelial cells and that the enos immunoprecipitated from enos- and pyk2-overexpressing hek293 cells was tyrosine-phosphorylated on tyr657. SIGNOR-178648 0.313 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI up-regulates quantity precursor of 9606 16939420 t miannu PRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. SIGNOR-267080 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata Akt phosphorylates s554 in acap1 SIGNOR-141343 0.2 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 SIGNOR-C17 19709076 t lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. SIGNOR-187766 0.393 MAPK1 protein P28482 UNIPROT PDE4C protein Q08493 UNIPROT down-regulates phosphorylation Ser641 YQSKIPRsPSDLTNP 9606 11030732 t The effect has been demonstrated using Q08493-2 gcesareni The short-form pde4b2 isoenzyme was activated by erk2 phosphorylation. sub-family selective actions in the ability of erk2 map kinase to phosphorylate and regulate the activity of pde4 cyclic amp-specific phosphodiesterases SIGNOR-83187 0.258 NatA complex SIGNOR-C415 SIGNOR CHEK2 protein O96017 UNIPROT down-regulates activity acetylation 9606 BTO:0001109 21351257 t miannu The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer.  lack of acetylation by hNatA activated H2A.X and Chk2 in both HCT116 cell lines independent of TP53 status (Fig. 6). SIGNOR-267228 0.2 SB 505124 chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 14978253 t gcesareni Sb-505124 is a selective inhibitor of transforming growth factor-beta type i receptors alk4, alk5, and alk7. SIGNOR-122910 0.8 AURKB protein Q96GD4 UNIPROT NINL protein Q9Y2I6 UNIPROT up-regulates phosphorylation Ser448 QGYRERLsLLRSEVE 9606 20864540 t lperfetto Importantly, nlp is characterized as a novel substrate of aurora b and can be phosphorylated by aurora b. The specific phosphorylation sites are mapped at ser-185, ser-448, and ser-585. The phosphorylation at ser-448 and ser-585 is likely required for nlp association with aurora b and localization at midbody. Meanwhile, the phosphorylation at ser-185 is vital to nlp protein stability. Disruptions of these phosphorylation sites abolish cytokinesis and lead to chromosomal instability. SIGNOR-168049 0.254 ATR protein Q13535 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates phosphorylation Ser601 EMDLAHNsQSMHASS 9606 21242293 t lperfetto Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair SIGNOR-171290 0.421 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TSPYL2 protein Q9H2G4 UNIPROT up-regulates activity phosphorylation Thr340 GRLVSHStPIRWHRG 9606 BTO:0000567 11395479 t llicata We observed that a CDA1 mutant with the two consensus CDK phosphorylation sites abolished (S20A and T340A) disabled its capacity to inhibit cell growth, indicating that these sites are important for the function of this protein. Furthermore, we showed that these sites are phosphorylated by cyclin/CDKs in vitro, suggesting that these kinases may regulate CDA1 function in vivo.  SIGNOR-250753 0.342 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251462 0.2 LCK protein P06239 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 10090 BTO:0000782 8114715 t Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. . SIGNOR-251387 0.602 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser275 DNVRYGIsNIDTTIE 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275948 0.2 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser102 EEGISQEsSEEEQ -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. SIGNOR-250892 0.333 DCC protein P43146 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity binding 9606 15494734 t miannu Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling. SIGNOR-268371 0.712 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG -1 11955436 t β-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC) SIGNOR-260015 0.893 CALM1 protein P0DP23 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t lperfetto The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases SIGNOR-232178 0.755 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263791 0.8 FBXW7 protein Q969H0 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by destabilization ubiquitination 9606 15546612 t lperfetto Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-254310 0.626 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273142 0.426 STAT5A protein P42229 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251787 0.2 NUAK1 protein O60285 UNIPROT LATS1 protein O95835 UNIPROT down-regulates phosphorylation Ser464 NIPVRSNsFNNPLGN 9606 19927127 t lperfetto Moreover, we show that nuak1 phosphorylates lats1 at s464 and this has a role in controlling its stabilitycells that constitutively express nuak1 suffer gross aneuploidies and show diminished expression of the genomic stability regulator lats1 SIGNOR-161792 0.394 JUN protein P05412 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 f miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. SIGNOR-252225 0.2 Immune complexes stimulus SIGNOR-ST15 SIGNOR FCGR3A protein P08637 UNIPROT up-regulates activity 9606 BTO:0000801 17558411 f lperfetto After binding their antibody ligands, FcgRI and FcgRIII deliver activating signals through an association with the FcRg-chain (FcRg), a transmembrane adaptor protein with an immuno-receptor tyrosine-based activation motif in its cytoplasmic domain. SIGNOR-249523 0.7 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 t The effect has been demonstrated using Q01196-8 lperfetto Previous studies have shown that phosphorylation of aml1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of aml1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (cdks) cdk1 and cdk2. Furthermore, these residues can be phosphorylated in vitro by purified cdk1/cyclin b and cdk2/cyclin a. SIGNOR-217340 0.2 CSNK2B protein P67870 UNIPROT SORT1 protein Q99523 UNIPROT up-regulates quantity by stabilization phosphorylation Ser825 KSGYHDDsDEDLLE 10090 BTO:0003449 25805502 t miannu  Phosphorylation of Ser-825 is required for insulin to induce Sort1 in AML12 cells. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation.  SIGNOR-273636 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR KLC1 protein Q07866 UNIPROT down-regulates phosphorylation 9606 21385839 t inferred from 70% family members gcesareni Phosphorylation of kinesin light chain 1 at serine 460 modulates binding and trafficking of calsyntenin-1mutation of klc1ser460 to an alanine residue, to preclude phosphorylation, increased the binding of calsyntenin-1, whereas mutation to an aspartate residueklc1ser460 is a predicted mitogen-activated protein kinase (mapk) target site, and we show that extracellular-signal-regulated kinase (erk) phosphorylates this residue in vitro. SIGNOR-270072 0.2 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 BTO:0000782 15623513 t lperfetto Protein kinase d1 (pkd1) was activated after tcr engagement, interacted with hdac7, and phosphorylated three serines (ser155, ser318, and ser448) at its n terminus, leading to its export from the nucleus. SIGNOR-132902 0.487 MAP3K6 protein O95382 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Thr180 RHTDDEMtGYVATRW 9534 8622669 t Manara These data indicate that MKK6 phosphorylates p38 MAP kinase on Thr-180 and Tyr-182, the sites of phosphorylation that activate p38 MAP kinase SIGNOR-260915 0.2 WNT7A protein O00755 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131900 0.587 STK11 protein Q15831 UNIPROT SIK3 protein Q9Y2K2 UNIPROT up-regulates phosphorylation Thr221 TPGQLLKtWCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122835 0.475 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2E1 protein P51965 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271325 0.714 ITGB1 protein P05556 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253176 0.805 PRKCQ protein Q04759 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates activity phosphorylation Ser591 DKEKSKGsLKRK 9606 BTO:0000914 35258455 t miannu SHP-1 phosphorylation is mediated through PKC-θ. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 'folded' state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in vivo. SIGNOR-277590 0.2 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. SIGNOR-248486 0.311 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser429 PQRERKSsSSSEDRN 9606 BTO:0000007 10869359 t Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo SIGNOR-251472 0.465 NLK protein Q9UBE8 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates phosphorylation Thr212 TYSNEHFtPGNPPPH 9606 12556497 t llicata Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk. SIGNOR-97873 0.767 PTEN protein P60484 UNIPROT ABI1 protein Q8IZP0 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr213 PPTVPNDyMTSPARL 9606 32673396 t lperfetto After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway. SIGNOR-276948 0.242 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RAD52 protein P43351 UNIPROT up-regulates activity phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 23836560 t Manara Have found that BCR-ABL1 interacts with the C-terminal portion of RAD52, resulting in tyrosine phosphorylation of Y104 located in RAD52 DNA II and enhanced nuclear foci formation SIGNOR-262531 0.2 NatB complex SIGNOR-C416 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. SIGNOR-267232 0.7 NEFL protein P07196 UNIPROT Neurofilament bundle assembly phenotype SIGNOR-PH72 SIGNOR up-regulates 9606 8376466 f miannu Neurofilaments (NFs), composed of three distinct subunits NF-L, NF-M, and NF-H, are neuron-specific intermediate filaments present in most mature neurons. SIGNOR-252392 0.7 TFAP2A protein P05549 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 9480831 t These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells. SIGNOR-254048 0.27 PPP1CC protein P36873 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252605 0.388 ROCK1 protein Q13464 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Thr480 TKEDGHRtSTSAVPN 9606 BTO:0000671 10209029 t lperfetto Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480 SIGNOR-66996 0.381 WNT8B protein Q93098 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132024 0.615 SBF1 protein O95248 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 10090 20937701 f miannu Reduced sciatic nerve axons and normal myelination in the absence of Mtmr5. However, Mtmr5−/− mice had significantly fewer total myelinated axons in sciatic nerves than wild-type controls (Fig. 5G). SIGNOR-269812 0.7 KRAS protein P01116 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 f miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 SIGNOR-267361 0.432 MYCT1 protein Q8N699 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000670;BTO:0000738 30283340 f miannu Overexpression of MYCT1 Inhibits Proliferation and Induces Apoptosis in Human Acute Myeloid Leukemia HL-60 and KG-1a Cells in vitro and in vivo SIGNOR-261729 0.7 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates activity dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 t The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels SIGNOR-248700 0.279 CDK7 protein P50613 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 t lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269319 0.958 TBXA2R protein P21731 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256744 0.251 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser394 TRQTPVDsPDDSTLS 9606 9271440 t gcesareni Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1. SIGNOR-50603 0.388 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. SIGNOR-267967 0.893 JAK2 protein O60674 UNIPROT PRMT5 protein O14744 UNIPROT down-regulates phosphorylation Tyr297 NRPPPNAyELFAKGY 9606 21316606 t llicata Oncogenic jak2 kinases phosphorylate prmt5 in_vivo phosphorylation of prmt5 by jak2v617f greatly impairs its methyltransferase activity SIGNOR-171994 0.685 STK16 protein O75716 UNIPROT STK16 protein O75716 UNIPROT unknown phosphorylation Tyr198 AQRCTISyRAPELFS -1 18184589 t Manara Indeed, our kinetic analysis of MPSK1 autophosphorylation showed that autophosphorylation is a slow process and that two of the three identified sites are largely buried in unphosphorylated MPSK1. However, two autophosphorylation sites are located in the P + 1 loop and phosphorylation at these locations might affect substrate recognition. SIGNOR-260805 0.2 oxymetazoline chemical CHEBI:7862 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 9913 BTO:0000142 9632357 t miannu Benzylimidazolines may represent a class of 5-HT1D ligands that has yet to be exploited. On the basis of a previous report that the 2-(substituted-benzyl)imidazoline alpha-adrenergic agonist oxymetazoline (8) binds with high affinity at calf brain 5-HT1D receptors, we explored the structure-affinity relationships of a series of related derivatives. SIGNOR-258928 0.8 LPAR1 protein Q92633 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 20331961 t gcesareni The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits) SIGNOR-164682 0.532 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr66 LHQEDNDyINASLIK -1 11506178 t Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. SIGNOR-248423 0.2 PTPN1 protein P18031 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 16291744 t gcesareni We show that coexpression of wild-type alpha-actinin and ptp 1b causes dephosphorylation at tyr-397 in fak. SIGNOR-141637 0.351 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171042 0.733 NELFE protein P18615 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271400 0.902 PI3K complex SIGNOR-C156 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 18721898 f lperfetto Phosphoinositide 3-kinase (pi3k)-dependent activation of the rheb-mtor pathway triggers the simultaneous local synthesis of tc10 and par3. SIGNOR-252705 0.569 PRKACA protein P17612 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates phosphorylation 9606 10464286 t gcesareni Identification of a novel phosphorylation site on histone h3 coupled with mitotic chromosome condensation. SIGNOR-265344 0.2 MMP2 protein P08253 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates cleavage 9606 10652271 t gcesareni We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-beta (tgf-beta), which constitutes a novel mechanism of tgf-beta activation SIGNOR-74384 0.566 EIF3A protein Q14152 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266400 0.919 PASK protein Q96RG2 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation 9606 BTO:0000567 17595531 t gcesareni Kinase assays, mass spectrometry and site-directed mutagenesis revealed PASKIN auto-phosphorylation as well as eEF1A1 target phosphorylation mainly but not exclusively at Thr432. SIGNOR-245862 0.378 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 15356634 t gcesareni Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128735 0.537 PPP2CA protein P67775 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 14712210 t Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage| Furthermore, in vitro phosphatase assays show that PP2A dephosphorylates p53 at S37. SIGNOR-248619 0.58 ADGRG1 protein Q9Y653 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0000142 31515243 t lperfetto Binding of collagen III to ADGRG1 provides a canonical example of adhesion GPCR interactions with ECM proteins (Luo et al., 2011). Identified by an in vitro biotinylation/proteomics approach, extracellular interactions with collagen III were subsequently proven capable of activating ADGRG1-mediated signaling via Gα12/13 followed by RhoA activation to regulate corticogenesis SIGNOR-272345 0.2 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser242 PSAPPDRsKGAEPSQ 9606 BTO:0000938 BTO:0000142 12871946 t gcesareni Two serine residues in rim1 (ser-241 and ser-287) and one serine residue in rim2 (ser-335) were required for 14-3-3 binding. Incubation with ca2+/calmodulin-dependent protein kinase ii greatly stimulated the interaction of recombinant n-terminal rim but not the s241/287a mutant with 14-3-3, SIGNOR-103886 0.351 paliperidone chemical CHEBI:82978 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258564 0.8 pravastatin chemical CHEBI:63618 ChEBI HMGCR protein P04035 UNIPROT down-regulates activity chemical inhibition -1 1597859 t miannu A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). SIGNOR-258350 0.8 palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 ChEBI up-regulates quantity precursor of 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267123 0.8 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr659 VADERVDyVVVDQQK 9606 10068651 t lperfetto Tyrosine phosphorylation of gab2 was induced by stimulation through gp130, il-2r, il-3r, tpor, scfr, and tcr. Gab1 and gab2 were shown to be substrates for shp-2 in vitro. SIGNOR-236254 0.952 PPP1CA protein P62136 UNIPROT PREX1 protein Q8TCU6 UNIPROT up-regulates activity dephosphorylation Ser1165 DSGHDTMsYRDSYSE 9606 22242915 t lperfetto MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation. SIGNOR-277023 0.2 MEF2A protein Q02078 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54086 0.737 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates activity phosphorylation Thr64 ENLRRATtDLGRSLG -1 10467162 t lperfetto Autophosphorylation of wild-type PKN increased the protein kinase activity, however, substitution of Thr64, Ser374, or Thr531 in the regulatory region of PKN with alanine, abolished this effect. SIGNOR-249019 0.2 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 10558990 t lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-180910 0.401 DLG1 protein Q12959 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity binding 9606 BTO:0000782 17187070 t Barakat Dlgh1 immunoprecipitates were specifically enriched for activated p38 phosphorylated at Thr180 and Tyr182; phosphorylated p38 was not detected in the unbound fraction from stimulated samples SIGNOR-274143 0.629 SWI/SNF complex complex SIGNOR-C92 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16452181 f irozzo C-myc is a direct target of SWI/SNF complex–dependent promoter repression. These results indicate that repression of c-myc is indeed dependent on the activity of SWI/SNF–related complexes and specifically on complexes that contain ARID1A. SIGNOR-256292 0.406 NEK11 protein Q8NG66 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser82 GSSESTDsGFCLDSP 9606 19734889 t lperfetto Nek11 regulates cdc25a degradation and the ir-induced g2/m checkpointincubation of wild-type cdc25a with nek11 led to a marked increase in phosphorylation of ser 82 and 88 as detected with the phosphospecific antibody recognizing these sites SIGNOR-187867 0.425 LAMC1 protein P11047 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253225 0.536 MAPK1 protein P28482 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser14 MGAELPSsPLAIEYV 9606 BTO:0000567 11416124 t lperfetto These residues are phosphorylated by erk2 but not by p38, jnk, and erk5 in vitro. However, the contribution of the mek/erk pathway to mafa phosphorylation in vivo appears to be moderate, implicating another kinase. The integrity of serine 14 and serine 65 residues is required for transcriptional activity, since their mutation into alanine severely impairs mafa capacity to activate transcription. SIGNOR-108560 0.338 TNK2 protein Q07912 UNIPROT KDM3A protein Q9Y4C1 UNIPROT down-regulates activity phosphorylation Tyr1114 ITPEDRKyGTTNLHL 9606 BTO:0000093 25148682 t miannu We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen. SIGNOR-276842 0.374 CEBPA protein P49715 UNIPROT ELANE protein P08246 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004408 19620402 f miannu The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression. SIGNOR-253769 0.311 CSNK2A1 protein P68400 UNIPROT DEK protein P35659 UNIPROT up-regulates phosphorylation Ser32 MPGPREEsEEEEDED 9606 15199154 t amattioni Dek is phosphorylated by the protein kinase ck2 in vitro and in vivo on ser32 SIGNOR-125912 0.353 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272710 0.763 cyclosporin A chemical CHEBI:4031 ChEBI PP2B proteinfamily SIGNOR-PF18 SIGNOR down-regulates chemical inhibition 9606 15276472 t inferred from 70% of family members gcesareni Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins. SIGNOR-269889 0.8 FOXO3 protein O43524 UNIPROT FASLG protein P48023 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10102273 f gcesareni Within the nucleus, fkhrl1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the fas ligand gene. SIGNOR-66035 0.702 SP1 protein P08047 UNIPROT ATP2C1 protein P98194 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 15955096 f miannu when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. SIGNOR-255194 0.2 SMARCB1 protein Q12824 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270697 0.853 PKC proteinfamily SIGNOR-PF53 SIGNOR KLHL3 protein Q9UH77 UNIPROT up-regulates quantity by stabilization phosphorylation Ser433 PMNTRRSsVGVGVVE 9534 BTO:0000298 25313067 t done miannu We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. SIGNOR-273780 0.2 SCN4A protein P35499 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253405 0.8 CDK1 protein P06493 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser105 TGAGAAGsPAQQHAH 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276520 0.26 SIRT2 protein Q8IXJ6 UNIPROT PGAM proteinfamily SIGNOR-PF78 SIGNOR up-regulates activity deacetylation 9606 24786789 t miannu Here we report that PGAM is acetylated at lysine 100 (K100), an active site residue that is invariably conserved from bacteria, to yeast, plant, and mammals. K100 acetylation is detected in fly, mouse, and human cells and in multiple tissues and decreases PGAM2 activity. The cytosolic protein deacetylase sirtuin 2 (SIRT2) deacetylates and activates PGAM2. SIGNOR-266519 0.282 ABL1 protein P00519 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity phosphorylation Tyr78 SSISTPHyEDIPFTR 10090 25368164 t We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ. SIGNOR-255912 0.344 DLGAP3 protein O95886 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264211 0.752 NR0B2 protein Q15466 UNIPROT NR1H2 protein P55055 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 12198243 f gcesareni Here we show that shp can interact with the liver x receptors lxr? (nr1h3) and lxr? (nr1h2), as demonstrated by glutathione-s-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, shp inhibits the expression of an artificial reporter driven by an lxr-response element and represses the transcriptional activation by lxr of the human atp-binding cassette transporter 1 (abca1) promoter. T SIGNOR-91901 0.467 RPS6 protein P62753 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 10090 23318442 f Luana Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program SIGNOR-264619 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Ser70 RDPVARTsPLQTPAA 9534 BTO:0004055 10677502 t lperfetto Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70. SIGNOR-244501 0.2 FBLIM1 protein Q8WUP2 UNIPROT FLNA protein P21333 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266105 0.885 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys70 GKAVRGAkGHHHPHP 9606 17098745 t gcesareni Sirt1 reversed acetyl-transferase (p300)-mediated acetylation of two lysine residues (lys-64 and -70) on smad7. sirt1-mediated deacetylation of smad7 enhanced smad ubiquitination regulatory factor 1 (smurf1)-mediated ubiquitin proteasome degradation, which contributed to the low expression of smad7 in sirt1-overexpressing mesangial cells. SIGNOR-150599 0.448 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser119 SFSSTSVsSLEAEAY 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129418 0.568 KSR2 protein Q6VAB6 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273875 0.541 FAM13A protein O94988 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260502 0.419 FAM83G protein A6ND36 UNIPROT CD2AP protein Q9Y5K6 UNIPROT up-regulates activity binding 9606 BTO:0001938 29175910 t lperfetto PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration. SIGNOR-264768 0.351 KLF1 protein Q13351 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002731 9707565 f Regulation miannu EKLF is an acetylated transcription factor, and that it interacts in vivo with CBP, p300, and P/CAF. However, its interactions with these histone acetyltransferases are not equivalent, as CBP and p300, but not P/CAF, utilize EKLF as a substrate for in vitro acetylation within its trans-activation region. The functional effects of these interactions are that CBP and p300, but not P/CAF, enhance EKLF's transcriptional activation of the beta-globin promoter in erythroid cells. SIGNOR-251790 0.411 EPHA2 protein P29317 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates 9606 BTO:0000782 7982920 f gcesareni In keeping with the above observations, activation of eck by its ligand, b61, increased phosphatidylinositol 3-kinase activity SIGNOR-35418 0.367 GSK3B protein P49841 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization phosphorylation Ser17 MVMSLRVsELQVLLG 10090 BTO:0002268 26157031 t miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.  SIGNOR-276923 0.336 HIF3A protein Q9Y2N7 UNIPROT EPAS1 protein Q99814 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000972 21479871 t Luana None of the long HIF-3α variants was capable of efficient induction of an HRE reporter in overexpression experiments, but instead inhibited the transcriptional activation of the reporter by HIF-1 and HIF-2.  SIGNOR-261616 0.517 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248312 0.484 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser253 APRRRAVsMDNSNKY 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-236671 0.746 IKBKB protein O14920 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates phosphorylation Ser8 MEPAAGSsMEPSADW 9606 20152798 t lperfetto Ikkbeta specifically binds to p16 and phosphorylates ser8 of p16 phosphorylation at ser8 of p16 brings about a significant loss of its cyclin-dependent kinase (cdk) 4-inhibitory activity SIGNOR-163801 0.401 SREBF1 protein P36956 UNIPROT VLDL_assembly phenotype SIGNOR-PH62 SIGNOR up-regulates 9606 11111091 f miannu SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100. SREBP1 induced the expression of the genes regulating the synthesis of all VLDL lipids SIGNOR-252112 0.7 PRKACA protein P17612 UNIPROT HSPB6 protein O14558 UNIPROT down-regulates phosphorylation Ser16 PSWLRRAsAPLPGLS 9606 10196226 t llicata Hosphorylation of hsp20 at ser16 is not only associated with cyclic nucleotide-dependent vasorelaxation but also inhibits agonist-induced contractile responses. SIGNOR-66493 0.2 RNF123 protein Q5XPI4 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25860612 t miannu  Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. SIGNOR-272221 0.403 LSM-20934 chemical CHEBI:109533 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258727 0.8 NDUFA7 protein O95182 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262158 0.82 ELF4 protein Q99607 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19380490 f miannu We found that elf4/mef activates mdm2 expression SIGNOR-185490 0.388 AKT1 protein P31749 UNIPROT ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. SIGNOR-252512 0.373 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 18650425 t gcesareni Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun. SIGNOR-179551 0.375 PGAM2 protein P15259 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI down-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266512 0.8 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC1R protein Q01726 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268701 0.2 PFKFB4 protein Q16877 UNIPROT beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI down-regulates quantity chemical modification -1 30553771 t PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species SIGNOR-267272 0.8 Apoptosome complex SIGNOR-C230 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-256471 0.735 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16943424 t lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. SIGNOR-149292 0.73 ZMIZ1 protein Q9ULJ6 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 10090 BTO:0001825 26522984 f miannu Our data suggest that Zmiz1 and Notch1 cooperatively recruit each other to chromatin through direct interaction via the TPR resulting in a slight increase in activating histone marks and decrease of repressive histone marks. SIGNOR-263938 0.7 KIT protein P10721 UNIPROT STAP1 protein Q9ULZ2 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10679268 t miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. SIGNOR-261820 0.493 BBOX1 protein O75936 UNIPROT 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI down-regulates quantity chemical modification 9606 11802770 t miannu In the last step, butyrobetaine is hydroxylated on the 3-position by γ-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. SIGNOR-269697 0.8 PTEN protein P60484 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260051 0.2 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR TRIM71 protein Q2Q1W2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269247 0.288 WNT1 protein P04628 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni Distinctly, wnt1 signals through fzd receptors 1 and 6 in the epaxial domain of the somite, to regulate myf5 expression via the canonical bcatenin pathway. SIGNOR-198846 0.685 ASXL1 protein Q8IXJ9 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 29967380 t miannu Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. SIGNOR-260119 0.304 DOK4 protein Q8TEW6 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 t gcesareni Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells. SIGNOR-101002 0.425 prostaglandin E2(1-) smallmolecule CHEBI:606564 ChEBI prostaglandin H2(1-) smallmolecule CHEBI:57405 ChEBI up-regulates quantity precursor of -1 10922363 t Luana Importantly, this enzyme is capable of converting COX-1-, but not COX-2-, derived PGH2 to PGE2 efficiently. SIGNOR-269767 0.8 TNF protein P01375 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity 9606 8530143 f andrea cerquone perpetuini Data from our laboratory demonstrate that the TNF signal transduction pathway-mediating NF-kappa B activation involves two phospholipases, a phosphatidylcholine-specific phospholipase C (PC-PLC) and an endosomal acidic sphingomyelinase (aSMase). The aSMase activation by TNF is secondary to the generation of 1,2-diacylglycerol (DAG) produced by a TNF-responsive PC-PLC. SMase and its product ceramide induce degradation of the NF-kappa B inhibitor I kappa B as well as NF-kappa B activation. SIGNOR-255689 0.671 bethanechol chemical CHEBI:3084 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258625 0.8 PLK1 protein P53350 UNIPROT TOPORS protein Q9NS56 UNIPROT up-regulates activity phosphorylation Ser718 KDRDGYEsSYRRRTL 9606 19473992 t lperfetto Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. SIGNOR-185838 0.452 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser491 GSDSDLDsDDEFVPY 9606 20864032 t lperfetto Here we report that tel2 and tti1 are targeted for degradation within mtorc1 by the scffbxo9 ubiquitin ligase to adjust mtor signalling to growth factor availability. This process is primed by ck2, which translocates to the cytoplasm to mediate mtorc1-specific phosphorylation of tel2/tti1. Here, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2) SIGNOR-168040 0.2 HTR2C protein P28335 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256877 0.282 GTP(4-) chemical CHEBI:37565 ChEBI 2'-3'-cGAMP(2-) smallmolecule CHEBI:143093 ChEBI up-regulates quantity precursor of 23258413 t lperfetto Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. SIGNOR-276595 0.8 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 20708156 t gcesareni Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination SIGNOR-167517 0.349 OCRL protein Q01968 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate smallmolecule CHEBI:18348 ChEBI down-regulates quantity chemical modification 9606 33722976 t miannu We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis. These observations raised the possibility that PtdIns(4,5)P2 depletion is in fact required for the completion of macropinocytosis or to prevent macropinosome back-fusion with the plasmalemma. SIGNOR-277773 0.8 PRKCG protein P05129 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. SIGNOR-249060 0.2 LEPR protein P48357 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity 27154742 f lperfetto Leptin binding inhibits the neuropeptide Y/agouti-related protein (NPY/AgRP) production and stimulates pro-opiomelanocortin (POMC) production SIGNOR-253074 0.474 SPI1 protein P17947 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 8079170 f Mice carrying a mutation in the PU.1 locus were generated by gene targeting. Homozygous mutant embryos died at a late gestational stage. [...]An invariant consequence of the mutation was a multilineage defect in the generation of progenitors for B and T lymphocytes, monocytes, and granulocytes. Thus, the developmental programs of lymphoid and myeloid lineages require a common genetic function likely acting at the level of a multipotential progenitor. SIGNOR-259954 0.7 JAK2 protein O60674 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Tyr158 Y-->S 9606 BTO:0000938 32599005 t lperfetto JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation|Patch-clamp electrophysiology revealed that through Y158, JAK2 controls FGF14-dependent modulation of Nav1.6 channels. In hippocampal CA1 pyramidal neurons, the JAK2 inhibitor Fedratinib reduced firing by a mechanism that is dependent upon expression of FGF14. SIGNOR-275747 0.2 POU1F1 protein P28069 UNIPROT GH1 protein P01241 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15998782 f miannu Such findings are consistent with the existence, in humans, of an LHX4-driven pathway leading to the expression of GH through transcriptional activation of POU1F1. SIGNOR-254559 0.363 ATM protein Q13315 UNIPROT NHEJ1 protein Q9H9Q4 UNIPROT unknown phosphorylation Ser251 ASLQGIDsQCVNQPE 9606 18644470 t lperfetto Here, we have identified two major in vitro dna-pk phosphorylation sites in the c-terminal region of xlf, serines 245 and 251. We show that these represent the major phosphorylation sites in xlf in vivo and that serine 245 is phosphorylated in vivo by dna-pk, while serine 251 is phosphorylated by ataxia-telangiectasia mutated (atm). SIGNOR-179528 0.581 CDK6 protein Q00534 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15809340 t gcesareni Phosphorylated by cdk6 and cdk4, and subsequently by cdk2 at ser-567 in g1, thereby releasing e2f1 which is then able to activate cell growth. Here we show that although these cdks phosphorylate multiple residues in prb, they do so with different residue selectivities in vitro;thr821 and thr826 are preferentially phosphorylated by cdk6 and cdk4, respectively. SIGNOR-135189 0.764 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 t lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-74300 0.369 PPARG protein P37231 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 17681149 f lperfetto Transcriptional repression of inflammatory response genes occurs by negative interference of PPARg with the nuclear factor kB (NF-kB), signal transducer and activator of transcription (STAT), and activating protein 1 (AP-1) signaling pathways SIGNOR-249556 0.382 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT down-regulates relocalization 9606 23151663 t gcesareni This is counteracted by respondin 1, which induces znrf3 internalization SIGNOR-199629 0.799 USP2 protein O75604 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity deubiquitination Lys502 LSQQEGIkM -1 29490279 t miannu Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. SIGNOR-273605 0.2 UCHL5 protein Q9Y5K5 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270852 0.604 IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR STAT1 protein P42224 UNIPROT up-regulates activity binding 9606 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249494 0.67 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL6 protein P41182 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0000785 9649500 t inferred from 70% family members gcesareni Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway. SIGNOR-270011 0.2 MAPK3 protein P27361 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr117 DFPKKPLtPYFRFFM 9606 11741541 t lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-112813 0.568 MMP10 protein P09238 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272378 0.7 CSNK2A1 protein P68400 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser513 GEDEESEsD -1 9045708 t llicata Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine. The protein kinase inhibitor CKI-7 and unlabeled GTP both block in vitro phosphorylation by cell homogenates, indicating a role for CKII and possibly CKI in vivo. Both kinases phosphorylate the VMAT2 fusion protein to a much greater extent than a similar fusion protein containing the carboxyl terminus of VMAT1, consistent with differential phosphorylation of the two transporters observed in intact cells.  SIGNOR-250952 0.349 PTEN protein P60484 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11494141 f miannu Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). SIGNOR-260052 0.2 CSNK2B protein P67870 UNIPROT CTDP1 protein Q9Y5B0 UNIPROT down-regulates activity phosphorylation Ser740 TKAQRENsPAAFPDR 9606 BTO:0000567 12591939 t llicata We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified SIGNOR-251064 0.33 HLX protein Q14774 UNIPROT CCNB1 protein P14635 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 t Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261619 0.2 RAD23B protein P54727 UNIPROT RPA3 protein P35244 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275700 0.51 ATF2 protein P15336 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16149046 f miannu Constitutively active mutants of activating transcription factor 2 (ATF2) and c-Jun additionally stimulated GTP cyclohydrolase I promoter activity, but to a lesser extent than the constitutively active CREB mutant. Enzymatic reactions that require tetrahydrobiopterin as cofactor are therefore indirectly controlled by signaling cascades involving the signal-responsive transcription factors CREB, c-Jun, and ATF2. SIGNOR-252226 0.2 NOG protein Q13253 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR down-regulates binding 9606 BTO:0000142 12478285 t Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmpby blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors SIGNOR-217541 0.59 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Ser397 TYHSRDEsTDSGLSM 9606 BTO:0000007 20048001 t lperfetto We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition SIGNOR-218034 0.837 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 17151142 f [...] TNF-alpha is critical for p38 activation during the early stages of myoblast differentiation SIGNOR-253600 0.379 RPSA protein P08865 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262414 0.842 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser636 SGDYMPMsPKSVSAP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulatesinsulin. SIGNOR-127912 0.784 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 BTO:0000782 BTO:0001253 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. SIGNOR-252998 0.676 HIPK2 protein Q9H2X6 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser8 MEPAPARsPRPQQDP 9606 19015637 t llicata In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death. SIGNOR-182432 0.445 MYOG protein P15173 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000887 8288123 f lperfetto The myogenic regulators myod, myogenin, myf5, and mrf4 share -80% amino acid identity within a basic helix-loop--helix (bhlh) motif that mediates dimerization and dna binding. / myogenic bhlh proteins form heterodimers with ubiquitous bhlh proteins, known as e proteins, and activate the transcription of muscle-specific genes by binding to the e-box consensus sequence (canntg) in muscle gene promoters and enancers. SIGNOR-37461 0.7 DYRK1A protein Q13627 UNIPROT SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr434 PARKLTAtPTPLGGM 9606 BTO:0000007 16512921 t llicata The present data show that the splicing factor sf3b1 is a substrate of the protein kinase dyrk1a and suggest that dyrk1a may be involved in the regulation of pre mrna-splicing. by mass spectrometry and mutational analysis of sf3b1, thr434 was identified as the major phosphorylation site for dyrk1a. SIGNOR-144975 0.51 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Thr41 GIHSGATtTAPSLSG 9606 11955436 t lperfetto Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-227905 0.893 ERCC2 protein P18074 UNIPROT ERCC3 protein P19447 UNIPROT up-regulates binding 9606 10024882 t miannu Xpd helps xpb in promoter opening and as such participates in the transcription reaction. SIGNOR-64672 0.954 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120092 0.314 CCL5 protein P13501 UNIPROT CCR5 protein P51681 UNIPROT up-regulates activity binding 9606 BTO:0000584 38339310 t miannu CCL5, also known RANTES (regulated on activation, normal T cell expressed and secreted), is a potent chemoattractant for a variety of leukocytes, including T cells, mono- cytes, NK cells, and basophils, signaling via the CCR1, CCR3, and CCR5 cell surface receptors [59]. Among these receptors, CCL5 has the highest affinity for CCR5. SIGNOR-277726 0.937 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248653 0.729 ROCK2 protein O75116 UNIPROT DPYSL2 protein Q16555 UNIPROT up-regulates phosphorylation Thr555 DNIPRRTtQRIVAPP 9606 BTO:0000938 10818093 t lperfetto Rho-kinase phosphorylated crmp-2 at thr-555 in vitro.we demonstrated that crmp-2 is phosphorylated by rho-kinase in drg neurons during lpa-induced growth cone collapse. SIGNOR-77543 0.389 BRCA1 protein P38398 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR up-regulates activity binding 10426999 t lperfetto BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50.| These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex. SIGNOR-251501 0.771 RNF13 protein O43567 UNIPROT SNAPIN protein O95295 UNIPROT up-regulates activity polyubiquitination 9534 BTO:0000298 22890573 t miannu  RNF13 directly interacted with snapin, a SNAP-25-interacting protein. Interestingly, snapin was ubiquitinated by RNF13 via the lysine-29 conjugated polyubiquitin chain, which in turn promoted the association of snapin with SNAP-25. Consistently, we found an attenuated interaction between snapin and SNAP-25 in the RNF13-null mice. Therefore, these results suggest that RNF13 is involved in the regulation of the SNARE complex, which thereby controls synaptic function. SIGNOR-272044 0.531 MBD2 protein Q9UBB5 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263835 0.728 IYD protein Q6PHW0 UNIPROT 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI down-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267036 0.8 KDM3A protein Q9Y4C1 UNIPROT H3-5 protein Q6NXT2 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276847 0.2 GATAD2B protein Q8WXI9 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263845 0.769 GRSF1 protein Q12849 UNIPROT FASTKD5 protein Q7L8L6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25683715 f miannu DHX30 siRNA treatment resulted in an increase of FASTKD2 levels, and FASTKD5 was increased in cells treated with siRNA for GRSF1. SIGNOR-261224 0.375 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269022 0.7 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser466 DEDDGEFsDDSGADQ 9606 BTO:0000007 11500362 t llicata The fifth site, which lies outside the catalytic domain of eIF2Bepsilon, can be phosphorylated by casein kinase 1. All five sites are phosphorylated in the eIF2B complex in vivo. | A phosphopeptide corresponding to this region was identified in Asp‐N digests of eIF2Bϵ phosphorylated in vitro by CK1, suggesting that Ser461 or Ser464 may be phosphorylated by this kinase in vivo. SIGNOR-250787 0.326 ARID1B protein Q8NFD5 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271437 0.339 SCF-FBW7 complex SIGNOR-C135 SIGNOR BLM protein P54132 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276912 0.277 BRSK1 protein Q8TDC3 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567 15150265 t lperfetto Overexpression of hssad1 resulted in an increased phosphorylation of cdc25c on ser-216 in vivo. Phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-107408 0.49 MAPK8 protein P45983 UNIPROT SARM1 protein Q6SZW1 UNIPROT down-regulates activity phosphorylation Ser548 AAREMLHsPLPCTGG 30333228 t lperfetto C-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD+ cleavage activity to inhibit mitochondrial respiration|Here, we report that NAD+ cleavage activity of SARM1 is regulated by its own phosphorylation at serine 548. The phosphorylation of SARM1 was mediated by c-jun N-terminal kinase (JNK) under oxidative stress conditions, resulting in inhibition of mitochondrial respiration concomitant with enhanced activity of NAD+ cleavage. Nonphosphorylatable mutation of Ser-548 or treatment with a JNK inhibitor decreased SARM1 activity. SIGNOR-275554 0.43 WASHC4 protein Q2M389 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR form complex binding 23721880 t lperfetto The WASH complex is composed of five proteins: KIAA1033 (also known as SWIP), Strumpellin, FAM21, WASH1 and CCDC53. SIGNOR-261018 0.2 SSTR1 protein P30872 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256679 0.511 PSMD4 protein P55036 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263347 0.901 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Ser6 sKKRKFVA 9606 19059439 t llicata Here we show that pkcdelta phosphorylates rps3 resulting in its mobilization in the nucleus to repair damaged dna. pkc? Kinase assay then indicated that at least two residues, serine 6 and threonine 221, are phosphorylated by pkc? SIGNOR-182619 0.2 TBX3 protein O15119 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249602 0.307 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT up-regulates activity phosphorylation Ser204 KNSRVTFsEDDEIIN -1 9407077 t llicata Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2. SIGNOR-251023 0.48 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA-PK complex SIGNOR-C107 SIGNOR up-regulates activity binding -1 9442054 t miannu These proteins are NF90 and NF45, which are the 90- and 45-kDa subunits of a protein known to bind specifically to the antigen receptor response element of the interleukin 2 promoter, and the alpha, beta, and gamma subunits of eukaryotic translation initiation factor eIF-2. We also show that NF90, NF45, and eIF-2 beta are substrates for DNA-PK in vitro. In addition, recombinant NF90 promotes formation of a complex between DNA-PKcs, Ku, and DNA, and antibodies to recombinant NF90 or recombinant NF45 immunoprecipitate DNA-PKcs in vitro. Together, our data suggest that NF90, in complex with NF45, interacts with DNA-PKcs and Ku on DNA and that NF90 and NF45 may be important for the function of DNA-PK. SIGNOR-268489 0.411 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser197 APRRRAAsMDSSSKL 10090 BTO:0004245 10217147 t Here we show that protein kinase B phosphorylates AFX, a human orthologue of daf -16 (refs 5, 6, 9), both in vitro and in vivo. SIGNOR-252838 0.909 NFIA protein Q12857 UNIPROT SLIT1 protein O75093 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268892 0.259 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr80 DQHSISYtLSRAQTV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276138 0.761 CENPT protein Q96BT3 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265204 0.723 PTPRB protein P23467 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1356 YVHVNATyVNVKCVA 9606 16101282 t gcesareni Ptp1b and shp-2 are bound to the c-met receptor to control its activity. Although the binding of ptp1b increases when there is a decrease in c-met activation and acts as a negative regulator of the receptor, the increased binding and phosphorylation of shp-2 coincide with maximal stimulation of c-met, acting as a positive regulator. SIGNOR-139560 0.368 PRKCA protein P17252 UNIPROT CFTR protein P13569 UNIPROT up-regulates activity phosphorylation Ser790 IHRKTTAsTRKVSLA -1 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC. SIGNOR-248851 0.404 CCR5 protein P51681 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 20219869 t areggio The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation. Furthermore, stimulation of myoblasts with CCL2, CCL3, or CCL4 was sufficient to induce phosphorylation and activation of ERK1/2. SIGNOR-255119 0.326 ACE protein P12821 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT up-regulates quantity cleavage 9606 32201502 t MIANNU Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I SIGNOR-260236 0.2 STAT5A protein P42229 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0004408 15353555 f miannu Here we report that a persistent activation of STAT5A in human CD34+ cells results in enhanced self-renewal. STAT5A drives the expression of a number of proto-oncogenes and cytokines in human CD34+ cells, as well as a number of erythroid-specific genes, favoring erythroid over myeloid differentiation and providing a long-term proliferative advantage for erythroid progenitors. SIGNOR-256074 0.7 AKT3 protein Q9Y243 UNIPROT GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 23552696 t lperfetto Active AKT, a common mediator of cell survival signals induced by radiation through multiple intracellular signaling pathways,11, 12 suppresses apoptosis. AKT positively regulates cyclin D1 expression through inactivation of glycogen synthase kinase 3_ (GSK3_). The AKT-mediated phosphorylation of glycogen synthase kinase 3_ on serine9 decreases its kinase activity for Thr286 of cyclin D1, which inhibits the nuclear export and the cytoplasmic proteasomal degradation of cyclin D1 SIGNOR-245424 0.728 SCF-SKP2 complex SIGNOR-C136 SIGNOR MEF2D protein Q14814 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 25733682 t miannu  MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitin-proteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding.  SIGNOR-276889 0.291 UIMC1 protein Q96RL1 UNIPROT BRCA1-A complex complex SIGNOR-C296 SIGNOR form complex binding 9606 BTO:0000007 20656690 t lperfetto We and others showed previously that BRCC36 is a component of the BRCA1-A complex, which consists of RAP80, CCDC98/ABRAXAS, BRCC45/BRE, MERIT40/NBA1, BRCC36, and BRCA1.  SIGNOR-263211 0.924 KRAS protein P01116 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates binding 9606 7744823 t fstefani Mitogen-activated protein kinase kinase kinase (mekk1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. Mekk1 is activated in response to growth factor stimulation of cells and by expression of activated ras. mekk1 directly binds ras.GTP. Thus, ras interacts with protein kinases of both the raf and mekk families. SIGNOR-32620 0.371 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JUND protein P17535 UNIPROT up-regulates phosphorylation 9606 22327296 t inferred from 70% family members gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. SIGNOR-270083 0.2 N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine chemical CHEBI:91340 ChEBI CHUK protein O15111 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258085 0.8 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr775 SSNYMAPyDNYVPSA -1 8940081 t miannu The SH2 domain of Grb7 can directly bind to the autophosphorylated PDGF beta-receptor in vitro. Grb7 association to the PDGF beta-receptor was dramatically reduced by replacement of tyrosine residues 716 or 775 with phenylalanine residues. SIGNOR-250259 0.2 CALM3 protein P0DP25 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 BTO:0001009 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-266341 0.2 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. SIGNOR-88748 0.343 CCL2 protein P13500 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261032 0.7 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser239 GAKLRKVsKQEEASG 9606 14679200 t lperfetto Three phosphorylation sites have been identified in VASP: Ser157, Ser239, and Thr278, all of which can be phosphorylated by either PKA or PKG in vitro SIGNOR-120351 0.732 PPARA protein Q07869 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 16511610 f Regulation miannu The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II.  SIGNOR-251849 0.582 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr534 NFLMDNAyFCEADAK 10029 BTO:0000246 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248393 0.297 GRK2 protein P25098 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251444 0.2 PKNOX1 protein P55347 UNIPROT HOXA1 protein P49639 UNIPROT up-regulates activity binding 9606 BTO:0000007 9582372 t miannu Our results are consistent with a primary interaction of the YPWM motif of HOXA1 with the homeodomain of PBX. HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding. SIGNOR-220242 0.577 SUN2 protein Q9UH99 UNIPROT LINC complex complex SIGNOR-C303 SIGNOR form complex binding 24481844 t lperfetto LINC complex couples the nuclear lamina to the cytoskeleton. SUN domain proteins, SUN1 and SUN2, located at the inner nuclear membrane (INM) interact with the nuclear lamins, Lamin A/C, B1, and B2, that line the nucleoplasmic face of the INM. SUN domain proteins interact with Nesprins in the perinuclear space (PNS). Nesprins protrude from the outer nuclear membrane (ONM) and interact with the cytoskeleton, often through an intermediate binding partner. Nesprin 1 giant (g) and Nesprin 2g potentially link the NE directly to the Z-disc (Z), whereas Nesprin 1alpha and 2alpha may connect via an unknown intermediate protein. In addition, the shorter isoforms of Nesprin 1 and Nesprin 2 may localize to the INM. SIGNOR-263286 0.537 panobinostat chemical CHEBI:85990 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257756 0.8 TAOK2 protein Q9UL54 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity binding 9606 BTO:0001130 10660600 t lperfetto Immunoprecipitated psk phosphorylates myelin basic protein and transfected psk stimulates mkk4 and mkk7 and activates the c-jun n-terminal kinase mitogen-activated protein kinase pathway. SIGNOR-74864 0.261 TNF protein P01375 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 11287630 f lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase SIGNOR-244458 0.49 CHUK protein O15111 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 SIGNOR-C14 15084260 t gcesareni Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation. SIGNOR-252893 0.56 ARHGEF7 protein Q14155 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 21048939 t gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2 SIGNOR-169217 0.463 SP1 protein P08047 UNIPROT PDGFC protein Q9NRA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001685 15247255 f The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter SIGNOR-254272 0.2 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Thr203 VRAMAVLtDHPYASL 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275645 0.2 SMURF1 protein Q9HCE7 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 17317136 t lperfetto Recruitment of WW and HECT domain E3-ubiquitin ligases Smurf1 and 2 to induce type I receptor ubiquitination and subsequent receptor degradation; SIGNOR-153414 0.686 CSNK2A2 protein P19784 UNIPROT SUZ12 protein Q15022 UNIPROT up-regulates activity phosphorylation Ser583 PQEMEVDsEDEKDPE 9606 BTO:0002181 36351927 t miannu CK2 is the kinase for the phosphorylation of S583 of SUZ12. SIGNOR-277797 0.2 ITGB1BP1 protein O14713 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257668 0.284 CHAMP1 protein Q96JM3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 21063390 f miannu Proper attachment of microtubules to kinetochores is essential for accurate chromosome segregation. These data suggest that CAMP is required for maintaining kinetochore-microtubule attachment during biorientation. SIGNOR-264901 0.7 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Ser440 NGTSGKDsATTSTLS 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276662 0.252 KDM1A protein O60341 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28720390 f gianni The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. SIGNOR-268728 0.7 Wnt proteinfamily SIGNOR-PF40 SIGNOR LPR5/6 complex SIGNOR-C219 SIGNOR up-regulates activity binding 9606 23209147 t miannu FZD and LRP5/6 transduce Wnt signal via engaging downstream cytoplasmic components, among which two scaffolding proteins, Dishevelled and Axin, have prominent roles. SIGNOR-256174 0.805 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr280 VEFMCKVySDPQPHI 9606 12601080 t lperfetto Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways. SIGNOR-98626 0.2 SLBP protein Q14493 UNIPROT H2BW1 protein Q7Z2G1 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265387 0.2 AP3D1 protein O14617 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260683 0.93 FRZB protein Q92765 UNIPROT WNT1 protein P04628 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, SIGNOR-51762 0.528 TAF1A protein Q15573 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 15970593 t lperfetto Gene promoters with a TATA box tend to be bound by the SAGA complex which includes TBP, SUPT3H, and GCN5 (Basehoar et al., 2004; Rodríguez-Navarro, 2009). Therefore, it was thought that TATA-containing genes were mainly regulated by the SAGA complex, while TATA-less genes were independently regulated by TFIID (Pugh and Tjian, 1991; Basehoar et al., 2004). However, recent studies in yeast indicate that most genes utilize both TFIID and SAGA, and that the relative contribution of each complex likely depends on the individual context SIGNOR-269591 0.356 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR 10116 7535768 t We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively SIGNOR-248463 0.781 TRAF2 protein Q12933 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys158 ALIHRDLkPPNLLLV 9606 BTO:0000007 20038579 t lperfetto Tumor necrosis factor receptor-associated factors 2 and 6 (traf2 and -6) act as the ubiquitin e3 ligases to mediate lys63-linked tak1 polyubiquitination at the lys158 residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. SIGNOR-162638 0.586 PRKCA protein P17252 UNIPROT RALBP1 protein Q15311 UNIPROT up-regulates activity phosphorylation Thr297 ACGRTTEtEKVQEFQ -1 16087181 t miannu In deletion mutant analyses of potential phosphorylation sites in RLIP76, we identified T297 and S509 as targets for phosphorylation by PKCalpha. Phosphorylation at T297 increased doxorubicin (DOX)-transport activity approximately 2-fold for RLIP76 purified from recombinant source SIGNOR-263164 0.394 WIPF1 protein O43516 UNIPROT WASL protein O00401 UNIPROT up-regulates activity binding 9606 10878810 t lperfetto Recruitment of N-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex. SIGNOR-261880 0.932 MMP28 protein Q9H239 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272395 0.7 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 10454565 t Phosphatase activity of Cdc25A is critical for its activating capacity (data not shown). In this context, it should also be mentioned that Cdc25A is able to activate cyclin B-Cdk1 in vitro SIGNOR-248479 0.839 SEH1L protein Q96EE3 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262092 0.63 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10090 15306821 t lperfetto Nevertheless, s6k1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from s6k1 to insulin receptor substrate 1 (irs1), which blunts s307 and s636/s639 phosphorylation; thus under conditions of nutrient satiation s6k1 negatively regulates insulin. SIGNOR-127904 0.784 ERBB4 protein Q15303 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-252674 0.549 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development. SIGNOR-266978 0.405 SCF-SKP2 complex SIGNOR-C136 SIGNOR RBL2 protein Q08999 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 phosphorylation:Ser672 TLYDRYSsPPASTTR 12435635 t miannu  The activity of the ubiquitin ligase complex Skp1-Cul1/Cdc53-F-box protein Skp2 (SCF(Skp2)) and the proteasome were necessary for p130 degradation. In vitro, recombinant Skp2 was able to bind hyperphosphorylated but not dephosphorylated p130. Furthermore, in vitro polyubiquitination of p130 by SCF(Skp2) was specifically dependent on phosphorylation of p130 on Serine 672.  SIGNOR-272598 0.553 bosutinib chemical CHEBI:39112 ChEBI SRC protein P12931 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190699 0.8 ENO1 protein P06733 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI down-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266528 0.8 (R)-5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:11957727 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258867 0.8 GDF5 protein P43026 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates activity binding 10090 15890363 t In contrast to other members of the TGF-beta superfamily, GDF-5 shows a pronounced specificity in type I receptor interaction in cross-link experiments binding only to BMP receptor IB (BMPR-IB). In mice, deletion of either GDF-5 or BMPR-IB results in a similar phenotype, indicating that GDF-5 signaling is highly dependent on BMPR-IB. SIGNOR-256483 0.776 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates activity phosphorylation Tyr162 QLAAKLAyLQILSEE 9606 BTO:0001282 16373505 t PKR autophosphorylates on Y101, Y162, and Y293. unctional characterization of Y101F and Y162F mutants revealed that phosphorylation at these sites is needed for efficient dsRNA binding and kinase dimerization and activation. SIGNOR-251113 0.2 nintedanib chemical CHEBI:85164 ChEBI FGFR3 protein P22607 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257798 0.8 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1355 SLGFKRSyEEHIPYT -1 3166375 t lperfetto This approach revealed that insulin stimulates autophosphorylation of the insulin-receptor beta-subunit in vitro on at least seven tyrosine residues distributed among three distinct domainsAt least two further tyrosine residues appeared to be phosphorylated after those in domains 2 and 3. These residues probably residue within a domain lying in close proximity to the inner face of the plasma membrane containing tyrosines 953, 960 and 972 SIGNOR-22577 0.2 MECP2 protein P51608 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0000007 24150225 t Luana MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2 SIGNOR-264683 0.273 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys626 KKKSKALkEEKMEID 9606 BTO:0000007 23686912 t miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. SIGNOR-263901 0.46 SS18 protein Q15532 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269782 0.635 PRKACA protein P17612 UNIPROT DYNLRB1 protein Q9NP97 UNIPROT up-regulates phosphorylation Ser73 LTFLRIRsKKNEIMV 9606 23333499 t llicata Our results show that km23-1 is required for camp-responsive element (cre) transcriptional activation by tgf_, with s73-km23-1 being required for the cre-dependent tgf_ stimulation of fibronectin (fn) transcription. SIGNOR-200456 0.2 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT down-regulates activity phosphorylation Thr315 GVPPPPAtPGAAPLA 9606 BTO:0000007 16848763 t miannu Further experiments showed that DAZAP1 was phosphorylated stoichiometrically in vitro by ERK2 (extracellular-signal-regulated protein kinase 2) at two Thr-Pro sequences (Thr269 and Thr315), and that both sites became phosphorylated in HEK-293 (human embryonic kidney 293) cells in response to PMA or EGF (epidermal growth factor), or RAW 264.7 macrophages in response to LPS. Phosphorylation of the ARE-binding protein DAZAP1 by ERK2 induces its dissociation from DAZ SIGNOR-262971 0.2 SOX9 protein P48436 UNIPROT PRAME protein P78395 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000849 19273910 f miannu Overexpression of SOX9 in both human and mouse melanoma cell lines induced cell cycle arrest by increasing p21 transcription and restored sensitivity to RA by downregulating expression of PRAME, a melanoma antigen. SIGNOR-255191 0.321 CKM complex complex SIGNOR-C406 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273174 0.2 DVL3 protein Q92997 UNIPROT PIP5K1A protein Q99755 UNIPROT up-regulates binding 9606 18772438 t gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. SIGNOR-180788 0.2 CASP3 protein P42574 UNIPROT KDM4C protein Q9H3R0 UNIPROT down-regulates activity cleavage 9606 29207681 t miannu JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels. SIGNOR-263870 0.2 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193546 0.8 PD173955 chemical CHEBI:49791 ChEBI SRC protein P12931 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258264 0.8 MAPK8 protein P45983 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation 9606 17525747 t gcesareni Our studies revealed a novel mechanism in which phosphorylation of jnk2 is mediated by jnk1 before phosphorylation of p53, and then p53 is directly phosphorylated by jnk2 at ser6. SIGNOR-155205 0.581 SOD1 protein P00441 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity 10116 BTO:0000452;BTO:0000099 BTO:0001279 31623154 f P00441:p.Gly94Ala (mutation increasing interaction) We found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis SIGNOR-262783 0.2 JAK1 protein P23458 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249492 0.674 Fe2S2 iron-sulfur cluster chemical CHEBI:49601 ChEBI SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-267735 0.8 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser362 FYTLNGSsVDSQPQS 9606 BTO:0004553 24614225 t gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. SIGNOR-266434 0.309 NADPH(4-) smallmolecule CHEBI:57783 ChEBI PGD protein P52209 UNIPROT down-regulates activity binding 9606 34765544 t miannu We determined that FASN inhibitor treatment resulted in NADPH accumulation and inhibition of PGDH enzyme activity. NADPH is a cofactor utilized by FASN, also a known allosteric inhibitor of PGDH. PGDH is the onl yrate-limiting unidirectional enzyme susceptible to allosteric inhibition by NADPH SIGNOR-267372 0.8 PRKCD protein Q05655 UNIPROT SRC protein P12931 UNIPROT up-regulates activity phosphorylation Ser12 KSKPKDAsQRRRSLE 9606 BTO:0001938 18069897 t gcesareni We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55 SIGNOR-247974 0.591 AKT proteinfamily SIGNOR-PF24 SIGNOR PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser318 CKIFRRPsLPCISRE 10090 BTO:0000011 10454575 t gcesareni PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B. SIGNOR-248027 0.2 1-phospho-alpha-D-glucuronic acid smallmolecule CHEBI:681 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1.Similarly, the affinities of D3 receptors for quinpirole and dopamine were much higher than the affinities of D:! receptors for the agonists in the presence of Gpp(NH)p and NaCl when [1251]-NCQ-298 was used to label receptors; however, when Gpp(NH)p and NaCl were not present, and when [12sI]-7-OH-PIPAT was used, receptors bound quinpirole and dopamine with nearly equal affinities (Table 1). SIGNOR-258435 0.8 EPO protein P01588 UNIPROT EPOR protein P19235 UNIPROT up-regulates binding 10090 9442088 t gcesareni Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s). SIGNOR-55300 0.874 SMAD6 protein O43541 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity binding 9606 BTO:0000007 19561075 t miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. SIGNOR-272786 0.826 SP1 protein P08047 UNIPROT PON1 protein P27169 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 15380450 f miannu These data suggest that Sp1 acts as a positive regulator of PON1 transcription, and that an interaction between Sp1 and PKC is a key mechanism for the effect of Sp1 on PON1 transcription. SIGNOR-255212 0.27 NPFFR2 protein Q9Y5X5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257104 0.253 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Thr81 APAPAAPtPAAPAPA 9606 BTO:0000007 11283254 t lperfetto Jnk phosphorylated p53 at t81 in response to dna damage and stress-inducing agents, as determined by phospho-specific antibodies to t81 . Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress. SIGNOR-106542 0.793 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT up-regulates activity phosphorylation Tyr81 EQGAAAIyTTQMDDF 9606 BTO:0000567 15342783 t lperfetto These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton SIGNOR-247441 0.367 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival. SIGNOR-163961 0.432 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 BTO:0000567 10411906 t Ser-967 is a critical component of the 14-3-3 interaction site of ASK1 and suggest that phosphorylation of this residue may be the major mode of regulation of 14-3-3 binding to ASK1 gcesareni 14-3-3 may suppress ask1-induced cell death by directly inhibiting the catalytic activity of ask1. SIGNOR-69408 0.2 CSNK1A1 protein P48729 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization phosphorylation Thr437 ARSISTPtCLGGSPA 9606 BTO:0002181 32111827 t miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  SIGNOR-277512 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 20937773 t lperfetto In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387 SIGNOR-216737 0.377 DLG4 protein P78352 UNIPROT TANC2 protein Q9HCD6 UNIPROT up-regulates activity binding 10116 BTO:0000142 21068316 t miannu In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. our results indicate that TANC-dependent spine/synapse maintenance requires TANC binding to PSD-95, which promotes synaptic localization of TANC proteins. Thus, it is likely that interaction with PSD-95 concentrates TANC proteins at synapses, where they play a role in mediating PSD-95-dependent maintenance of spines and synapses. SIGNOR-266895 0.315 MRGPRD protein Q8TDS7 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 23446738 f Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. SIGNOR-262309 0.7 VAV1 protein P15498 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 9013873 f lperfetto Vav may link gp130 activation to downstream mapk activation in hematopoietic cells. SIGNOR-244640 0.518 FOXO3 protein O43524 UNIPROT TSC22D3 protein Q99576 UNIPROT up-regulates activity transcriptional regulation 10090 15031210 t We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal SIGNOR-256094 0.402 AATK protein Q6ZMQ8 UNIPROT STK39 protein Q9UEW8 UNIPROT down-regulates 9606 17267545 f gcesareni Taken together, our data are consistent with aatyk1 indirectly inhibiting the spak/wnk4 activation of the cotransporter by scaffolding an inhibitory phosphatase in proximity to a stimulatory kinase. SIGNOR-152921 0.346 NFIL3 protein Q16649 UNIPROT CYP3A4 protein P08684 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 18004209 f miannu The oscillation in the expression of the CYP3A4 gene seemed to be the underlying cause of the rhythmic change in its metabolic activity. Luciferase reporter gene analysis and electrophoretic mobility shift assay revealed that the circadian transcriptional factor, D-site-binding protein (DBP), activated the transcription of the CYP3A4 gene by binding to the DNA sequence near the upstream of the transcriptional start site. The transactivation of the CYP3A4 gene by DBP was repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock. SIGNOR-253836 0.2 MAPK1 protein P28482 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. SIGNOR-134837 0.437 CSNK2A1 protein P68400 UNIPROT VTN protein P04004 UNIPROT up-regulates activity phosphorylation Thr69 VTRGDVFtMPEDEYT 10090 BTO:0000944 9733784 t llicata  Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant SIGNOR-250970 0.331 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 RSVPEPLsPVSSLQA 9606 16027724 t miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation SIGNOR-250092 0.421 SNAI1 protein O95863 UNIPROT SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19055748 f lperfetto We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. SIGNOR-252262 0.424 MECOM protein Q03112 UNIPROT PBX1 protein P40424 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001271 19767769 f miannu In this study, we identified pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of evi-1. Overexpression of evi-1 increased pbx1 expression in hematopoietic stem/progenitor cells SIGNOR-188155 0.431 NR1I2 protein O75469 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 11706036 t gcesareni The constitutive androstane receptor (car, nr1i4), like fxr and pxr, binds dna as a heterodimer with rxr? SIGNOR-111624 0.541 MLL1 complex complex SIGNOR-C89 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 24680668 t miannu Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal corecomplexthat is required for multiple lysine methylation. SIGNOR-268802 0.2 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys262 DSDDALLkMTISQQE -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272744 0.471 WNK2 protein Q9Y3S1 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 t Manara WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). | We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro. SIGNOR-260790 0.554 TP53 protein P04637 UNIPROT ANKRD11 protein Q6UB99 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 18840648 t miannu Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53. SIGNOR-266735 0.312 PI3K complex SIGNOR-C156 SIGNOR Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 23994464 f apalma The PI3Kγ pathway (but not PLCβ2/3) is required for chemotaxis of the cells while both pathways are required for GPCR-induced superoxide release SIGNOR-255012 0.7 DDB1 protein Q16531 UNIPROT RAD23B protein P54727 UNIPROT up-regulates 24086044 f lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). SIGNOR-275689 0.637 FZD7 protein O75084 UNIPROT FZD7/SDC4 complex SIGNOR-C216 SIGNOR form complex binding 9606 BTO:0002314 BTO:0001103 23290138 t apalma We next examined whether endogenous Fzd7 and Sdc4 form a receptor complex in satellite cells […] Therefore, we conclude that Fzd7 and Sdc4 form a co-receptor complex in activated satellite cells. SIGNOR-255848 0.547 ELOVL3 protein Q9HB03 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267886 0.8 SOD3 protein P08294 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272271 0.8 MAPK14 protein Q16539 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates activity phosphorylation 10090 20682789 t ggiuliani We therefore propose that Osterix binds to Sp1 sequences on target gene promoters and that its phosphorylation by p38 enhances recruitment of coactivators to form transcriptionally active complexes SIGNOR-255791 0.415 CDK1 protein P06493 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1. SIGNOR-111507 0.388 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser330 SFRVRASsDGEGTMS -1 8349691 t llicata These data suggest that casein kinase II mediates a portion of the insulin-stimulated serine/threonine phosphorylation of overexpressed IRS-1 in vivo. | Thr-502 was identified as the major casein kinase II-catalyzed phosphorylation site in rat IRS-1. SIGNOR-251073 0.322 PRKCG protein P05129 UNIPROT VTN protein P04004 UNIPROT up-regulates quantity by stabilization phosphorylation Ser381 RNRKGYRsQRGHSRG -1 9030777 t lperfetto Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin. SIGNOR-248964 0.287 CDK1 protein P06493 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Thr611 ETLPISStPSKSVLP 9606 SIGNOR-C17 19737929 t lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity SIGNOR-187880 0.756 CRK protein P46108 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates binding 9606 7806500 t gcesareni The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo. SIGNOR-33732 0.9 HSP90AB1 protein P08238 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 9580552 t miannu Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS. SIGNOR-252214 0.536 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262999 0.539 KAT2B protein Q92831 UNIPROT H3Y2 protein P0DPK5 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269615 0.2 GNB3 protein P16520 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14668344 t gcesareni Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein. SIGNOR-252680 0.386 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL 9606 16116087 t llicata The present experiments demonstrate that ptn stimulates phosphorylation of serines 713 and 726 in the marcks domain of _-adducin (and serine 724 in _-adducin) and serines 152 and 156 in the marcks protein itself through the activation of either pkc _ or _ and perhaps other pkc(s) isoforms. SIGNOR-139906 0.724 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. SIGNOR-183674 0.364 PRKDC protein P78527 UNIPROT LIG4 protein P49917 UNIPROT down-regulates phosphorylation Ser672 CVMSGTDsQPKPDLE 9606 15194694 t lperfetto Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability. SIGNOR-125873 0.804 LAMTOR complex SIGNOR-C26 SIGNOR RAGAC complex SIGNOR-C113 SIGNOR up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto We identify the trimeric Ragulator protein complex as a new component of the mTORC1 pathway that interacts with the Rag GTPases, is essential for localizing them and mTORC1 to the lysosomal surface, and is necessary for the activation of the mTORC1 pathway by amino acids. SIGNOR-228155 0.876 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser1101 GCRRRHSsETFSSTP 10029 BTO:0000246 15364919 t lperfetto Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101). SIGNOR-249267 0.637 ATG12 protein O94817 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 t lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). SIGNOR-226689 0.866 TSPOAP1 protein O95153 UNIPROT RIMS3 protein Q9UJD0 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264373 0.2 DHFR2 protein Q86XF0 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. SIGNOR-268261 0.8 ATM protein Q13315 UNIPROT PPP1R2 protein P41236 UNIPROT down-regulates phosphorylation Ser44 DEELSKKsQKWDEMN 9606 18250156 t gcesareni Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1. SIGNOR-160648 0.2 PRKCZ protein Q05513 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 t done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). SIGNOR-273906 0.2 KEL protein P23276 UNIPROT EDN3 protein P14138 UNIPROT up-regulates activity cleavage Trp117 YCHLDIIwINTPEQT -1 10438732 t miannu These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles. SIGNOR-256354 0.669 BBS9 protein Q3SYG4 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262555 0.789 PRKG1 protein Q13976 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation 9606 16331690 t The effect has been demonstrated using Q13507-3 llicata The present study demonstrates that human trpc3 expressed in hek293 cells forms store-operated ca2+ influx channels, the activity of which is inhibited by pkg. The inhibition is due to a direct phosphorylation of pkg on trpc3 channels at position t11 and s263. SIGNOR-142964 0.414 PELI1 protein Q96FA3 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000815 36841821 t miannu EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. SIGNOR-277875 0.2 BDKRB1 protein P46663 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257237 0.251 KIFC1 protein Q9BW19 UNIPROT CENPE protein Q02224 UNIPROT up-regulates activity binding 9606 BTO:0000948 33361741 t miannu We found that KIFC1 could directly bind to CENPE in SKOV3 cells (Figure 4C, 4D). SIGNOR-266116 0.561 FLT4 protein P35916 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276180 0.2 OAT protein P04181 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256032 0.8 TLR2 protein O60603 UNIPROT TIRAP protein P58753 UNIPROT up-regulates activity binding 10090 22664090 t scontino To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-266745 0.72 androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI estrone smallmolecule CHEBI:17263 ChEBI up-regulates quantity precursor of 9606 BTO:0000975 27702664 t lperfetto The cytochrome P450 aromatase is involved in the last step of sex hormones biosynthesis by converting androgens into estrogens. |Human aromatase (CYP19A1) is a membrane-bound class II cytochrome P450 that converts androgens into estrogens [1], [2], [3], [4]. Specifically, the enzyme is involved sex hormones biosynthesis where it is responsible for the conversion of androstenedione, testosterone and 16alpha-hydroxytestosterone into estrone, estradiol and estriol, respectively SIGNOR-268668 0.8 NBR1 protein Q14596 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family SIGNOR-184261 0.753 LAMTOR3 protein Q9UHA4 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164775 0.93 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163941 0.8 PPP1CA protein P62136 UNIPROT TRIM28 protein Q13263 UNIPROT up-regulates activity dephosphorylation Ser824 LPGAGLSsQELSGGP 9606 20424263 t miannu PP1\u03b1 dephosphorylates KAP1 at Ser 824 . SIGNOR-277075 0.325 CITED2 protein Q99967 UNIPROT MMP1 protein P03956 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003859 12960175 f miannu CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway. SIGNOR-253778 0.362 CSNK1E protein P49674 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation 9606 15747065 t gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. SIGNOR-134497 0.27 GLDC protein P23378 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268240 0.693 NLGN1 protein Q8N2Q7 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264164 0.826 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 UNIPROT up-regulates activity binding -1 14662005 t Luana Adenosine is a physiological nucleoside which acts as an autocoid and activates G protein-coupled membrane receptors, designated A1, A2A, A2B and A3. SIGNOR-268419 0.8 MSH2/MSH6 complex SIGNOR-C60 SIGNOR BLM protein P54132 UNIPROT up-regulates binding 9606 15064730 t lperfetto We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro SIGNOR-217223 0.603 PRKCA protein P17252 UNIPROT TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260882 0.366 CEBPB protein P17676 UNIPROT ADM protein P35318 UNIPROT up-regulates quantity by expression transcriptional regulation 9480831 t These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells. SIGNOR-254047 0.246 FZD3 protein Q9NPG1 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 14977528 t gcesareni Gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-122892 0.245 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni Furthermore, we show that pkd2 can be activated by classical and novel members of the protein kinase c (pkc) family such as pkc alpha, pkc epsilon, and pkc eta. These pkcs are activated by gastrin in ags-b cells. Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. SIGNOR-89411 0.2 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9927207 t llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. SIGNOR-64190 0.581 TFIIE complex SIGNOR-C458 SIGNOR TFIIH complex SIGNOR-C457 SIGNOR up-regulates activity relocalization 9606 31064989 t lperfetto The heterodimer TFIIE (composed of the TFIIEα and TFIIEβ subunits) seems to play a pivotal role in transcription by directly influencing the transition from initiation to elongation3,4. TFIIE interacts with different factors within the PIC, including Pol II5,6 as well as with DNA immediately upstream of the transcription bubble region7,8. Furthermore, TFIIE seems to influence TFIIH activity9, although it is not clear how this molecular process can occur. SIGNOR-269363 0.732 MMP1 protein P03956 UNIPROT COL1A1 protein P02452 UNIPROT down-regulates quantity by destabilization cleavage Gly776 IGPPGPAgAPGDKGE -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272336 0.384 VEGFC protein P49767 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103;BTO:0000763 9435229 t gcesareni Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown SIGNOR-55208 0.914 RAB38 protein P57729 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR up-regulates activity relocalization 9606 23247405 t miannu Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-268526 0.281 PSMA3 protein P25788 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263362 0.849 ERBB2 protein P04626 UNIPROT ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR up-regulates activity phosphorylation -1 1706616 t inferred from 70% of family members ¬†Y1023 and Y1248, Y1139 and Y1222 also serve as autophosphorylation sites of HER2. SIGNOR-269875 0.616 NEDD4 protein P46934 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272753 0.458 AML1-ETO fusion protein SIGNOR-FP1 SIGNOR JAK2 protein O60674 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001271 22740448 f miannu Chromosome translocation 8q22;21q22 [t(8;21)] is commonly associated with acute myeloid leukemia (AML), and the resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression microarray and promoter occupancy (ChIP-chip) profiling using Lin(-)/Sca1(-)/cKit(+) cells, the major leukemia cell population, from an AML mouse model induced by AML1-ETO9a (AE9a).CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is among those targets. Its expression is substantially down-regulated in leukemia cells. Consequently, JAK/STAT signaling is enhanced. SIGNOR-260120 0.2 KAR proteinfamily SIGNOR-PF57 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 15919192 f miannu Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. The glutamate receptor ion channels (iGluRs) are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5–7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits. SIGNOR-264693 0.7 AKT1 protein P31749 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser694 QTSKRHDsDTFPELK 9606 20085797 t lperfetto We identify a novel akt phosphorylation site in brca1 at s694 which is responsive to activation of these signaling pathways. These data suggest akt phosphorylation of brca1 increases total protein expression by preventing proteasomal degradation SIGNOR-163472 0.515 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-153622 0.601 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 19008118 t FFerrentino In mesenchymal precursor cells, Wnt10b (and Wnt10a) binding to frizzled (FZD1) SIGNOR-253511 0.657 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes. SIGNOR-157533 0.774 MSL1 protein Q68DK7 UNIPROT MSL acetyltransferase complex SIGNOR-C344 SIGNOR form complex binding 9606 BTO:0000567 16227571 t miannu We describe a stable, multisubunit human histone acetyltransferase complex (hMSL) that contains homologs of the Drosophila dosage compensation proteins MOF, MSL1, MSL2, and MSL3. This complex shows strong specificity for histone H4 lysine 16 in chromatin in vitro, and RNA interference-mediated knockdown experiments reveal that it is responsible for the majority of H4 acetylation at lysine 16 in the cell. SIGNOR-263942 0.852 WNT1 protein P04628 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131574 0.784 PKA proteinfamily SIGNOR-PF17 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser950 EGFHPRRsSQGATQM 19018281 t miannu  Our results demonstrate that PKA activates human HSL against lipid substrates in vitro primarily through phosphorylation of Ser649 and Ser650.  SIGNOR-276174 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270364 0.8 PRKAA1 protein Q13131 UNIPROT HNF4A protein P41235 UNIPROT down-regulates activity phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 SIGNOR-C15 12740371 t lperfetto Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect SIGNOR-101101 0.288 RREB1 protein Q92766 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 17550981 f RREB-1 bound to the prostate-specific antigen (PSA) promoter as assessed by chromatin immunoprecipitation. Transient expression of RREB-1 down-regulated AR-mediated promoter activity and suppressed expression of PSA protein. SIGNOR-253661 0.2 lofepramine chemical CHEBI:47782 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258881 0.8 FYN protein P06241 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates activity phosphorylation Tyr436 EWKVVNAyHLRVRRK 10090 BTO:0000944 27626315 t miannu Here we identified that Fyn phosphorylates the α subunit of AMPK on Y436 and inhibits AMPK enzymatic activity without altering the assembly state of the AMPK heterotrimeric complex.  SIGNOR-277279 0.259 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation 9606 14532121 t inferred from 70% family members gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. SIGNOR-270063 0.2 HBA1 protein P69905 UNIPROT ADAMTS13 protein Q76LX8 UNIPROT down-regulates activity 9606 15367436 f Regulation of binding miannu Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher. SIGNOR-251749 0.2 PRKCD protein Q05655 UNIPROT SMPD1 protein P17405 UNIPROT up-regulates phosphorylation Ser510 DGNYSGSsHVVLDHE 9606 17303575 t lperfetto Activation of acid sphingomyelinase by protein kinase cdelta-mediated phosphorylation. Phosphorylation of ser(508) proved to be an indispensable step for asmase activation and membrane translocation in response to pma SIGNOR-153276 0.258 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu72 MEEKCSFeEAREVFE 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263692 0.675 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 BTO:0000007 10942774 t lperfetto Mammalian target of rapamycin-dependent phosphorylation of phas-i in four (s/t)p sites detected by phospho-specific antibodies. SIGNOR-236702 0.754 ALG11 protein Q2TAA5 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 t lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. SIGNOR-260417 0.8 CNR1 protein P21554 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256867 0.528 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser567 VLSDNDRsLLERWTR 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259823 0.2 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT up-regulates activity phosphorylation Tyr304 TDDDKNIyLTLPPND -1 8756631 t lperfetto To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation. SIGNOR-249337 0.521 SRC protein P12931 UNIPROT BCKDK protein O14874 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr246 RRLCEHKyGNAPRVR 9606 BTO:0001615 32238881 t lperfetto Src phosphorylated BCKDK at the tyrosine 246 (Y246) site in vitro and ex vivo. Knockdown and knockout of Src downregulated the phosphorylation of BCKDK. Importantly, phosphorylation of BCKDK by Src enhanced the activity and stability of BCKDK, thereby promoting the migration, invasion, and EMT of CRC cells. SIGNOR-275584 0.2 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90521 0.789 MDH2 protein P40926 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266286 0.8 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser129 VNTRAGPsQHSSPAV 9606 BTO:0000671 12628002 t lperfetto Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149) SIGNOR-99127 0.695 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr5 tQTQDQPM 9606 BTO:0000567 2507541 t lperfetto Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha. SIGNOR-248887 0.434 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 QQEGGFAsPRTGKGK -1 22411829 t miannu Importantly, the S652ph antibody identifies phosphorylated UHRF1 in mitotic cells and consistently S652 can be phosphorylated by the M phase-specific kinase CDK1-cyclin B in vitro. UHRF1 S652 phosphorylation significantly reduces UHRF1 interaction with USP7 in vitro and in vivo, which is correlated with a decreased UHRF1 stability in the M phase of the cell cycle. In contrast, UHRF1 carrying the S652A mutation, which renders UHRF1 resistant to phosphorylation at S652, is more stable.  SIGNOR-276408 0.321 etoposide chemical CHEBI:4911 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 16101488 t miannu Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. SIGNOR-259325 0.8 Terfenadine chemical CHEBI:9453 ChEBI KCNH2 protein Q12809 UNIPROT down-regulates activity chemical inhibition -1 19660947 t Luana  hERG activity was initially determined in a high throughput patch clamp screening assay (Ionworks)5 while a human H1 binding assay was used to determine H1 binding affinity.6 Selected results were confirmed in vitro using an IonWorks Quattro patch clamp assay and in vivo in the guinea pig.7, 8 Histamine H1activity was confirmed in vivo in the guinea pig.7 SIGNOR-257826 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser221 KVAAETQsPSLFGST 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188131 0.2 PTPN11 protein Q06124 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 17974954 t Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B SIGNOR-248671 0.644 MYC protein P01106 UNIPROT ST3GAL1 protein Q11201 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-253961 0.2 GSK3B protein P49841 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization phosphorylation Ser13 ELKQMVMsLRVSELQ 10090 BTO:0002268 26157031 t miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.  SIGNOR-276924 0.336 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk SIGNOR-88736 0.357 DRD5 protein P21918 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257156 0.284 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRNB3 protein Q05901 UNIPROT up-regulates activity chemical activation 9606 BTO:0000227 28901280 t miannu Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cysloop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. SIGNOR-264258 0.8 UBC protein P0CG48 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding 9606 BTO:0000938 26161729 t lperfetto Mechanism of phospho-ubiquitin-induced PARKIN activation|PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN|Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. SIGNOR-249692 0.2 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 19118012 t gcesareni Phosphorylation by activated jnk protects c-jun from ubiquitination;phosphorylation of c-jun on ser73 by jnk is sufficient to protect c-jun from ubiquitination c-jun is targeted for ubiquitination by its association with inactive c-jun nh2-terminal kinase (jnk). Phosphorylation by activated jnk protects c-jun from ubiquitination, thus by prolonging its half-life targets of the jnk signal transduction pathway include the transcription factors atf2 and c-jun apoptosis, altered;apoptosis, induced;transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) transcription, altered;cell growth, altered;jnk1(disrupts);pin1(induces);dna(disrupts) SIGNOR-183017 0.883 MN1 protein Q10571 UNIPROT MYBBP1A protein Q9BQG0 UNIPROT up-regulates activity binding -1 12569362 t irozzo Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300. SIGNOR-256021 0.2 WWTR1 protein Q9GZV5 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 22153608 t Activation of Wnt signaling induces the hyperphosphorylation of Dishevelled (DVL), and this, via a poorly understood mechanism, ultimately leads to a rise in beta-Catenin levels and to the activation of beta-Catenin target genes. gcesareni Taz binds to dvl proteins, thereby inhibiting dvl phosphorylation by casein kinase 1-delta and -epsilon kinases (ck1d/e), thus promoting beta-catenin degradation. SIGNOR-195212 0.362 UNG protein P13051 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 27875297 f lperfetto Uracil N-glycosylase 2 (UNG2), the nuclear isoform of UNG, catalyzes the removal of uracil or 5-fluorouracil lesions that accumulate in DNA following treatment with the anticancer agents 5-fluorouracil and 5-fluorodeoxyuridine (floxuridine), a 5-fluorouracil metabolite. By repairing these DNA lesions before they can cause cell death, UNG2 promotes cancer cell survival and is therefore critically involved in tumor resistance to these agents.  SIGNOR-264889 0.7 TYK2 protein P29597 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates activity phosphorylation Tyr466 VFLRCINyVFFPSLK -1 8605876 t lperfetto We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2. SIGNOR-246934 0.909 KIF5B protein P33176 UNIPROT SYBU protein Q9NX95 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 t miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. SIGNOR-264811 0.571 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù SIGNOR-267189 0.8 ANKRD11 protein Q6UB99 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0000142 29274743 f miannu We showed that ANKRD11 regulates dendrite outgrowth, arborization, and spine formation via Trkb transcription and activation of its downstream effectors in the developing mouse brain. SIGNOR-266733 0.7 TNC protein P24821 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 BTO:0001521 38058842 t miannu TNC is shown to bind to integrin receptors expressed in adjacent PAAD cells, thereby inducing EMT. In addition, TNC expression in CAFs had significant positive correlations with ITGαV, ITGβ1, or ITGβ3 expression in cancer cells, which supports our speculations that the TNC-integrin signaling axis promotes the EMT pathway in cancer cells. SIGNOR-277736 0.415 PRKACA protein P17612 UNIPROT FXYD1 protein O00168 UNIPROT up-regulates activity phosphorylation Ser83 EEGTFRSsIRRLSTR -1 15621037 t miannu PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA. SIGNOR-263117 0.437 MAP4K5 protein Q9Y4K4 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates 9606 9405407 f gcesareni Here we report the identification of a tnf-responsive serine/threonine protein kinase termed gck related (gckr) that likely signals via mitogen-activated protein kinase (mapk)/extracellular signal-regulated kinase (erk) kinase kinase 1 (mekk1) to activate the sapk pathway. SIGNOR-53779 0.441 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 9606 12213813 t lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. SIGNOR-252768 0.2 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131391 0.2 SEC23IP protein Q9Y6Y8 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI down-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269651 0.8 ERBB2 protein P04626 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 10085134 t gcesareni Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase SIGNOR-65579 0.803 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188123 0.394 TRIM24 protein O15164 UNIPROT TP53 protein P04637 UNIPROT down-regulates ubiquitination 9606 19844164 t miannu New ring-domain e3-ubiquitin ligase trim24 that targets p53 for degradation SIGNOR-188726 0.542 STAT3 protein P40763 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16510571 f lperfetto Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene. SIGNOR-253049 0.783 FYN protein P06241 UNIPROT CNN1 protein P51911 UNIPROT down-regulates activity phosphorylation Tyr261 SQRGMTVyGLPRQVY 9534 BTO:0000298 15206927 t We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin SIGNOR-251158 0.336 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR STK4 protein Q13043 UNIPROT up-regulates 9606 22683405 f milica In response to growth inhibitory signal (e.g. cell–cell contact), MST1/2 in active form phosphorylates LATS1/2 that sequentially phosphorylates YAP at Ser-127. SIGNOR-230693 0.7 ERCC5 protein P28715 UNIPROT ERCC2 protein P18074 UNIPROT up-regulates quantity by stabilization binding 9606 20840796 t Regulation of binding The NER protein XPG was also found to associate with the TFIIH complex by interacting directly with XPD stabilizing the interaction between TFIIH and the CAK-XPD complex SIGNOR-251974 0.947 glutaryl-CoA(5-) smallmolecule CHEBI:57378 ChEBI glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity precursor of 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271815 0.8 bisphenol F chemical CHEBI:34575 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268731 0.8 SARS1 protein P49591 UNIPROT Ser-tRNA(Ser) smallmolecule CHEBI:29162 ChEBI up-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270498 0.8 ITGAL protein P20701 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253189 0.913 PSMC5 protein P62195 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263372 0.879 FSTL3 protein O95633 UNIPROT MSTN protein O14793 UNIPROT down-regulates binding 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 t gcesareni Fstl3 inhibits myostatin via its n-terminal domain. SIGNOR-199063 0.688 INTS2 protein Q9H0H0 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261466 0.749 HK3 protein P52790 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266457 0.8 UBE3A protein Q05086 UNIPROT SCRIB protein Q14160 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 11027293 t miannu Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase SIGNOR-272573 0.542 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser290 GRIVARNsRKMAFRA -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249007 0.307 ABL1 protein P00519 UNIPROT ERCC6 protein Q03468 UNIPROT up-regulates activity phosphorylation Tyr932 GANRVVIyDPDWNPS 9606 17626041 t Regulation miannu N-terminal region of CSB interacts with the SH3 domain of c-Abl in vitro and in vivo. In addition, c-Abl kinase phosphorylates CSB at Tyr932. our results suggest that c-Abl interacts with and tyrosine phosphorylates CSB. This interaction may play an important role in the response to oxidative stress, resulting in activation of c-Abl, tyrosine phosphorylation of CSB and more efficient BER of oxidative DNA damage. Tyrosine-phosphorylated CSB may serve as a signal for repair proteins to localize to DNA damage and may help maintain active transcription in the nucleolus. SIGNOR-251933 0.273 HOMER proteinfamily SIGNOR-PF59 SIGNOR SHANK3 protein Q9BYB0 UNIPROT up-regulates activity binding 9606 BTO:0000938 17243894 t miannu It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD SIGNOR-264697 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 phosphorylation of nup50 reduces affinity for importin-beta SIGNOR-263043 0.2 GDNF protein P39905 UNIPROT DNM2 protein P50570 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and a-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. SIGNOR-252173 0.2 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT up-regulates quantity by stabilization phosphorylation Ser1424 SYELPARsQIGQKSP 10090 29301787 t lperfetto Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466 SIGNOR-272269 0.262 BTRC protein Q9Y297 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates ubiquitination 9606 10228155 t gcesareni Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels. SIGNOR-67374 0.869 DRAM2 protein Q6UX65 UNIPROT RHOB protein P62745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259145 0.2 PRKACA protein P17612 UNIPROT TH protein P07101 UNIPROT up-regulates activity phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins. SIGNOR-250061 0.372 CEBPA protein P49715 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001370 9706399 t Among several known transcription factor binding motifs, nuclear protein(s) of VD3-treated HL-60 cells and THP-1 cells bound to the CCAAT/enhancer binding protein (C/EBP)-binding motif that was located in the upstream region of the MRP14 gene (-81), as evidenced by the competitive gel mobility-shift assay.|Thus, it was concluded that C/EBP alpha and -beta were able to bind to the C/EBP motif, and that C/EBP alpha bound to the motif in THP-1 cells and C/EBP beta bound to that in the VD3-treated HL-60 cells. SIGNOR-254041 0.228 MTF1 protein Q14872 UNIPROT MCAT protein Q8IVS2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15378601 f miannu MRE-binding transcription factor-1 (MTF-1) is a highly conserved heavy metal-induced transcriptional activator. MTF-1 also activates transcription in response to oxidative stress and regulates the expression of several cytoprotective factor genes, including MT, gamma-glutamylcysteine synthetase, and Cu/Zn-superoxide dismutase. SIGNOR-254600 0.2 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser54 QPLPPRPsPAALPGG 23871434 t lperfetto WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 SIGNOR-275480 0.427 NOTCH1 protein P46531 UNIPROT ZMIZ1 protein Q9ULJ6 UNIPROT up-regulates activity binding 10090 BTO:0001825 26522984 t miannu The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions SIGNOR-263937 0.459 2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)-1-oxopropyl]amino]-1-oxoethyl]amino]-1-oxoethyl]amino]-1-oxo-3-phenylpropyl]amino]-4-methylpentanoic acid chemical CHEBI:91634 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258805 0.8 SLBP protein Q14493 UNIPROT H3-3A protein P84243 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265418 0.2 cyproterone acetate chemical CHEBI:50743 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191235 0.8 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates activity dephosphorylation 9606 BTO:0000007 16461343 t In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. SIGNOR-248837 0.454 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217791 0.775 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259224 0.8 PCSK7 protein Q16549 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000130 19544470 t gcesareni Addition of active p38a induced phosphorylation of wild-type c/ebp_? (c/ebp_?WT) on serine 21 SIGNOR-186202 0.2 sertindole chemical CHEBI:9122 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258548 0.8 DLL4 protein Q9NR61 UNIPROT KDR protein P35968 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18339870 f gcesareni Dll4 down-regulates vascular endothelial growth factor (vegf) receptor 2 and nrp1 expression and inhibits vegf function SIGNOR-178026 0.484 ENMD-2076 chemical CID:16041424 PUBCHEM AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191466 0.8 DVL1 protein O14640 UNIPROT RND1 protein Q92730 UNIPROT up-regulates 9606 23151663 f gcesareni In pcp , dvl binds to proteins such as pkc, atypical pkc (apkc), dvl?associated Activator of morphogenesis 1 (daam1), dvl-associating protein with a high frequency of leu residues (daple) and partitioning defective 6 (par6), which are important for the regulation of small gtpases such as rho and rac and, consequently, the cytoskeleton and cell polarity58. SIGNOR-199387 0.275 EEF1A1 protein P68104 UNIPROT Asp-tRNA(Asp) smallmolecule CHEBI:29158 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269507 0.8 uridine smallmolecule CHEBI:16704 ChEBI uridine 5'-monophosphate(2-) smallmolecule CHEBI:57865 ChEBI up-regulates quantity precursor of 11306702 t lperfetto Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.|We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. SIGNOR-275856 0.8 TFIIH complex SIGNOR-C457 SIGNOR RARA protein P10276 UNIPROT unknown phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 11955452 t llicata Thus, we demonstrate that the cdk7 kinase of tfiih phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes. SIGNOR-269332 0.271 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000763;BTO:0000149 10197981 t gcesareni These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-66763 0.742 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser72 SKVQTTPsKPGGDRY 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250607 0.992 RPS6KA1 protein Q15418 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 10558990 t lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. SIGNOR-72117 0.742 CDK1 protein P06493 UNIPROT TSC1 protein Q92574 UNIPROT unknown phosphorylation Ser584 ETSIFTPsPCKIPPP 9606 14551205 t llicata In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. SIGNOR-118588 0.498 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation 9606 20230789 t inferred from 70% family members lperfetto Accumulating evidence indicates that protein phosphorylation regulates nox activity. In this report, we show that serine282 residue of nox activator 1 (noxa1) is phosphorylated by erk in response to egf resulting in desensitization of nox1 activity SIGNOR-270203 0.2 5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene]thiazolidine-2,4-dione chemical CHEBI:94690 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189912 0.8 GAMT protein Q14353 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates -1 26319512 f Luana GAMT enzyme (EC#2.1.1.2) deficiency caused by mutations in the GAMT gene (MIM# 601240) results in the depletion of creatine and accumulation of guanidinoacetate (GAA). Creatine has a buffering and transport function of high-energy phosphates in brain and muscle and is essential for growth cone migration, dendritic and axonal elongation, neurotransmitter release, and co-transmission on gamma amino butyric acid (GABA) postsynaptic receptors in the central nervous system SIGNOR-265794 0.7 GSK3A protein P49840 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000812 27875297 t lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation SIGNOR-264886 0.2 MAPK1 protein P28482 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser64 QAATGFGsPLQYSAD -1 15133517 t miannu We tested the transcriptional properties of Irx2 by dividing it into amino- and carboxy terminal parts and found that Mek1-mediated phosphorylation activates and derepresses the amino and carboxyl parts, respectively. When Ser46 and Ser65 were mutated to alanine (S46A and S65A), phosphorylation was reduced, whereas substitution of Ser83 and Ser103 (S83A and S103A) did not affect phosphorylation. SIGNOR-263053 0.2 MMP1 protein P03956 UNIPROT COL1A2 protein P08123 UNIPROT down-regulates quantity by destabilization cleavage Gly775 NGPPGPAgSRGDGGP -1 17318226 t lperfetto In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.  SIGNOR-272337 0.408 GGCX protein P38435 UNIPROT PROS1 protein P07225 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265924 0.605 LMX1A protein Q8TE12 UNIPROT CUX2 protein O14529 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 30770393 t miannu Lmx1a drives Cux2 expression in the cortical hem through activation of a conserved intronic enhancer. Lmx1a knockdown abolishes activation of the Cux2 enhancer in the cortical hem SIGNOR-263961 0.288 TNF protein P01375 UNIPROT AKT2 protein P31751 UNIPROT up-regulates 9606 11287630 f lperfetto Tumor necrosis factor (tnf) inhibited insulin-promoted tyrosine phosphorylation of irs-1 and activated the akt/protein kinase b serine-threonine kinase, a downstream target for phosphatidylinositol 3-kinase SIGNOR-106596 0.322 DIP2A protein Q14689 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity binding 10090 BTO:0003102 33622779 t miannu Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. SIGNOR-266593 0.2 WASL protein O00401 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261003 0.784 SOCS1 protein O15524 UNIPROT IFNGR1 protein P15260 UNIPROT down-regulates binding 9606 18708154 t gcesareni Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling SIGNOR-180140 0.666 CAMK2G protein Q13555 UNIPROT SPR protein P35270 UNIPROT unknown phosphorylation Ser213 QQLARETsVDPDMRK 11825621 t llicata Phosphorylation sites of rat sepiapterin reductase (rSPR) by Ca2+/calmodulin-dependent protein kinase II were determined in the present study. Using specific monoclonal anti-phospho-Ser and -Thr antibodies, we found that only Ser residues of rSPR were phosphorylated. We constructed several point mutants of SPR by systematically replacing the three Ser residues by Ala ones. These mutants showed that all three Ser residues, i.e. S46, S196, and S214, of rSPR were phosphorylated. We also recognized that only Ser-213 of human SPR was phosphorylated.  SIGNOR-250705 0.309 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser527 RFRKRTHsAGTSPTI 10090 BTO:0002572 18498745 t lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 SIGNOR-236595 0.784 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9534 BTO:0000318 8378084 t miannu CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription SIGNOR-219634 0.517 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity phosphorylation Ser1773 AAHGKRPsIGNLEHV -1 19074150 t miannu We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry. SIGNOR-263109 0.382 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT up-regulates activity phosphorylation Ser49 CHRLPPGsLSSTPLS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159365 0.2 TSPOAP1 protein O95153 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264363 0.2 Synaptonemal_complex complex SIGNOR-C351 SIGNOR Meiotic_recombination phenotype SIGNOR-PH162 SIGNOR up-regulates 9606 33262143 f miannu The synaptonemal complex (SC) is a meiosis-specific structure formed between homologous chromosomes during prophase that promotes DSB formation and biases repair of DSBs to homologs over sister chromatids. SIGNOR-264204 0.7 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Ala369 DYAPVIPaNMDKKYR -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.Va treated with HNE indicated cleavage at Ala341, Ile508, and Thr1767 under conditions, which the cofactor became inactivated, as measured by prothrombinase activity. SIGNOR-263635 0.37 EGFR protein P00533 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates phosphorylation Tyr199 AFLASPEyVNLPING 9606 BTO:0000150 19254954 t llicata Taken together, these results and those of the ms/ms analyses confirmed tyr-3, tyr-7, and tyr-198 to be primary residues phosphorylated by egfr in the gstp1 protein. The phosphorylation increased gstp1 enzymatic activity significantly, SIGNOR-184379 0.444 Set1-Ash2 HMT complex complex SIGNOR-C352 SIGNOR H3-4 protein Q16695 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 12670868 t miannu The Set1/Ash2 HMT methylates histone H3 at Lys 4 (K4), but not if the neighboring K9 residue is already methylated. SIGNOR-264483 0.2 PTEN protein P60484 UNIPROT RPS6KB1 protein P23443 UNIPROT down-regulates activity dephosphorylation 9606 19436944 f miannu Expression of WT-PTEN also caused decreased activation of Akt, p70 S6K, and Erk signaling pathways.|This may potentially be a result of PTEN inhibition of p70 S6K phosphorylation and may explain the mechanism by which PTEN inhibits proliferation of HSCs. SIGNOR-277080 0.542 CEBPB protein P17676 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 15044620 f miannu C/EBPbeta activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBPbeta interaction region within the proximal MDR1 promoter (-128 to -75). SIGNOR-253771 0.451 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268783 0.8 maraviroc chemical CHEBI:63608 ChEBI CCL3 protein P10147 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193928 0.8 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269173 0.7 PTAFR protein P25105 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257387 0.422 DUSP22 protein Q9NRW4 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 16636663 f miannu IL-6 and LIF-induced LMW-DSP2 expression in murine testicular or hepatoma cell lines, while LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3.|These results strongly suggest that LMW-DSP2 acts as a negative regulator of the IL-6/LIF/STAT3-mediated signaling pathway. SIGNOR-277149 0.363 PICK1 protein Q9NRD5 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity binding 9534 BTO:0000298 25784538 t inferred from family member miannu RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a‚Äìc). The existence of such complex is supported by our co-immunoprecipitation experiments shown above. SIGNOR-270236 0.804 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 BTO:0000782 9710204 t gcesareni The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2). SIGNOR-59635 0.757 MAPK3 protein P27361 UNIPROT SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation Thr622 LGTQVPGtPPPKYNT -1 11805112 t lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-249449 0.282 GATA1 protein P15976 UNIPROT HBG1 protein P69891 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004911 20395365 f Regulation miannu BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. SIGNOR-251806 0.382 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2D3 protein P61077 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271348 0.728 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 SIGNOR-C110 11955436 t gcesareni Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). SIGNOR-116524 0.858 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser1261 PMKKLHVsTINLQKA 10090 BTO:0002572 31186373 t miannu AMPK directly activates mTORC2 to promote cell survival during acute energetic stress. AMPK associates with and phosphorylates mTOR within mTORC2., these data indicate that AMPK phosphorylates mTOR on Ser1261 within mTORC2, an event that correlates with increased mTORC2 autophosphorylation and downstream signaling. SIGNOR-262535 0.556 STOML2 protein Q9UJZ1 UNIPROT LCK protein P06239 UNIPROT up-regulates activity binding 9606 18641330 t Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. SIGNOR-260376 0.2 USP45 protein Q70EL2 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR up-regulates activity deubiquitination 9606 BTO:0001938 25538220 t miannu USP45 associates with the ERCC1–XPF endonuclease. USP45 interacts specifically with ERCC1–XPF via its N-terminal 61 residues. USP45 deubiquitylates ERCC1. USP45 promotes survival of cells exposed to agents that induce DNA damage responses controlled by ERCC1–XPF endonuclease SIGNOR-268504 0.542 HRH1 protein P35367 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257050 0.2 GPER1 protein Q99527 UNIPROT GNB1 protein P62873 UNIPROT up-regulates activity binding 10696571 t GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNB1 stands for the subunit β, which dissociates from the receptor after the binding of GTP on α-subunit. SIGNOR-251103 0.368 BAK1 protein Q16611 UNIPROT DIABLO protein Q9NR28 UNIPROT up-regulates 9606 21210296 f gcesareni Permeabilization of the outer mitochondrial membrane allows the leakage of at least five apoptotic mediators from the mitochondrial intermembrane space, such as cyt c, (diablo/diablo), htra2/omi, apoptosis-inducing factors (aif), and endonuclease g. Such modifications result in their activation and translocation to outer mitochondrial membrane (omm) which helps it to interact with multidomain pro-apototic members, bax/baklike proteins, leading to their oligomerization and formation of pore. SIGNOR-170963 0.51 CADPS protein Q9ULU8 UNIPROT SNAP25 protein P60880 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interacted independently with either syntaxin-1 or SNAP-25 suggesting that CAPS might promote QaQbc-SNARE heterodimer formation. CAPS binding to syntaxin-1 was mediated by the membrane-proximal C-terminal SNARE motif (H3) and membrane linker domain sequences of syntaxin-1 SIGNOR-264338 0.373 FABP4 protein P15090 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264458 0.7 belinostat chemical CHEBI:61076 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257744 0.8 CHEK1 protein O14757 UNIPROT WEE1 protein P30291 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni Chk1 also phosphorylates and stabilizes wee1. SIGNOR-163164 0.601 UBE2I protein P63279 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity sumoylation Lys452 EKSLVLVkLEPWLCR 9606 BTO:0002181 22951831 t scontino One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses. We recently documented that LMP1 induces a third major protein modification by physically interacting with the SUMO-conjugating enzyme Ubc9 through CTAR3 and inducing the sumoylation of cellular proteins in latently infected cells. we identified that IRF7 is sumoylated at lysine 452. SIGNOR-266837 0.29 IKBKB protein O14920 UNIPROT NFKBIB protein Q15653 UNIPROT down-regulates phosphorylation 9606 9346241 t gcesareni We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-52932 0.76 ESRRA protein P11474 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15955695 f miannu In cancer tissue, the expression levels of EAR-2, COUP-TF1, EARgamma, Snail, and Slug decrease, and aromatase expression is then up-regulated through the binding of ERRalpha to S1 and the binding of CREB1 or related factors to CREaro. SIGNOR-253790 0.254 SMO protein Q99835 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 10090 BTO:0002572 16885213 t gcesareni We found that Smo, by virtue of what appears to be constitutive activity, activates all members of the G(i) family but does not activate members of the G(s), G(q), and G(12) families. The activation is suppressed by cyclopamine and other inhibitors of Hedgehog signaling and is enhanced by the Smo agonist purmorphamine. SIGNOR-148487 0.504 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser304 SLLKKRDsFRTPRDS 9606 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163776 0.275 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 10212258 t Manara Tyrosine Phosphorylation of Rad51 by ABL1 Enhances the Interaction between Rad51 and Rad52 | our studies of Rad51·Rad52 complex formation in vitro and in vivo suggest that the ATM and ABL1-mediated signaling is likely to promote repair given the biochemical evidence that Rad51 acts in concert with Rad52 in homologous recombination SIGNOR-260777 0.767 regorafenib chemical CHEBI:68647 ChEBI ABCB1 protein P08183 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu It is suggested that in vitro, regorafenib is an inhibitor of ABCB1 and ABCG2, but not a substrate, and that its active metabolites, M2 (N-Oxide metabolite) and M5 (N-Oxide/N-desmethyl metabolite), are substrates of ABCB1 and ABCG2 SIGNOR-259182 0.8 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 SIGNOR-C3 21071439 t inferred from 70% family members lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-270032 0.2 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT down-regulates activity phosphorylation Tyr731 PYDTLHIyGYEGSES 10029 BTO:0000246 16027153 t lperfetto cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity. SIGNOR-246466 0.578 MAPK1 protein P28482 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 t lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-249454 0.673 clofarabine chemical CHEBI:681569 ChEBI PRIM2 protein P49643 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258360 0.8 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 phosphorylation:Ser62 LLPTPPLsPSRRSGL 15103331 t lperfetto We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1 SIGNOR-249638 0.758 ACTL6B protein O94805 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270749 0.676 3-isobutyl-1-methyl-7H-xanthine smallmolecule CHEBI:34795 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 8754811 f fspada The differentiation of 3t3 preadipocytes into adipocytes is accompanied by a transient induction of c/ebpbeta and c/ebpdelta expression in response to treatment of the cells with methylisobutylxanthine (mix) and dexamethasone (dex), respectively SIGNOR-210068 0.8 TSC2 protein P49815 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT down-regulates 9606 12172553 f gcesareni Here, we show that tsc1-tsc2 inhibits the p70 ribosomal protein s6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4e binding protein 1 (4e-bp1, an inhibitor of translational initiation). SIGNOR-91395 0.536 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser188 QNRYSFYsTCSGQKA -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273490 0.269 RNF125 protein Q96EQ8 UNIPROT DDX58 protein O95786 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0005029 17460044 t miannu Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production. SIGNOR-271647 0.664 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251588 0.699 STRN4 protein Q9NRL3 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 t miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms SIGNOR-261697 0.58 INSR protein P06213 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Tyr350 RRSSLKAyGNGYSSN 10029 BTO:0000246 8557631 t Insulin (10 nM)-stimulated rIR-catalyzed phosphorylation of β2-adrenergic receptor peptides was found prominently in peptides L339 (Tyr350 and Tyr354), T362 (Tyr364), and to a lesser extent peptides Y132 (Tyr132 and Tyr141), and I135 (Tyr141). G-protein-linked receptors and intrinsic tyrosine-kinase growth receptors represent two prominent modalities in cell signaling. Cross-regulation among members of both receptor superfamilies has been reported, including the counter-regulatory effects of insulin on β-adrenergic catecholamine action. Cells stimulated by insulin show loss of function and increased phosphotyrosine content of β2-adrenergic receptors. SIGNOR-251301 0.381 PRKCG protein P05129 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. SIGNOR-248915 0.436 chloroquine chemical CHEBI:3638 ChEBI IL6 protein P05231 UNIPROT down-regulates quantity 9606 32283152 f miannu Chloroquine inhibits the production and release of TNF and IL-6, which indicates that chloroquine may suppress the cytokine storm in patients infected with COVID-19. SIGNOR-260854 0.8 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0001616 16670084 t gcesareni Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein. SIGNOR-245336 0.499 AURKA protein O14965 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 17563743 t llicata Aurora-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest. SIGNOR-155815 0.455 TRIM13 protein O60858 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 t miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. SIGNOR-271851 0.378 CNOT9 protein Q92600 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268303 0.2 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 9606 BTO:0000007 15466476 t lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. SIGNOR-129690 0.563 ACTN1 protein P12814 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 17243894 f miannu On most principal neurons in the mammalian brain (e.g., pyramidal neurons of cortex and hippocampus, Purkinje cells of cerebellum, medium spiny neurons of striatum), the postsynaptic specialization is housed on tiny actin rich protrusions called dendritic spines The size, shape, motility, and stability of dendritic spines depend largely on actin, the primary cytoskeleton within spines. SIGNOR-264618 0.7 ACTR8 protein Q9H981 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270848 0.624 MAPK8 protein P45983 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 9534 BTO:0000298 8137421 t miannu JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain. SIGNOR-250122 0.906 ERBB4 protein Q15303 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-146882 0.472 JAK2 protein O60674 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000599 9575217 t lperfetto Inactive cytoplasmic STATs are recruited to the activated receptor by docking of the STAT SH2 domain to selected receptor tyrosine phosphopeptides, where they are in turn phosphorylated on a single tyrosine by Jak kinases. Has been identified tyrosine 705 of Stat3 as the likely site of phosphorylation by Jak kinases during signal transduction. SIGNOR-238638 0.815 CC2D1A protein Q6P1N0 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 20171170 t nucleus lperfetto Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor. SIGNOR-268295 0.377 MAPK1 protein P28482 UNIPROT CIC protein Q96RK0 UNIPROT down-regulates phosphorylation Ser1409 SAPEDPTsPKRKMRR 9606 BTO:0000848 21087211 t gcesareni Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3 SIGNOR-169875 0.377 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257979 0.8 SIRT5 protein Q9NXA8 UNIPROT HMGCS2 protein P54868 UNIPROT up-regulates activity post translational modification Lys310 PFCKMVQkSLARLMF 9606 BTO:0000007 24315375 t desuccinylation lperfetto We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5 SIGNOR-267642 0.348 SNIP1 protein Q8TAD8 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR down-regulates binding 9606 10887155 t lperfetto In this study, we characterize a novel nuclear protein, termed snip1 its principal mechanism of action appears to be through transcription by binding to cbp/p300 and interfering with the ability of these coactivators to interact with smad4 SIGNOR-217661 0.596 MAML1 protein Q92585 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 11101851 t inferred from 70% of family members gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4 SIGNOR-269934 0.922 PRKCQ protein Q04759 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270273 0.293 SRC protein P12931 UNIPROT VAV3 protein Q9UKW4 UNIPROT up-regulates phosphorylation Tyr173 EDEGGEVyEDLMKAE 9606 BTO:0000785 17998938 t gcesareni Activation of rac1 and the exchange factor vav3 are involved in npm-alk signaling in anaplastic large cell lymphomas. SIGNOR-159240 0.329 GRPR protein P30550 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256917 0.251 KLF1 protein Q13351 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates 9606 BTO:0000725 28026072 f irozzo Activation of KLF1 at day 10 of the differentiation process when hematopoietic progenitor cells were present, enhanced erythroid commitment and differentiation. SIGNOR-256086 0.7 BGJ-398 chemical CHEBI:63451 ChEBI FGFR2 protein P21802 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190266 0.8 NCAPH2 protein Q6IBW4 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity binding 9606 BTO:0000567 31026066 t miannu Taken together these observations suggest that NCAPH2 promotes telomere stability, possibly through a direct interaction with the TRF1 shelterin component, and prevents telomere dysfunction resulting from impaired DNA replication. SIGNOR-263914 0.2 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9534 BTO:0000298 16757346 t miannu We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ SIGNOR-261717 0.292 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265818 0.2 SP3 protein Q02447 UNIPROT ASNS protein P08243 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 11867623 t Luana Sp1 and Sp3 Activate Transcription Driven by the AS Promoter SIGNOR-268020 0.2 MYLIP protein Q8WY64 UNIPROT LDLR protein P01130 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 30896554 t miannu The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells.  SIGNOR-271485 0.719 MECP2 protein P51608 UNIPROT BDNF protein P23560 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 14593183 t Luana We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene. SIGNOR-264540 0.481 TRIM38 protein O00635 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 22323536 t miannu As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6.  SIGNOR-272009 0.437 MCM5 protein P33992 UNIPROT MCM complex SIGNOR-C268 SIGNOR form complex binding 9606 19946136 t The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. SIGNOR-261675 0.767 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA3 protein Q9Y5H0 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265699 0.2 EGR1 protein P18146 UNIPROT PTGES protein O14684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21983014 f In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression.|EGR1 downregulation seems to be the major effect of DMC leading to transcriptional inhibition of mPGES-1 SIGNOR-254249 0.34 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Thr205 EGPSEYQtIPLNKIE -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275519 0.334 Non-structural protein 10 protein P0C6X7-PRO_0000037317 UNIPROT MT-ND4L protein P03901 UNIPROT down-regulates activity binding 9606 BTO:0000764 16157265 t lperfetto This result suggests that the nsp10 protein could affect the activities of NADH and cytochrome oxidase II via a direct interaction while being involved in viral replication. SIGNOR-260253 0.2 CAMKK1 protein Q8N5S9 UNIPROT CAMK1D protein Q8IU85 UNIPROT up-regulates activity phosphorylation Thr180 GKGDVMStACGTPGY BTO:0000567 12935886 t llicata CaM-KIdelta exhibits Ca(2+)/CaM-dependent activity that is enhanced (approximately 30-fold) in vitro by phosphorylation of its Thr180 by CaM-K kinase (CaM-KK)alpha, consistent with detection of CaM-KIdelta-activating activity in HeLa cells. | This sustained activation of CaM-KIdelta was completely abolished by Thr180Ala mutation and inhibited by CaM-KK inhibitor, STO-609, indicating a functional CaM-KK/CaM-KIdelta cascade in HeLa cells. SIGNOR-250715 0.422 CDK1 protein P06493 UNIPROT KMT5A protein Q9NQR1 UNIPROT up-regulates quantity by stabilization phosphorylation Ser100 SKIYSYMsPNKCSGM 9606 20966048 t miannu We found that PR-Set7 is phosphorylated at Ser 29 (S29) specifically by the cyclin-dependent kinase 1 (cdk1)/cyclinB complex, primarily from prophase through early anaphase, subsequent to global accumulation of H4K20me1. While S29 phosphorylation did not affect PR-Set7 methyltransferase activity, this event resulted in the removal of PR-Set7 from mitotic chromosomes. S29 phosphorylation also functions to stabilize PR-Set7 by directly inhibiting its interaction with the anaphase-promoting complex (APC), an E3 ubiquitin ligase. SIGNOR-259832 0.2 PTEN protein P60484 UNIPROT PTK6 protein Q13882 UNIPROT down-regulates activity dephosphorylation Tyr342 RLIKEDVyLSHDHNI -1 29142193 t lperfetto PTEN inhibits PTK6 activity and downstream signaling in prostate cancer cells.|Using an in vitro phosphatase assay, we observed that PTEN was able to dephosphorylate PTK6 at tyrosine residue 342 in a dose dependent manner. SIGNOR-276975 0.423 NCS1 protein P62166 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity 10116 21104311 f miannu In chromaffin and PC12 cells, NCS-1 can enhance secretion via its activation of PI4 kinaseIIIb with the subsequent increase in PIP2 levels. PIP2 has been shown to be an important requirement for exocytosis SIGNOR-263963 0.662 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000938 24916379 t lperfetto Expression of wild-type LRRK2 promoted neuronal survival against apoptosis through activation of the downstream effector, Akt by phosphorylation of Ser473. Phosphorylated Akt in turn inhibited FOXO 1 signaling SIGNOR-205115 0.384 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates activity phosphorylation Tyr206 PGPTRKHyQPYAPPR 8992971 t EMT can phosphorylate all four tyrosines of the CD28 tail. in vivo, tyrosines other than tyrosine 173 become phosphorylated following CD28 stimulation, this finding suggests that, like LCK, one function of EMT during CD28 signaling is phosphorylation of the receptor. SIGNOR-251334 0.682 IRS1 protein P35568 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 10090 BTO:0000944 11416002 t lperfetto To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1 SIGNOR-235487 0.716 IFNG protein P01579 UNIPROT IFNGR2 protein P38484 UNIPROT up-regulates binding 9606 7673114 t gcesareni Ifn-g Binds to the ifn-g Receptor binding subunit (ifn-gR1;receptor chain 1), a species-specific cell surface transmembrane receptor chain (41, 42). A second transmembrane protein (ifn-gR2) (43 45) is required for signal transduction SIGNOR-31013 0.64 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 SIGNOR-C3 20516213 t fstefani The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-165795 0.705 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates 9606 23075495 f inferred from 70% of family members gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-269867 0.8 4-oxobutanoate smallmolecule CHEBI:57706 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 19300440 t miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. SIGNOR-266615 0.8 SREBF2 protein Q12772 UNIPROT LDLR protein P01130 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21123766 t miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. SIGNOR-254453 0.768 PRKCA protein P17252 UNIPROT CD163 protein Q86VB7 UNIPROT unknown phosphorylation Ser1084 QRQRLAVsSRGENLV 9606 BTO:0000801 11298324 t lperfetto Furthermore, we demonstrated that the cytoplasmic domains of CD163 variants are phosphorylated by PKC-alpha in vitro. Inhibition studies using specific kinase inhibitors reveal that both CKII and PKC are involved in the CD163 signaling mechanism resulting in the secretion of proinflammatory cytokines. SIGNOR-249082 0.326 S1PR2 protein O95136 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257289 0.368 IFNG protein P01579 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001760 11009425 f gcesareni In contrast, in differentiated myotubes, tnf plus interferon-gamma (ifn-gamma) signaling was required for nf-kappab-dependent down-regulation of myod and dysfunction of skeletal myofibers. SIGNOR-82467 0.293 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser181 NPLLRKEsAPPSLRR -1 15738054 t lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. SIGNOR-249273 0.487 WNT5B protein Q9H1J7 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131885 0.585 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2C protein P18825 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257455 0.8 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR CDT1 protein Q9H211 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 14578910 t miannu We show that radiation-mediated CDT1 proteolysis is independent of ATM and CHK2 and can occur in G1-phase cells. Loss of the COP9-signalosome (CSN) or CUL4-ROC1 complexes completely suppresses CDT1 proteolysis. CDT1 is specifically polyubiquitinated by CUL4 complexes and the interaction between CDT1 and CUL4 is regulated in part by gamma-irradiation. Our study reveals an evolutionarily conserved and uncharacterized G1 checkpoint that induces CDT1 proteolysis by the CUL4-ROC1 ubiquitin E3 ligase and CSN complexes in response to DNA damage. SIGNOR-272810 0.527 BORA protein Q6PGQ7 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation 9606 18615013 t gcesareni Bora/aurora-a-dependent phosphorylation is a prerequisite for plk1 to promote mitotic entry after a checkpoint-dependent arrest. SIGNOR-179425 0.784 RGCC protein Q9H4X1 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity binding 9606 BTO:0001685 11687586 t miannu RGC-32 was physically associated with cyclin-dependent kinase p34CDC2 and increased the kinase activity in vivo and in vitro. In addition, RGC-32 was phosphorylated by p34CDC2-cyclin B1 in vitro. Mutation of RGC-32 protein at Thr-91 prevented the p34CDC2-mediated phosphorylation and resulted in loss of p34CDC2 kinase enhancing activity. SIGNOR-262726 0.54 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t lperfetto Mtor may promote g1 progression in part through sgk1 activation and deregulate the cell cycle in cancers through both akt- and sgk-mediated p27 t157 phosphorylation and cytoplasmic p27 mislocalization. SIGNOR-244202 0.2 PAK2 protein Q13177 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity phosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277182 0.363 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 9606 BTO:0001271 8622703 t lperfetto We have previously demonstrated that the bcr protein is tyrosine phosphorylated within first-exon sequences by the bcr-abl oncoprotein. Here we report that in addition to tyrose 177 (y-177), y-360 and y283 are phosphorylated in bcr-abl proteins in vitro. Tyrosine-phosphorylated bcr, phosphorylated in vitro by bcr-abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of bcr. SIGNOR-40615 0.2 PRKCA protein P17252 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates activity phosphorylation Ser259 FPLRKTAsEPNLKVR 10116 BTO:0002320 15367659 t lperfetto We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. | Finally, we assessed the ability of PKD to phosphorylate HDAC5 in cells by employing an antibody that specifically recognizes HDAC5 that has been phosphorylated at serine 259. HDAC5 was basally phosphorylated at serine 259, and phosphorylation at this site was dramatically increased by coexpression of constitutively active PKD S/E SIGNOR-249268 0.2 STAT5A protein P42229 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 15498859 t lperfetto Pim-1 is know to be up regulated by signal transducer and activator of transcription 5 (stat5) SIGNOR-259436 0.418 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267866 0.8 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu50 RANTFLEeVRKGNLE -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263676 0.661 PRKCA protein P17252 UNIPROT CSPG4 protein Q6UVK1 UNIPROT up-regulates activity phosphorylation Thr2252 YLRKRNKtGKHDVQV 9606 BTO:0002035 15504744 t miannu Protein kinase C (PKC)-alpha phosphorylation of recombinant NG2 cytoplasmic domain and phorbol ester-induced PKC-dependent phosphorylation of full-length NG2 expressed in U251 cells are both blocked by mutation of Thr(2256), identifying this residue as a primary phosphorylation site. PKC-alpha-mediated NG2 phosphorylation at Thr(2256) is therefore a key step for initiating cell polarization and motility. SIGNOR-263162 0.2 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161605 0.597 ACVR1 protein Q04771 UNIPROT VPS39 protein Q96JC1 UNIPROT up-regulates activity binding 9534 12941698 t miannu TLP interacts with TGF-β and activin receptors in vivo. Endogenous TLP associates with both active and kinase-deficient TGF-beta and activin type II receptors, but interacts with the common-mediator Smad4 only in the presence of TGF-beta/activin signaling. SIGNOR-261376 0.2 SPAST protein Q9UBP0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates cleavage -1 15716377 f Gianni Using real-time imaging, we show that Spastin severs microtubules when added to permeabilized, cytosol-depleted cells stably expressing GFP-tubulin. SIGNOR-269046 0.7 DICER1 protein Q9UPY3 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR form complex binding 9606 23661684 t miannu SIGNOR-143105 0.894 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-192859 0.8 NMDA receptor_2D complex SIGNOR-C350 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266602 0.29 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2T protein Q9NPD8 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271316 0.687 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260128 0.2 HTR1B protein P28222 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256999 0.472 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser41 RTDALTSsPGRDLPP 9606 16446360 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-143996 0.961 LAMB1 protein P07942 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 t lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. SIGNOR-253230 0.714 CYSLTR2 protein Q9NS75 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257024 0.505 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser702 AVILTVEsEEEEEES 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275503 0.2 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 14670079 t gcesareni We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. SIGNOR-120330 0.528 JAK2 protein O60674 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR up-regulates activity phosphorylation 9606 15526160 t miannu Downstream of JAKs are the signal transducers and activators of transcription (STATs), which are phosphorylated by JAKs. SIGNOR-254999 0.809 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARRB2 protein P32121 UNIPROT up-regulates activity phosphorylation Thr276 FCKVYTItPLLSDNR 10090 BTO:0002572 26324936 t done miannu ERK1/2-dependent βarr2 phosphorylation on S14 and T276 induces CXCR4 intracellular sequestration. SIGNOR-274019 0.2 GBAF complex SIGNOR-C467 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 30397315 f miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269790 0.7 CDC23 protein Q9UJX2 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252008 0.914 SAGA complex complex SIGNOR-C465 SIGNOR H3Y1 protein P0DPK2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkATAWQAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269631 0.2 AKT1 protein P31749 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser42 GGRKRRSsRRSAGGG 9606 20400976 t llicata Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis. SIGNOR-164884 0.446 POLR2F protein P61218 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266170 0.873 NSMCE2 protein Q96MF7 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265484 0.881 IKBKB protein O14920 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-124207 0.683 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation 9606 14500912 t �Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. SIGNOR-254978 0.2 PSMA2 protein P25787 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263367 0.849 CADPS protein Q9ULU8 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates activity binding 9606 BTO:0000938 SIGNOR-C346 24363652 t miannu CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly. SIGNOR-264340 0.436 RNGTT protein O60942 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates quantity chemical modification 9606 9512541 f lperfetto The human mRNA 5'-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNAcappingenzyme1), HCE1A and HCE1B , were isolated from a HeLa cDNA library. The HCE1 cDNA has the longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3'-half of the HCE1 ORF was missing in HCE1A and HCE1B , and, additionally, HCE1B has an early translation termi SIGNOR-268356 0.7 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 35318320 t miannu Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. SIGNOR-273843 0.752 SREBF2 protein Q12772 UNIPROT LRP1 protein Q07954 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20980003 f miannu In the present study we report that specific silencing of either SREBP-1 or SREBP-2 enhanced LRP1 whereas overexpression of the active SREBP isoforms decreased LRP1 expression. SIGNOR-254461 0.331 AURKB protein Q96GD4 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Ser192 VNSVRRKsCLVKEVE 9606 17567953 t lperfetto Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres. SIGNOR-155898 0.725 DDR2 protein Q16832 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 16186108 t gcesareni Collectively, our findings are consistent with the following mechanism for src-dependent ddr2 activation and signaling: 1) ligand binding promotes phosphorylation of tyr-740 in the ddr2 activation loop by src;2) tyr-740 phosphorylation stimulates intramolecular autophosphorylation of ddr2;3) ddr2 autophosphorylation generates cytosolic domain phosphotyrosines that promote the formation of ddr2 cytosolic domain-shc signaling complexes. SIGNOR-140724 0.399 PRKAA1 protein Q13131 UNIPROT SYN1 protein P17600 UNIPROT down-regulates activity phosphorylation Ser9 NYLRRRLsDSNFMAN 9606 10880969 t lperfetto It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation SIGNOR-78891 0.2 AKT1 protein P31749 UNIPROT LARP1 protein Q6PKG0 UNIPROT down-regulates activity phosphorylation Ser1056 EGRKRCPsQSSSRPA 9606 BTO:0002181 28650797 t SARA LARP1 is a direct substrate of Akt/S6K1 and mTORC1. Akt is a physiologically relevant primary kinase for S770/S979 phosphorylation of LARP1|Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. SIGNOR-260992 0.291 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268586 0.2 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation Thr208 TFGNKLDtFCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122628 0.576 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 BTO:0000776 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163938 0.8 SOSTDC1 protein Q6X4U4 UNIPROT WNT5B protein Q9H1J7 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242727 0.279 DIO proteinfamily SIGNOR-PF83 SIGNOR 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Thyroid hormone (TH) deiodinases play a pivotal role in the functional diversification of TH signaling. They are involved in development, growth, and metabolic processes, and act in a cell-specific manner in the fine regulation of TH homeostasis. TH deiodinases catalyze activation and inactivation of THs through the removal of one iodine atom in the outer or inner ring of the TH molecule.¬† SIGNOR-267044 0.8 ADRB2 protein P07550 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257192 0.316 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 17010989 t lperfetto Pkc-betaii sensitizes cardiac myofilaments to ca2+ by phosphorylating troponin i on threonine-144. SIGNOR-149957 0.2 GTF2A2 protein P52657 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding -1 8626665 t lperfetto The general transcription factor IIA (TFIIA) binds to the TATA binding protein (TBP) and mediates transcriptional activation by distinct classes of activators. |Our results show that different activators utilize the general factor TFIIA in unique ways and that TFIIA contributes transcription activation functions in addition to the facilitation of TBP-DNA binding. SIGNOR-262591 0.898 MRAP protein Q8TCY5 UNIPROT MC5R protein P33032 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252368 0.402 PTPRG protein P23470 UNIPROT VCL protein P18206 UNIPROT down-regulates activity dephosphorylation Tyr822 KSFLDSGyRILGAVA -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254731 0.2 AURKB protein Q96GD4 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 12686604 t lperfetto We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro. SIGNOR-100165 0.445 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr677 LPITGPEyATPIIMD -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273943 0.354 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 BTO:0000150;BTO:0000782 SIGNOR-C13 16046471 t lperfetto Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. SIGNOR-138903 0.883 VARS1 protein P26640 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates quantity chemical modification 9606 30755602 t miannu Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. SIGNOR-270530 0.8 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR LIN28A protein Q9H9Z2 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269246 0.53 ERG protein P11308 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22140532 f miannu ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. The up-regulation of PIM1 induced by tERG over-expression significantly modified Cyclin B1 levels and increased the percentage of aneuploid cells in the RWPE-1 cell line after taxane-based treatment. Here we provide the first evidence for an ERG-mediated PIM1 up-regulation in prostate cells in vitro and in vivo, suggesting a direct effect of ERG transcriptional activity in the alteration of genetic stability. SIGNOR-254065 0.2 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 9606 BTO:0000007 27383048 t miannu Upon stimulation with TNFα, TNFR1 recruits TRADD, which provides a scaffold for the assembly of complex I at the plasma membrane by binding with RIP1, TRAF2 and cIAP. SIGNOR-42980 0.867 CPSF3 protein Q9UKF6 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 30507380 f lperfetto Replication-dependent (RD) core histone mRNA produced during S-phase is the only known metazoan protein-coding mRNA presenting a 3' stem-loop instead of the otherwise universal polyA tail. A metallo β-lactamase (MBL) fold enzyme, cleavage and polyadenylation specificity factor 73 (CPSF73), is proposed to be the sole endonuclease responsible for 3' end processing of both mRNA classes. SIGNOR-268336 0.7 AKT1 protein P31749 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr39 LKKIRLDtETEGVPS 9606 18354084 t lperfetto Akt phosphorylates cdk2 at threonine 39 residue both in vitro and in vivo. Although cdk2 threonine 39 phosphorylation mediated by akt enhances cyclin-a binding, it is dispensable for its basal binding and the kinase activity. SIGNOR-178058 0.332 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 21808241 t gcesareni Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms. SIGNOR-175779 0.73 A2M protein P01023 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity binding -1 9344465 t lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261801 0.479 CAST protein P20810 UNIPROT CAPN2 protein P17655 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 t lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain SIGNOR-251609 0.902 SLC25A13 protein Q9UJS0 UNIPROT aspartic acid smallmolecule CHEBI:22660 ChEBI up-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265157 0.8 RUNX3 protein Q13761 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 19800882 t gcesareni To investigate the possible mechanism of the down-regulation of hes-1 by runx3, we performed western blot and reporter assay and found that runx3 suppressed intracellular domain of notch1 (icn1)-mediated transactivation of notch signaling while it did not alter the expression of icn1 and recombination signal binding protein-j kappa (rbp-j) in smmc7721 cells. SIGNOR-188338 0.682 ACLY protein P53396 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 19286649 t miannu ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes the synthesis of acetyl-CoA and oxaloacetate using citrate, CoA, and ATP as substrates and Mg(2+) as a necessary cofactor. SIGNOR-267102 0.8 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Thr383 HYRYSDTtDSDPENE 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248545 0.2 SH3PXD2B protein A1X283 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates activity binding 9606 BTO:0000007 20943948 t lperfetto Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation SIGNOR-264707 0.352 NLRC4 protein Q9NPP4 UNIPROT NLRC4 inflammasome complex SIGNOR-C223 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256404 0.746 SLBP protein Q14493 UNIPROT H2AZ1 protein P0C0S5 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265408 0.2 TH protein P07101 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Tyrosine produced in the liver is then transported by an active transport mechanism into the dopaminergic neurons within the brain. This is followed by the conversion of L-tyrosine into L-DOPA through hydroxylation at the phenol ring by the enzyme tyrosine hydroxylase (TH). SIGNOR-263991 0.8 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1B protein P47901 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257462 0.8 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Ser381 RKFNILTsNQKTLTP 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276763 0.291 MAPK3 protein P27361 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-156860 0.697 MAPKAPK2 protein P49137 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Ser326 LTIPPRFsIAPSSLD 9606 18695677 t llicata Here, we have identified mk2 as a major plk1 kinase toward ser326, whose phosphorylation is critical to recruit ?-Tubulin to centrosomes and subsequent establishment of functional bipolar spindles. To our knowledge, this is the first direct evidence to demonstrate that the essential function of plk1 in centrosome maturation and bipolar spindle formation is controlled by its upstream kinase. SIGNOR-179968 0.354 RORA protein P35398 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates quantity by expression transcriptional regulation 28608249 t lperfetto Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005). SIGNOR-265137 0.268 ARHGAP22 protein Q7Z5H3 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260478 0.531 CFL1 protein P23528 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR down-regulates quantity binding 9606 BTO:0000132 27871158 t lperfetto Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. SIGNOR-261836 0.7 AR protein P10275 UNIPROT SEPTIN7 protein Q16181 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253677 0.2 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257923 0.8 P2RY10 protein O00398 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257348 0.2 adenosine smallmolecule CHEBI:16335 ChEBI PI4K2A protein Q9BTU6 UNIPROT down-regulates activity chemical inhibition -1 21704602 t Luana Both PI4K2A and PI4K2B were inhibited by adenosine at concentrations that do not significantly inhibit PI4KA and PI4KB actitvity SIGNOR-258317 0.8 PAX6 protein P26367 UNIPROT GCG protein P01275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000120 12783165 f miannu In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3. SIGNOR-254905 0.602 NMDA proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264704 0.2 Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton SIGNOR-266596 0.7 DVL1 protein O14640 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 15735151 t amattioni Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1. SIGNOR-134285 0.802 KDM6A protein O15550 UNIPROT HOXA10 protein P31260 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260020 0.269 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIF22 protein Q14807 UNIPROT up-regulates phosphorylation Thr463 QGAPLLStPKRERMV 9606 12727876 t lperfetto Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes SIGNOR-216793 0.371 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser68 GQNGEEKsPPNASHP -1 15850461 t miannu CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263085 0.289 LPCAT4 protein Q643R3 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272771 0.8 MBL2 protein P11226 UNIPROT MASP2 protein O00187 UNIPROT up-regulates activity binding 9606 9087411 t lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). SIGNOR-263415 0.734 NMBR protein P28336 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. SIGNOR-107025 0.284 MC5R protein P33032 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268712 0.445 pemetrexed disodium chemical CHEBI:63722 ChEBI DHFR protein P00374 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 t miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). SIGNOR-259290 0.8 NR2F1 protein P10589 UNIPROT PCDH19 protein Q8TAB3 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 34215582 t miannu We demonstrated that high expression of COUP-TFI induces MEC cell fate and protocadherin 19 expression. We next demonstrated that COUP-TFI is able to directly bind to a conserved Sp1/COUP-TFI binding site in the Pcdh19 promoter region by chromatin immunoprecipitation (ChIP) (Fig. 6, E and F). SIGNOR-267223 0.2 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP -1 12468540 t gcesareni Incorporation of Pmp at the 536 site led to 4-fold stimulation of the SHP-1 tyrosine phosphatase activity whereas incorporation at the 564 site led to no effect SIGNOR-246236 0.419 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 23151663 t gcesareni Ror1 and ror2 bind wnt5a. SIGNOR-199644 0.741 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-one chemical CHEBI:91346 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity chemical inhibition 25309440 t inferred from 70% of family members lperfetto Different agents were used to inhibit either the PI3K/Akt or MEK/ERK pathways. The PI3K inhibitor, LY294002, and the Akt inhibitor, Akt inhibitor VIII, were used to inhibit the PI3K/Akt pathway. SIGNOR-269849 0.8 BLK protein P51451 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268214 0.639 HDLBP protein Q00341 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 33941620 f miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. SIGNOR-266695 0.7 NF1 protein P21359 UNIPROT ADCY7 protein P51828 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204246 0.289 GNAI1 protein P63096 UNIPROT HCK protein P08631 UNIPROT up-regulates activity binding -1 11007482 t Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases. SIGNOR-256528 0.336 bisphenol F chemical CHEBI:34575 ChEBI AR protein P10275 UNIPROT down-regulates activity chemical inhibition -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity. Here, we evaluated the endocrine-disrupting risks of the bisphenols by investigating their agonist and antagonist activities with the estrogen (ER), androgen (AR), and aryl hydrocarbon (AhR) receptors. Our results showed that BPA, BPS, and BPF (BPs) have estrogen agonist and androgen antagonist activities and decrease the ERα protein level. . SIGNOR-268734 0.8 trimipramine chemical CHEBI:9738 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258742 0.8 (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI TET2 protein Q6N021 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001883 29090344 t miannu Various studies have tried to investigate how the accumulation of R2-HG promotes leukemogenesis in cooperation with other frequently observed mutations in AML. An important role appears to be the ability of R2-HG to competitively inhibit multiple αKG-dependent dioxygenases. While TET2 normally catalyzes the conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), inhibition of TET2 by R2-HG has been found to result in a hypermethylated gene signature in HSPCs, which overlaps with the signatures of both IDH and TET2-mutated leukemic cells. SIGNOR-261829 0.8 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248557 0.318 UBE3C protein Q15386 UNIPROT CAND2 protein O75155 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000165 12692129 t miannu We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination. SIGNOR-271454 0.396 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250555 0.2 amisulpride chemical CHEBI:64045 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258364 0.8 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser144 NSDESNFsEKLRAST 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276289 0.768 QARS1 protein P47897 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270358 0.2 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser110 SDKKEKKsFSLEEKS 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166317 0.367 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser352 AATNRPNsIDPALRR 9606 BTO:0000150 16551632 t llicata Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I SIGNOR-252491 0.518 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11085989 f miannu We also show for the first time that leptin rapidly stimulates the mRNA expression of the zinc finger transcription factor, Egr-1, in the hypothalamus of mice. Our transfection results suggest that this regulation by leptin occurs by activation of theegr-1 promoter via activation of SHP-2 and of the ERK pathway.  SIGNOR-263507 0.2 AARS1 protein P49588 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270450 0.8 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001061 14761977 t miannu  MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein. SIGNOR-272954 0.656 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 24627466 t lperfetto Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function. SIGNOR-251717 0.742 EEF1A1 protein P68104 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205606 0.301 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 10634209 t lperfetto TNF-induced apoptosis is mediated primarily through the activation of type I receptors SIGNOR-226676 0.924 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT down-regulates activity phosphorylation Ser941 NVRSKVGsTENIKHQ -1 8631898 t miannu Here we show that p110mark phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4. Phosphorylation in vitro leads to the dissociation of MAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability. SIGNOR-250171 0.444 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 t gcesareni Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta SIGNOR-252616 0.891 HOXA11 protein P31270 UNIPROT PRL protein P01236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003697 19727442 t Luana HoxA-11 enhanced upregulation of PRL only in differentiated cells. SIGNOR-261630 0.356 KIF3B protein O15066 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272516 0.7 CAMK2B protein Q13554 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL BTO:0003036 8940188 t llicata By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons. SIGNOR-250688 0.596 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-70436 0.2 PRDM1 protein O75626 UNIPROT FCER2 protein P06734 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000776 11342629 f In this study, we report that PRDI-BF1/Blimp1 can bind to the same functional element in the human CD23b promoter to which BCL-6 and IRF-4 had previously been shown to bind, and that, like BCL-6, Blimp1 can repress IRF-4-transactivating ability SIGNOR-253926 0.258 RPS6KA5 protein O75582 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 12628924 t gcesareni Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276. SIGNOR-99210 0.711 FZD5 protein Q13467 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 25902418 t areggio Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. SIGNOR-258969 0.662 Core Binding Factor complex complex SIGNOR-C214 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 19813271 f The core binding factor (CBF), consisting of a Runx protein and the CBFβ protein, is a transcription factor complex that is essential for emergence of the hematopoietic stem cell (HSC) from an endothelial cell stage. The hematopoietic defects observed in either Runx1 or CBFβ knockout mice underscore the necessity of this complex for definitive hematopoiesis. SIGNOR-255740 0.7 IKBKE protein Q14164 UNIPROT CDK2AP1 protein O14519 UNIPROT unknown phosphorylation Ser46 LSDYGPPsLGYTQGT -1 22427660 t lperfetto CDK2AP1 is phosphorylated at a conserved Ser-46 site in the N-terminal "intrinsically disordered" region by IkappaB kinase epsilon. SIGNOR-264780 0.2 EIF2S1 protein P05198 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity transcriptional regulation 9606 27629041 t miannu ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2alpha, the core of ISR. This leads to global attenuation of Cap dependent translation while concomitantly initiates the preferential translation of ISR specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. eIF2alpha phosphorylation causes a reduction in global protein synthesis while allowing the translation of selected genes including activating transcription factor 4 (ATF4), aiding cell survival and recovery SIGNOR-260169 0.632 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Ser342 RHEAKQRsVQRWREA -1 21423175 t miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). SIGNOR-276316 0.2 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR MECOM protein Q03112 UNIPROT up-regulates quantity by expression methylation 10090 BTO:0001271 22553314 t miannu We hypothesize, based on our ChIP data, that MLL-AF9 up-regulates EVI1 transcription via H3K79 methylation, which is known to be a major gene regulatory mechanism used by some MLL-fusion proteins in leukemia. SIGNOR-260107 0.2 clonidine chemical CHEBI:46631 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258904 0.8 F2 protein P00734 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261859 0.568 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser419 S-->N 9606 25605940 t miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. SIGNOR-276476 0.442 APC-c complex SIGNOR-C150 SIGNOR AURKA protein O14965 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0004055 12023018 t miannu We previously showed that human Aurora-A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora-A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora-A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity. SIGNOR-272612 0.43 RYK protein P34925 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 15454084 t gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled. SIGNOR-129568 0.492 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser1132 RDRVRSMsGGHGLRV -1 27451907 t miannu SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.  SIGNOR-277265 0.59 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219337 0.71 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB3 protein Q9Y5G1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265685 0.2 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR PDPK1 protein O15530 UNIPROT down-regulates activity dephosphorylation 9606 21075311 t gcesareni Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. SIGNOR-243515 0.285 KATNB1 protein Q9BVA0 UNIPROT KATNA1 protein O75449 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 10751153 t miannu In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer SIGNOR-267173 0.769 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR ACTA1 protein P68133 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136175 0.349 YWHAZ protein P63104 UNIPROT GEM protein P55040 UNIPROT up-regulates quantity by stabilization binding 9534 BTO:0000298 14701738 t miannu In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. ​(Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase SIGNOR-261725 0.305 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates activity phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu  Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities. SIGNOR-250272 0.6 HRH1 protein P35367 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257318 0.2 UBXN1 protein Q04323 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 15362974 f miannu Our working hypothesis is that SAKS1 acts as scaffolding protein to enhance the unfolding and proteolytic destruction of a subset of proteins. PNGase removes high-mannose-containing oligosaccharides from MGPs [30], and our results suggest this may be facilitated by the formation of a complex between PNGase, VCP, SAKS1 and ubiquitinated MGPs, as illustrated schematically in Figure 7(B). PNGase has been reported to bind to the S4 component of the proteasome [30], so that the deglycosylation of MGPs by PNGase, followed by VCP-catalysed unfolding, may facilitate their destruction by the proteasome. SIGNOR-261059 0.7 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu612 IKTEEISeVKMDAEF -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261766 0.497 FFAR2 protein O15552 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257276 0.388 PTPRB protein P23467 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni Inally, mrna tissue distribution of these ptps by rt-pcr analysis and coexpression of the wild-type ptps to test their ability to dephosphorylate ligand-activated ghr suggest ptp-h1 and ptp1b as potential candidates involved in ghr signaling. SIGNOR-104580 0.297 carbachol chemical CHEBI:3385 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258618 0.8 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr131 KENLIREyVKQTWNL 9606 BTO:0000776 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246601 0.2 CCNK protein O75909 UNIPROT CyclinK/CDK13 complex SIGNOR-C38 SIGNOR form complex binding 9606 22012619 t miannu We identified a 70-kda cyclin k (cyck) that binds cdk12 and cdk13 to form two different complexes (cyck/cdk12 or cyck/cdk13) in human cells SIGNOR-176786 0.916 LAMTOR4 protein Q0VGL1 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164778 0.924 PPP1R9A protein Q9ULJ8 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 f miannu Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc SIGNOR-269180 0.7 GSK3B protein P49841 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr1938 HREKKEStPSTASLP 10116 BTO:0000938 29642012 t lperfetto In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity. SIGNOR-275763 0.2 CDK1 protein P06493 UNIPROT NDE1 protein Q9NXR1 UNIPROT up-regulates phosphorylation 9606 16682949 t gcesareni We found that nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative cdc2 phosphorylation sites in nde1 and found that alteration of these sites diminishes phosphorylation by cdc2 in vitro and affects the stability of su48-nde1 interactions and the centrosomal localization of nde1. SIGNOR-146734 0.646 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser679 SPDSMNAsRLSQPGQ 9606 BTO:0000007 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251277 0.2 FERMT2 protein Q96AC1 UNIPROT FBLIM1 protein Q8WUP2 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266102 0.779 PTPN22 protein Q9Y2R2 UNIPROT CD247 protein P20963 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 16461343 t amattioni T cell signaling is negatively regulated by the activity of protein-tyrosine phosphatases. Native ptpn22 dephosphorylated tcrzeta in vitro and in cells. SIGNOR-144337 0.454 AGT protein P01019 UNIPROT REN protein P00797 UNIPROT up-regulates activity binding 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260224 0.927 COL1A1 protein P02452 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 f Collagen is the major structural protein in skeletal muscle ECM;...Several studies suggest that perimysial collagen is predominantly type I SIGNOR-254662 0.7 ERG protein P11308 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253925 0.2 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007 SIGNOR-C3 9465032 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). Raft1 phosphorylation of 4e-bp1 on thr-36 and thr-45 blocks its association with the cap-binding protein, eif-4e,in vitro. in response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-55701 0.925 TELO2 protein Q9Y4R8 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000007 20427287 t miannu MTOR exists in two distinct complexes, mTORC1 and mTORC2, that differ in their subunit composition. In this study, we identified KIAA0406 as a novel mTOR-interacting protein. Because it has sequence homology with Schizosaccharomyces pombe Tti1, we named it mammalian Tti1. Tti1 constitutively interacts with mTOR in both mTORC1 and mTORC2. Knockdown of Tti1 suppresses phosphorylation of both mTORC1 substrates (S6K1 and 4E-BP1) and an mTORC2 substrate (Akt) and also induces autophagy. Furthermore, using immunoprecipitation and size-exclusion chromatography analyses, we found that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. SIGNOR-272001 0.534 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT up-regulates activity phosphorylation Tyr232 SQKKEGVyDVPKSQP 10090 BTO:0000938 11279201 t lperfetto Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons. SIGNOR-247084 0.426 SRC protein P12931 UNIPROT MPZL1 protein O95297 UNIPROT up-regulates phosphorylation Tyr241 SHQGPVIyAQLDHSG 9606 11751924 t lperfetto Indeed, our studies indicated that cross-linking of pzr by cona lead to activation of c-src, which may be responsible for phosphorylation of pzr and possibly other proteins. Phosphorylation of pzr in turn recruits shp-2, which by itself is an essential signal transducertyrosine residues 241 and 263 embedded in the itims are responsible for the tyrosine phosphorylation of pzr SIGNOR-113406 0.476 ELF3 protein P78545 UNIPROT SPRR2A protein P35326 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 10773884 f Interestingly, ELF3 suppressed basal keratin 4 promoter activity in both esophageal and cervical epithelial cancer cell lines, a novel result, while simultaneously activating the late-differentiation linked SPRR2A promoter. SIGNOR-254292 0.404 COL12A1 protein Q99715 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Types XII and XIV collagen are fibril-associated collagens with interrupted triple helices (FACITs) localized primarily to perimysium.23 While they appear to link fibrillar collagen to other ECM components, their precise function is not known SIGNOR-254671 0.7 BACE2 protein Q9Y5Z0 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe709 ENPTYKFfEQMQN 9606 10931940 t lperfetto BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein.|Figure 6 Preferred BACE1 and BACE2 cleavage sites. (A) Sequence of APP indicating α- and β-cleavage sites, BACE1- and BACE2-cleavage sites, and the location of mutations analyzed here. APP numbering is that of the 770-aa isoform. SIGNOR-261779 0.555 ZNHIT1 protein O43257 UNIPROT H2AZ1 protein P0C0S5 UNIPROT unknown 9606 BTO:0000887 20473270 f gcesareni The chromatin-remodelling complex snf2-related cbp activator protein (srcap) regulates chromatin structure in yeast by modulating the exchange of histone h2a for the h2a.z variant. We also show that p18hamlet is required for h2a.z accumulation into this genomic region and for subsequent muscle gene transcriptional activation. SIGNOR-165610 0.2 PTP4A3 protein O75365 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity dephosphorylation Tyr783 DTGENPIyKSAVTTV 9606 23092334 t miannu In this study, we demonstrate that PRL-3 directly binds to integrin \u03b21 and dephosphorylates integrin \u03b21-Y783, a key residue for integrin \u03b21 function [ ].|These results indicate that PRL-3 dephosphorylates integrin \u03b21 in vitro and in vivo. SIGNOR-277050 0.515 EIF2B4 protein Q9UI10 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269137 0.691 HHAT protein Q5VTY9 UNIPROT SHH protein Q15465 UNIPROT up-regulates palmitoylation 9606 18534984 t gcesareni Both the shh precursor and mature protein are n-palmitoylated by hhatn-palmitoylation of cys-24 by hhat is required for n-product multimerization and full activity SIGNOR-161548 0.675 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 t lperfetto We show that grb10 is a direct substrate of the p42/44 mitogen-activated protein kinase (mapk)we identified ser(150), ser(418), and ser(476) of human grb10zeta as mapk-mediated in vitro phosphorylation sites. Replacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation. Taken together, our findings suggest that phosphorylation of the adaptor protein may provide a feedback inhibitory mechanism by which grb10 regulates insulin signaling. SIGNOR-138167 0.378 PRKCD protein Q05655 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Ser246 QYQEERRsVKHILFS -1 16479000 t miannu HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. ​(Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient. SIGNOR-276048 0.2 IGF1R protein P08069 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity binding -1 7541045 t lperfetto In our present work, we show that both IRS-1 and SHC interact directly with the juxtamembrane region of the IGFIR in a phosphotyrosine-dependent manner. |We propose a model in which IGFIR autophosphorylation of Tyr-950 forms a direct binding site for the amino-terminal receptor binding domains of SHC and IRS-1. This interaction is presumed to facilitate tyrosine phosphorylation of SHC on Tyr-317 leading to GRB2/SOS interaction SIGNOR-262587 0.73 MAP3K7 protein O43318 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation 9606 9278437 t lperfetto Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway. SIGNOR-50618 0.702 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269352 0.721 H2BC11 protein P06899 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-263720 0.2 PTK2 protein Q05397 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 9416004 t gcesareni Pi3-kinase has also been shown to bind fak in a cell cell adhesion-dipendent manner at the major autophosphorylation site y397. This association could live to activation of pi3-kinase and its downstream effectors. SIGNOR-252726 0.558 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR CRTC2 protein Q53ET0 UNIPROT down-regulates quantity by destabilization ubiquitination Lys212 LDGEMDPkVPAIEEN 9606 BTO:0000007 17805301 t miannu  In the presence of relevant cofactors (DDB1, DET1), COP1 promoted the ubiquitination of wild-type but not COP1-interaction defective VP/AA TORC2 (Fig. 3e). COP1 also stimulated the ubiquitination of TORC2(K213R) but had no effect on TORC2(K628R), suggesting an important role for Lys 628 in this regard (Fig. 3e). We performed mass spectrometry studies to characterize residues in TORC2 that undergo COP1-mediated ubiquitination. This analysis revealed one major (Lys 628) and one minor (Lys 213) site on TORC2 SIGNOR-271666 0.2 SMARCA4 protein P51532 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132922 0.913 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 BTO:0000007 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-252958 0.713 ARNTL protein O00327 UNIPROT CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253626 0.932 ETS1 protein P14921 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12377757 f miannu We have determined that the GP6 sequence -191 to -39 represents the core promoter and that transcription is driven largely by GATA-1 (-176) and c-Ets-1 (-45) sites within this segment. SIGNOR-254082 0.2 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates activity phosphorylation Tyr568 EEINGNNyVYIDPTQ 9606 BTO:0001271 12824176 t lperfetto Upon binding its ligand, stem cell factor (scf), c-kit forms an active dimer that autophosphorylates itself and activates a signaling cascade that induces cell growth./ Tyr-568 and tyr-570 are significantly phosphorylated SIGNOR-102633 0.2 TNF protein P01375 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253477 0.2 PLK2 protein Q9NYY3 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 19889641 t lperfetto Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein. SIGNOR-182155 0.486 RAD23B protein P54727 UNIPROT ERCC1 protein P07992 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275703 0.643 EEF1A1 protein P68104 UNIPROT Lys-tRNA(Lys) smallmolecule CHEBI:16047 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269502 0.8 KMT2A protein Q03164 UNIPROT MLL1 complex complex SIGNOR-C89 SIGNOR form complex binding 9606 24680668 t miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. SIGNOR-204813 0.2 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS1 protein O95835 UNIPROT down-regulates 10090 22863277 f milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-198517 0.8 C3 protein P01024 UNIPROT C3AR1 protein Q16581 UNIPROT up-regulates activity binding 9606 cleavage:Arg671;Arg748 QPAARRRrSVQLTEK;ASHLGLArSNLDEDI 8765043 t complement C3a fragment: PRO_0000005910 lperfetto A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a. SIGNOR-263451 0.727 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 8162590 t gcesareni The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. SIGNOR-36557 0.8 MAP2K4 protein P45985 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation 9606 7839144 t lperfetto Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. SIGNOR-34121 0.581 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr853 HLGRVLGyGAFGKVV 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165055 0.5 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20089851 f Regulation miannu PGC-1α has been reported to induce Mn-SOD expression SIGNOR-251762 0.379 CPSF7 protein Q8N684 UNIPROT CFI complex complex SIGNOR-C388 SIGNOR form complex binding 9606 BTO:0000567 8626397 t lperfetto We report here the purification of CF Im from HeLa cell nuclear extracts. Three polypeptides of 68, 59, and 25 kDa copurified with CF Im activity. SIGNOR-266124 0.784 ARRB2 protein P32121 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity relocalization 21296876 t lperfetto Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs) SIGNOR-275506 0.402 PIK3CA protein P42336 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-252634 0.814 CSF3 protein P09919 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 t gcesareni Granulocyte-macrophage colony-stimulating factor (gm-csf) is an important hematopoietic cytokine that exerts its effects by interaction with the gm-csf receptor (gmr) on the surface of responsive cells. The gm-csf receptor consists of two subunits: gmralpha, which binds gm-csf with low affinity, and gmrbeta, which lacks intrinsic ligand-binding capability but complexes with gmralpha to form a high-affinity receptor (gmralpha/beta). SIGNOR-72511 0.46 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 t gianni In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. SIGNOR-266436 0.537 NFYA protein P23511 UNIPROT SOX18 protein P35713 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 18496767 f miannu co-transfection experiments revealed that over-expression of Sp3 and ZBP-89 down-regulate, while over-expression of NF-Y up-regulates SOX18 promoter activity in HeLa cells SIGNOR-254818 0.2 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR CDH1 protein P12830 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265817 0.2 OGT protein O15294 UNIPROT PFKP protein Q01813 UNIPROT down-regulates activity glycosylation Ser540 VMVPATVsNNVPGSD 9606 BTO:0000018 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267583 0.259 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr217 MAEEKKAyKKAKERE 9606 BTO:0000567 19059208 t miannu We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262850 0.421 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1337 LDSDEDFsDFDEKTD 9606 18171681 t llicata Plk1 phosphorylates ser(1337) and ser(1524) of topoiialpha plk1-associated phosphorylation is essential for the functions of topoiialpha in mitosis SIGNOR-160233 0.489 DCK protein P27707 UNIPROT CDK1 protein P06493 UNIPROT down-regulates activity binding 22850745 t lperfetto We demonstrate that dCK interacts with cyclin-dependent kinase 1 (Cdk1) after IR and that the interaction inhibits Cdk1 activity both in vitro and in vivo. SIGNOR-275805 0.384 COP9 signalosome variant 2 complex SIGNOR-C487 SIGNOR 26S Proteasome complex SIGNOR-C307 SIGNOR up-regulates activity binding 9606 26497135 t miannu The COP9 signalosome (CSN) and the proteasomal LID are conserved macromolecular complexes composed of at least eight subunits with molecular weights of approximately 350 kDa. CSN and LID are part of the ubiquitin–proteasome pathway and cleave isopeptide linkages of lysine side chains on target proteins. CSN cleaves the isopeptide bond of ubiquitin-like protein Nedd8 from cullins, whereas the LID cleaves ubiquitin from target proteins sentenced for degradation. The evolutionary conserved ubiquitin proteasome pathway (UPP) mediates degradation of intracellular proteins in all eukaryotes. This essential process requires three protein complexes: E3 ubiquitin ligases as e.g., cullin-RING ligases (CRLs), CSN and the 26S proteasome. SIGNOR-270794 0.319 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser405 SHPLSLTsDQYKAYL -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikk? And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178411 0.819 MMP11 protein P24347 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272379 0.7 MSH2 protein P43246 UNIPROT BLM protein P54132 UNIPROT up-regulates binding 9606 SIGNOR-C60 15064730 t miannu We show that the recombinant hmsh2/6 protein complex stimulated the ability of the bloom's syndrome gene product, blm, to process holliday junctions in vitro SIGNOR-123699 0.594 PTP4A1 protein Q93096 UNIPROT CDK2 protein P24941 UNIPROT up-regulates 9606 14643450 f gcesareni Cells overexpressing either prl-1 or prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity and significantly lower p21cip1/waf1 protein levels SIGNOR-119418 0.2 P2RY6 protein Q15077 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257277 0.385 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SLC25A27 protein O95847 UNIPROT up-regulates quantity by expression transcriptional regulation 20385226 t lperfetto We present the first direct evidence that UCP4 is regulated by NF-kappaB, mediated via a functional NF-kappaB site in its promoter region, and that UCP4 has a significant role in NF-kappaB prosurvival signaling, mediating its protection against MPP(+) toxicity.|NF-kappaB inhibition significantly suppressed the MPP(+)-induced increase in UCP4 expression. SIGNOR-268984 0.2 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268650 0.8 CLIP1 protein P30622 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates binding 17889670 t lperfetto Microtubule plus end binding proteins (+TIPs) localize to the dynamic plus ends of microtubules, where they stimulate microtubule growth and recruit signaling molecules. Three main +TIP classes have been identified (XMAP215, EB1, and CLIP-170) SIGNOR-264830 0.7 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR NANOS3 protein P60323 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269259 0.355 ACVR1 protein Q04771 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity 9606 18801898 f gcesareni Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle. SIGNOR-243185 0.249 GNAQ protein P50148 UNIPROT PLCE1 protein Q9P212 UNIPROT up-regulates binding 9606 17251915 t gcesareni Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152609 0.285 UBTF protein P17480 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR up-regulates activity binding 9606 15970593 t lperfetto Therefore, we propose that SL1 directs PIC formation, functioning in core promoter binding, RNA polymerase I recruitment, and UBF stabilization and that SL1-promoter complex formation is a necessary prerequisite to the assembly of functional and stable PICs that include the UBF activator in mammalian cells. SIGNOR-269568 0.493 BRIP1 protein Q9BX63 UNIPROT BLM protein P54132 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 21240188 t irozzo In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. SIGNOR-259186 0.648 AURKA protein O14965 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 16082213 t lperfetto We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353 SIGNOR-139396 0.715 PRKACA protein P17612 UNIPROT CHKB protein Q9Y259 UNIPROT up-regulates activity phosphorylation Ser40 PKRRRASsLSRDAER 27149373 t lperfetto Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar. SIGNOR-275629 0.254 PP2B proteinfamily SIGNOR-PF18 SIGNOR DNM2 protein P50570 UNIPROT unknown dephosphorylation 10116 20496096 t inferred from 70% family members CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II |We have recently discovered that the ubiquitously expressed dynamin isoform, dynII, is phosphorylated at S764 specifically during mitosis (unpublished data). We now show that S764 is phosphorylated throughout mitosis and is dephosphorylated at the time of cytokinesis(dynII). SIGNOR-269990 0.2 PRKCA protein P17252 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr760 LFKSATTtVMNPKFA 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249125 0.345 RIPK3 protein Q9Y572 UNIPROT DLD protein P09622 UNIPROT up-regulates activity phosphorylation Thr135 STAVKALtGGIAHLF -1 29358703 t miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. SIGNOR-266372 0.2 COPS4 protein Q9BT78 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270773 0.942 SNAI1 protein O95863 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19055748 f lperfetto We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. SIGNOR-252263 0.324 FOXO1 protein Q12778 UNIPROT FBXO32 protein Q969P5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-236540 0.435 CSF2 protein P04141 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 BTO:0000130 7691413 t gcesareni A g-csfr expression plasmid was introduced into interleukin-3 (il-3)-dependent mouse myeloid precursor fdc-p1 cells that normally do not respond to g-csf. G-csf stimulated proliferation of the transformants these results suggested that the g-csfr, but not the il-3/gm-csf receptors, transduced the neutrophilic differentiation signal into cells. SIGNOR-31963 0.588 4-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-(4-morpholinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-pyridinone chemical CHEBI:91454 ChEBI IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190443 0.8 NGF protein P01138 UNIPROT NGFR protein P08138 UNIPROT up-regulates binding 9606 14699954 t amattioni Neurotrophin binding to p75ntrhas also been shown to induce apoptosis SIGNOR-120555 0.833 CD40 protein P25942 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 12324477 f gcesareni Cd40 ligation up-regulated bcl-2 and bcl-xl as much as 9.7- (p < 0.01) and 6.8-fold (p < 0.01), respectively (fig. 2, b and c). Under similar conditions, cd27 ligation also up-regulated bcl-2 and bcl-xl as much as 5.0- (p < 0.01) and 3.9-fold (p < 0.01), respectively. SIGNOR-93387 0.435 MRPL37 protein Q9BZE1 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262360 0.689 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20044479 t lperfetto We have described that upon ligand binding, igf-1r directly interacts with and phosphorylates pdk1 at tyr373/376 SIGNOR-236544 0.345 Rigosertib sodium chemical CID:23696523 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-195028 0.8 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 15241418 t gcesareni We have mapped cdk4 and cdk2 phosphorylation sites to thr 8, thr 178 and ser 212 in smad3. taken together, these findings indicate that cdk phosphorylation of smad3 inhibits its transcriptional activity and antiproliferative function SIGNOR-126740 0.737 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser434 LTLASERsSPQRKSQ -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262748 0.288 AKT1 protein P31749 UNIPROT MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto Although AKT phosphorylated mTOR at two COOH-terminal sites (Thr2446 and Ser2448) in vitro, Ser2448 was the major phosphorylation site in insulin-stimulated or -activated AKT-expressing human embryonic kidney cells. Transient transfection assays with mTOR mutants bearing Ala substitutions at Ser2448 and/or Thr2446 indicated that AKT-dependent mTOR phosphorylation was not essential for either PHAS-I phosphorylation or p70S6K activation in HEK cells. SIGNOR-251099 0.929 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR down-regulates 10090 BTO:0002572 22863277 f inferred from 70% of family members milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-269868 0.8 USP7 protein Q93009 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270837 0.78 ADORA3 protein P0DMS8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256814 0.438 LCK protein P06239 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr667 ESQEELHyATLNFPG 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Phosphorylation of the tyrosine located at position 667 in an itim motif appears to be necessary for the recruitment of shp-1 and partial recruitment of shp-2 SIGNOR-112495 0.262 regorafenib chemical CHEBI:68647 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259452 0.8 NUMA1 protein Q14980 UNIPROT TUBB4B protein P68371 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-117078 0.389 arachidonic acid smallmolecule CHEBI:15843 ChEBI PTGS2 protein P35354 UNIPROT up-regulates 9606 15878913 f miannu AA increases PC-3 prostate tumor cell growth, total DNA content and endogenous PGE 2 levels via induction of c-fos , cPLA 2 and cox-2 mRNA transcription. SIGNOR-255394 0.8 sorafenib tosylate chemical CHEBI:50928 ChEBI RAF1 protein P04049 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). SIGNOR-259228 0.8 ADCY1 protein Q08828 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates chemical modification 9606 17251915 t gcesareni Typically Gas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate many molecules, including phospholipases, ion channels and lipid kinases. SIGNOR-152546 0.8 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267037 0.8 SIRT5 protein Q9NXA8 UNIPROT SHMT2 protein P34897 UNIPROT down-regulates activity post translational modification Lys280 IVTTTTHkTLRGARS 34929314 t desuccinylation lperfetto Mitochondrial serine hydroxymethyl transferase (SHMT2) is a rate-limiting enzyme that catalyzes the catabolism of serine and drives the proliferation of osteosarcoma cells and colon cancer cells. SIRT5 directly mediates the desuccinylation of Lysine 280 on SHMT2. Therefore, SIRT5 is a candidate target to inhibit serine catabolism SIGNOR-267644 0.236 Caspase 3 complex complex SIGNOR-C221 SIGNOR DFFA protein O00273 UNIPROT up-regulates activity cleavage 9606 9108473 t lperfetto DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3. SIGNOR-256464 0.749 SRC protein P12931 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Tyr1474 GSSNGHVyEKLSSIE -1 11483655 t lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases SIGNOR-247180 0.57 MAPK1 protein P28482 UNIPROT RBFOX2 protein O43251 UNIPROT unknown phosphorylation Thr7 tPGYHGFP 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262761 0.2 prazosin chemical CHEBI:8364 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258473 0.8 SREBF1 protein P36956 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 t inferred from family member gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-267799 0.338 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270895 0.584 POLR1H protein Q9P1U0 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16373708 f miannu ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. SIGNOR-259907 0.2 MECP2 protein P51608 UNIPROT FKBP5 protein Q13451 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16002417 t Luana These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress. SIGNOR-264542 0.31 DYRK1A protein Q13627 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser329 STISGRLsPIMTEQD 9606 BTO:0000887;BTO:0001103 11311120 t lperfetto The kinase dyrk1a phosphorylates the transcription factor fkhr at ser329 in vitro, a novel in vivo phosphorylation siteser(329) phosphorylation also decreases the ability of fkhr to stimulate gene transactivation and reduces the proportion of fkhr present in the nucleus SIGNOR-106829 0.516 PRKCI protein P41743 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation 9606 17609107 t esanto Numb is regulated by phosphorylation since the protein is released from ccss and no longer binds integrins when phosphorylated by atypical protein kinase c (apkc). SIGNOR-156765 0.765 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 t miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251566 0.2 ERG protein P11308 UNIPROT ENG protein P17813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22235125 f miannu It has been shown that ERG is a positive regulator of several EC-restricted genes including VE-cadherin, endoglin, and von Willebrand factor, and a negative regulator of other genes such as interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1. SIGNOR-253916 0.2 MUSK protein O15146 UNIPROT DOK7 protein Q18PE1 UNIPROT up-regulates activity phosphorylation Tyr395 CLPGTVEyQVPTSLR 10090 20603078 t miannu Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes. SIGNOR-273845 0.737 TBX3 protein O15119 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249603 0.402 HES5 protein Q5TA89 UNIPROT ATOH1 protein Q92858 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265145 0.413 AP-3 complex complex SIGNOR-C247 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260668 0.449 CDK11A protein Q9UQ88 UNIPROT CDK11B protein P21127 UNIPROT up-regulates phosphorylation Thr726 KHEYFREtPLPIDPS 9606 21078675 t lperfetto Overall, our data indicated that thr-370 is responsible for the autophosphorylation, dimerization, and kinase activity of cdk11(p58) SIGNOR-169628 0.308 Calcineurin complex SIGNOR-C155 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation Ser67 LKSTLAMsPRQRKKM 10116 11278334 t In vitro and in vivo studies indicated that phospho-Ser-67 inhibitor-1 was dephosphorylated by protein phosphatases-2A and -2B. | However, inhibitor-1 phosphorylated at Ser-67 was a less efficient substrate for cAMP-dependent protein kinase. These results demonstrate regulation of a Cdk5-dependent phosphorylation site in inhibitor-1 and suggest a role for this site in modulating the amplitude of signal transduction events that involve cAMP-dependent protein kinase activation. SIGNOR-252334 0.396 MAPK1 protein P28482 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates phosphorylation Ser250 SSSGVPYsPAIPNKR 9606 22595671 t lperfetto Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling. SIGNOR-197543 0.335 PHF2 protein O75151 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264516 0.2 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 20626350 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-166633 0.806 trichostatin A chemical CHEBI:46024 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257936 0.8 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9694870 f lperfetto Here we report the identification of Smad Binding Elements (SBEs) composed of the sequence CAGACA in the promoter of the JunB gene, an immediate early gene that is potently induced by TGF-beta, activin, and bone morphogenetic protein (BMP) 2. Two JunB SBEs are arranged as an inverted repeat that is transactivated in response to Smad3 and Smad4 co-overexpression and shows inducible binding of a Smad3- and Smad4-containing complex in nuclear extracts from TGF-beta-treated cells. SIGNOR-59476 0.566 SREBF1 protein P36956 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 t inferred from family member gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-270288 0.338 HNF1A protein P20823 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 f inferred from family member miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators SIGNOR-270224 0.315 protriptyline chemical CHEBI:8597 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258737 0.8 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 12645577 t gcesareni These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-99314 0.366 PRKACA protein P17612 UNIPROT CAD protein P27708 UNIPROT down-regulates phosphorylation Ser1406 GAGGRRLsSFVTKGY 9606 17206380 t gcesareni Protein kinase a phosphorylation at thr456 of the multifunctional protein cad antagonizes activation by the map kinase cascade. SIGNOR-151816 0.309 EPHA3 protein P29320 UNIPROT SRC protein P12931 UNIPROT up-regulates binding 9606 BTO:0000938 9632142 t gcesareni We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation. SIGNOR-58139 0.515 WNT7A protein O00755 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-253130 0.764 PAK1 protein Q13153 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 15225553 t lperfetto Pak1 binds and phosphorylates rhogdi both in vitro and in vivo at ser101 and ser174. This resulted in dissociation of rac1-rhogdi, but not rhoa-rhogdi, complexes, as determined by in vitro assays of complexation and in vivo by coimmunoprecipitation analysis. We observed that cdc42-induced rac1 activation is inhibited by expression of pak1 autoinhibitory domain. The dissociation of rac1 from rhogdi and its subsequent activation stimulated by pdgf or egf is also attenuated by pak1 autoinhibitory domain, and this is dependent on the ability of rhogdi to be phosphorylated at ser101/174. SIGNOR-126654 0.602 (S)-selisistat chemical CHEBI:90371 ChEBI SIRT1 protein Q96EB6 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191511 0.8 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser155 FPLRKTVsEPNLKLR -1 15738054 t lperfetto We demonstrate that protein kinase D (PKD; also known as PKCmi), which is activated upon engagement of the TCR, stimulates HDAC7 nuclear export by direct phosphorylation on four serine residues. Conversely, selective PKD inhibition blocks TCR-induced HDAC7 nuclear export and Nur77 expression. In addition, an HDAC7 mutant specifically deficient in phosphorylation by PKD blocks TCR-mediated apoptosis. | PKD1 phosphorylates S155, S181, S321, and S449 of HDAC7 in vitro. SIGNOR-249275 0.487 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser221 QAQRFRFsPMGVDHM 9606 20086103 t lperfetto Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur. SIGNOR-163524 0.628 EP300 protein Q09472 UNIPROT P300/PCAF complex SIGNOR-C7 SIGNOR form complex binding 9606 21131905 t lperfetto Histone acetyltransferases (hats) gcn5 and pcaf (gcn5/pcaf) and cbp and p300 (cbp/p300) are transcription co-activators. SIGNOR-170273 0.659 Y-27632 chemical CHEBI:75393 ChEBI ROCK2 protein O75116 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207893 0.8 SMARCA4 protein P51532 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270608 0.832 BRCA1 protein P38398 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 19074868 t gcesareni The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation SIGNOR-252458 0.515 CAPN2 protein P17655 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains SIGNOR-251611 0.44 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 10656682 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-74831 0.787 DENR protein O43583 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004163 35440133 t miannu DENR directly regulates JAK2 expression. SIGNOR-269675 0.2 F2RL2 protein O00254 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257033 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120196 0.319 NCOA1 protein Q15788 UNIPROT RARA protein P10276 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16606617 f irozzo We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR. SIGNOR-255932 0.701 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007 15327770 t lperfetto TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2. SIGNOR-128406 0.86 TARDBP protein Q13148 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates post transcriptional regulation 9606 BTO:0000567 29562314 t in ALS TDP-43 induces alternative splicing of HNTNPA1 which increases its pathogenic aggregation. TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis SIGNOR-262824 0.41 XL-647 chemical CID:10458325 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 22722787 t XL647 administered on an intermittent or daily-dosing schedule demonstrated antitumor activity in patients with EGFR-activating mutations. gcesareni Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4). SIGNOR-197959 0.8 Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR Cell_polarity phenotype SIGNOR-PH213 SIGNOR up-regulates 9606 23397623 f miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270894 0.7 ZEB2 protein O60315 UNIPROT CTBP1 protein Q13363 UNIPROT up-regulates activity binding 9606 BTO:0000007 12743039 t Luisa The two members of the ZEB family of zinc finger factors (ZEB-1/deltaEF1 and ZEB-2/SIP1) regulate TGFbeta/BMP signaling in opposite ways: ZEB-1/deltaEF1 synergizes with Smad-mediated transcriptional activation, while ZEB-2/SIP1 represses it. Here we report that these antagonistic effects by the ZEB proteins arise from the differential recruitment of transcriptional coactivators (p300 and P/CAF) and corepressors (CtBP) to the Smads. Thus, while ZEB-1/deltaEF1 binds to p300 and promotes the formation of a p300-Smad transcriptional complex, ZEB-2/SIP1 acts as a repressor by recruiting CtBP. SIGNOR-268953 0.482 CYP27B1 protein O15528 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI up-regulates quantity chemical modification 9606 BTO:0000671 12050193 t lperfetto The rate-limiting, hormonally regulated step in the biological activation of vitamin D is its 1alpha-hydroxylation to 1,25-dihydroxyvitamin D [1,25-(OH)(2)D] in the kidney, catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. SIGNOR-270559 0.8 RPS2 protein P15880 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262431 0.904 CD3E protein P07766 UNIPROT NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 BTO:0000661 12110186 t We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. SIGNOR-259934 0.376 AKT2 protein P31751 UNIPROT BCL3 protein P20749 UNIPROT up-regulates quantity by stabilization phosphorylation Ser41 KRPLRAPsPEPAAPR -1 28689659 t miannu Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.  SIGNOR-277359 0.272 EEF1A2 protein Q05639 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269538 0.8 tyrosine smallmolecule CHEBI:18186 ChEBI AminoAcids stimulus SIGNOR-ST5 SIGNOR up-regulates quantity 29259120 t lperfetto All extant life employs the same 20 amino acids for protein biosynthesis SIGNOR-264757 0.7 MED16 protein Q9Y2X0 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266671 0.786 DOT1L protein Q8TEK3 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly. SIGNOR-267151 0.2 INSIG2 protein Q9Y5U4 UNIPROT SCAP protein Q12770 UNIPROT down-regulates activity binding 10029 BTO:0000246 12242332 t insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. SIGNOR-256209 0.71 GCC2 protein Q8IWJ2 UNIPROT IGF2R protein P11717 UNIPROT up-regulates activity relocalization 18195106 t lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector SIGNOR-253085 0.517 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser12 KTLYSFFsPSPARKR 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276087 0.281 SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR PAX7 protein P23759 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000165;BTO:0002314 20887952 t lperfetto TNF-activated p38a kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzy- matic subunit of the complex, leading to the for- mation of repressive chromatin on Pax7 promoter. SIGNOR-235583 0.329 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75013 0.787 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268777 0.8 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 SIGNOR-C301 23438602 t lperfetto We examined the effect of XRCC3 depletion on redistribution of RAD51 upon IR damage|Interestingly, cells expressing the XRCC3 S225A phosphomutant showed compromised chromatin loading of RAD51 upon IR damage (Fig. 4G) while the nuclear and cytosolic fractions of RAD51 were largely unchanged|It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. SIGNOR-263258 0.741 TP53BP1 protein Q12888 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 10090 23333305 t miannu RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination. SIGNOR-259058 0.678 FOXO1 protein Q12778 UNIPROT TCF4 protein P15884 UNIPROT down-regulates activity binding 9606 BTO:0000797 18250171 t Gianni Here we show that the beta-catenin binding to FOXO serves a dual effect. beta-catenin, through binding, enhances FOXO transcriptional activity. In addition, FOXO competes with TCF for interaction with beta-catenin, thereby inhibiting TCF transcriptional activity. SIGNOR-262529 0.269 MPG protein P29372 UNIPROT IGBP1 protein P78318 UNIPROT down-regulates quantity by destabilization monoubiquitination 9606 BTO:0000007 22613722 t miannu  We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. MID1 serves as the E3 ligase for α4 (2B), leading to a conformational change in α4 whereby the UIM of α4 binds in cis to the covalently attached ubiquitin (Ub; 3). This structural rearrangement then leads to calpain-mediated cleavage of the C terminus of α4 (4), allowing for polyubiquitination of PP2Ac by a currently unknown E3 ligase (5) and subsequent degradation by the proteasome. SIGNOR-272040 0.2 PAICS protein P22234 UNIPROT 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-268110 0.8 MMP1 protein P03956 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0005387 19584257 f lperfetto However, we show that soluble factors secreted by SUM102 breast cancer cells stimulated the expression of MMP-1 and CXCR4 in HMFs. As a result, these stromal cells acquired an invasive and migratory phenotype SIGNOR-252265 0.7 ATF6 protein P18850 UNIPROT Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 31226023 f miannu Apart from ER protein chaperones, ATF6 also induces the expression of CHOP and XBP1, thereby connecting the three UPR branches into an integrated signaling network SIGNOR-260182 0.7 PRC1 protein O43663 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity binding 9606 16431929 t miannu KIF14 interacts with PRC1 and citron kinase. We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. I SIGNOR-266423 0.624 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Ser1064 NRKVTIYsFTGNQRN -1 36040231 t miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. SIGNOR-276866 0.2 SNAI2 protein O43623 UNIPROT ESR1 protein P03372 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 20509143 f miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. SIGNOR-255154 0.429 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr154 ICLEDIHtSRVVAHV 9606 17568776 t lperfetto Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53 SIGNOR-156068 0.298 NF1 protein P21359 UNIPROT ADCY6 protein O43306 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204195 0.265 MAPK3 protein P27361 UNIPROT MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation Ser454 TGSTPPVsPTPSERS 9606 18694962 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-179963 0.2 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser6 sQLDSDFS 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100649 0.871 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182975 0.737 AR protein P10275 UNIPROT WEE1 protein P30291 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253678 0.262 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258005 0.8 PRKCD protein Q05655 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Ser139 EEWTRHGsFVNKPTR 9606 16963224 t The effect has been demonstrated using P29353-2 gcesareni Pkc delta phosphorylates p52shca at ser29 to regulate erk activation in response to h2o2. SIGNOR-149398 0.557 FBXO6 protein Q9NRD1 UNIPROT CHEK1 protein O14757 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19716789 t miannu  Here, we report that DNA damage not only activates Chk1, but also exposes a degron-like region at the carboxyl terminus of Chk1 to an Fbx6-containing SCF (Skp1-Cul1-F box) E3 ligase, which mediates the ubiquitination and degradation of Chk1 and, in turn, terminates the checkpoint. SIGNOR-271879 0.505 NLGN4X protein Q8N0W4 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264155 0.764 HIPK2 protein Q9H2X6 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser85 PLPDAGAsPAPSRCC 23871434 t lperfetto WIP1, a homeostatic regulator of the DNA damage response, is targeted by HIPK2 for phosphorylation and degradation|Analysis of the phosphoamino acids of WIP1 revealed that both Ser85 and Ser54 are phosphorylation sites, confirming that HIPK2 is a protein kinase for WIP1 phosphorylation at Ser54 as well as Ser85 SIGNOR-275481 0.427 DLGAP5 protein Q15398 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264598 0.454 nitric oxide smallmolecule CHEBI:16480 ChEBI GUCY1A2-B2 complex SIGNOR-C137 SIGNOR up-regulates activity chemical activation 9606 15036565 t gcesareni One of the most biologically relevant actions of NO is its binding to the heme moiety in the heterodimeric enzyme, soluble guanylyl cyclase (sGC). Activation of sGC by NO results in the production of the second messenger molecule, 3€²,5€²-cyclic guanosine monophosphate (cGMP) SIGNOR-243961 0.8 DLL1 protein O00548 UNIPROT NOTCH3 protein Q9UM47 UNIPROT up-regulates binding 9606 11006133 t gcesareni These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors. SIGNOR-82398 0.62 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258793 0.8 PXN protein P49023 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity 9606 BTO:0000182 phosphorylation:Tyr88 PQSSSPVyGSSAKTS 27447856 f lperfetto Together, our data suggest that phosphorylation of paxillin Y88 activates AKT through the paxillin-p130Cas-p85/PI3K-AKT signaling axis and promotes colorectal tumorigenesis SIGNOR-263979 0.918 NEU1 protein Q99519 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR down-regulates activity binding 9606 BTO:0003554 32164705 t miannu NEU1 disrupts FN/ α5β1 interaction. taken together, strongly indicate that overexpressed NEU1 inhibits the Akt pathway by disrupting FN-integrin α5β1 interaction. SIGNOR-260658 0.2 TNKS protein O95271 UNIPROT TARDBP protein Q13148 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0000142 32409565 t lperfetto Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. SIGNOR-262115 0.2 DYRK2 protein Q92630 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 BTO:0000150 22307329 t lperfetto Degradation of c-jun/c-myc is a critical process for the g(1)/s transition, which is initiated upon phosphorylation by glycogen synthase kinase 3 ? (gsk3?). However, a specific kinase or kinases responsible for priming phosphorylation events that precede this gsk3? Modification has not been definitively identified. Here, we found that the dual-specificity tyrosine phosphorylation-regulated kinase dyrk2 functions as a priming kinase of c-jun and c-myc.The finding that kinase-active dyrk2 phosphorylated gst_c-jun210_310-wt by detection with an anti_phospho_c-jun(ser243) antibody demonstrated that dyrk2 is a ser243 kinase in vitro SIGNOR-195771 0.258 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270912 0.547 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI down-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5√¢‚Ǩ¬≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-268059 0.8 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT up-regulates activity phosphorylation Ser299 FLELVVSsDKREARQ 9606 17006539 t gcesareni A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. SIGNOR-149948 0.2 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 t inferred from family member miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-267802 0.8 EDNRA protein P25101 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257378 0.531 SMARCA2 protein P51531 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270688 0.824 AURKA protein O14965 UNIPROT AURKA protein O14965 UNIPROT up-regulates phosphorylation Thr288 APSSRRTtLCGTLDY 9606 24867643 t lperfetto The upstream pak1 kinase can phosphorylate aurora a at t288, autophosphorylation appears to be the essential mode of activation. Our experiments suggest that phosphorylation of t288 is important for regulation of the aurora2 kinase both for its activity and its stability SIGNOR-205106 0.2 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Ser367 GTQNPVSsPGMSQEL 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276587 0.432 PRKAA1 protein Q13131 UNIPROT USP10 protein Q14694 UNIPROT up-regulates activity phosphorylation Ser76 DTLPRTPsYSISSTL 9606 BTO:0001109 26876938 t miannu Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10.  SIGNOR-277207 0.311 STAT1 protein P42224 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 19029990 f lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249496 0.7 BLVRB protein P30043 UNIPROT biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity chemical modification 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275524 0.8 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates ubiquitination 9606 17591695 t gcesareni Arkadia interacts with snon and induces its ubiquitination irrespective of tgf-beta/activin signaling, but snon is efficiently degraded only when it forms a complex with both arkadia and phosphorylated smad2 or smad3 SIGNOR-156430 0.717 PRKAA2 protein P54646 UNIPROT HNF4A protein P41235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser313 GKIKRLRsQVQVSLE 10029 BTO:0000246 12740371 t miannu AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. Phosphorylation of HNF4α on Ser-304 reduces protein stability. SIGNOR-250322 0.372 PRKCA protein P17252 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249278 0.422 PRKACA protein P17612 UNIPROT GLI1 protein P08151 UNIPROT down-regulates phosphorylation 16293631 t We report that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1.We provide direct evidence to support that the cAMP/PKA signaling axis regulates Gli1 protein localization primarily through a site at Thr374. .These data suggest that Thr374 is an important PKA site responsible for PKA phosphorylation and for the transcriptional activity of Gli1. SIGNOR-253539 0.538 EXOSC8 protein Q96B26 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261384 0.912 ARHGAP35 protein Q9NRY4 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260492 0.891 CDK3 protein Q00526 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273169 0.244 HRH2 protein P25021 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257317 0.251 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser91 ALDCSQVsPPRPATS 9606 BTO:0000567 12851383 t lperfetto We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner. SIGNOR-103254 0.463 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp78 PNVVAARdVPEGMQN 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-256434 0.37 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates activity phosphorylation Thr312 QATQPLAtPVVSVTT 9606 9858528 t lperfetto We show that mef2a, but not mef2b or mef2d, is a substrate for p38. Threonines 312 and 319 are the key regulatory phosphorylation sites by p38 in mef2a. Phosphorylation at these sites enhances transcriptional activity of mef2a SIGNOR-62780 0.652 PTEN protein P60484 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity binding 9606 BTO:0000007 25829446 t irozzo Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity. SIGNOR-259190 0.612 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser772 LFKKIFPsLELNITD 9606 BTO:0004553 24614225 t gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. SIGNOR-266433 0.309 1-(1-naphthalenyl)piperazine chemical CHEBI:108599 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258683 0.8 NELFCD protein Q8IXH7 UNIPROT NELF complex SIGNOR-C521 SIGNOR form complex binding 9606 18628398 t miannu The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. It is composed of four subunits, NELF-A, NELF-B, NELF-C/D, and NELF-E. SIGNOR-271399 0.857 IL5RA protein Q01344 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 21106848 f Human blood eosinophils exhibit a hyperactive phenotype in response to chemotactic factors after cell priming with IL-5 family cytokines. Earlier work has identified ERK1/2 as molecular markers for IL-5 priming SIGNOR-254350 0.2 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252883 0.403 UDP-D-galactose smallmolecule CHEBI:18307 ChEBI lactose smallmolecule CHEBI:17716 ChEBI up-regulates quantity precursor of 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268471 0.8 ITGB8 protein P26012 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257729 0.457 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194346 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFB6 protein O95139 UNIPROT up-regulates activity phosphorylation Thr5 tPDEKLRL 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275597 0.25 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 30230471 f lperfetto In keeping with the overall improvement in insulin sensitivity we found that insulin-induced IR Y1162/Y1163 tyrosine phosphorylation and activation and downstream PI3K/AKT signaling in the liver (as monitored by AKT Ser-473 phosphorylation) were dramatically enhanced by POMC TCPTP deficiency (Figure 4h).|This would suggest that TCPTP deletion, or decreased TCPTP in POMC neurons in response to feeding, represses HGP by enhancing IR signaling and permitting POMC neurons to be activated by insulin. SIGNOR-276956 0.611 NDFIP2 protein Q9NV92 UNIPROT NEDD4 protein P46934 UNIPROT up-regulates activity relocalization 9606 BTO:0002181 26363003 t SARA Ndfip1 is primarily localized in the Golgi apparatus where it recruits Nedd4-2 to mediate the degradation of mature hERG proteins during channel trafficking to the plasma membrane. Although Ndfip2 directs Nedd4-2 to the Golgi apparatus, it also recruits Nedd4-2 to the multivesicular bodies (MVBs), which may impair MVB function and impede the degradation of mature hERG proteins mediated by Nedd4-2. SIGNOR-260996 0.58 BRAF protein P15056 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 BTO:0000142 8668348 t gcesareni We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l. SIGNOR-42664 0.743 RUNX3 protein Q13761 UNIPROT CHUK protein O15111 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255090 0.2 GSK3B protein P49841 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Thr171 ETSKSFVtPPQSHFV 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276906 0.261 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser81 AAGSGAAsPSAAEKG -1 8034575 t lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | The other phosphorylated peptides were subjected to the same analysis, and Ser45 (peptide K5), Sel-80(peptide K7), and Ser99 (peptide K8) were confirmed to be the phosphorylation sites. SIGNOR-248910 0.724 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT up-regulates quantity deubiquitination 9606 BTO:0003704 27302062 t Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes. SIGNOR-266905 0.457 INSR protein P06213 UNIPROT CALM2 protein P0DP24 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266320 0.356 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr519 EDPYAGStDENTDSE 9606 BTO:0000567 15367657 t lperfetto Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair. Rcc1 is phosphorylated in vivo and in vitro by ck2, and ck2 phosphorylation of xrcc1 on s518, t519, and t523 SIGNOR-128897 0.401 IL12A protein P29459 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10653850 f miannu IL-18, originally described as IFN-γ-inducing factor, is secreted from activated macrophages and Kupffer cells (1–3). The major activity associated with this cytokine is induction of IFN-γ production from CD4+ Th1 cells, T cells, B cells and NK cells, especially in collaboration with IL-12 SIGNOR-260861 0.371 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CD274 protein Q9NZQ7 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002548 27572267 t miannu We show that glycogen synthase kinase 3β (GSK3β) interacts with PD-L1 and induces phosphorylation-dependent proteasome degradation of PD-L1 by β-TrCP. SIGNOR-277277 0.2 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding -1 BTO:0000567 16729043 t lperfetto We determined interaction partners to all cytosolic tyrosine residues of the four members of the ErbB-receptor family in an unbiased fashion by quantitative proteomics using pull-down experiments with pairs of phosphorylated and nonphosphorylated synthetic peptides. Each receptor had characteristic preferences for interacting proteins and most interaction partners had multiple binding sites on each receptor. EGFR and ErbB4 had several docking sites for Grb2, while ErbB3 was characterized by six binding sites for PI3K. SIGNOR-236327 0.922 SRC protein P12931 UNIPROT KRAS protein P01116 UNIPROT up-regulates phosphorylation 9606 9096340 t gcesareni Expression of v-src, a transforming nonreceptor tyrosine kinase, results in ras activation, and ras function in nih 3t3 cells suppresses transformation by v-src, indicating that in these cells ras-dependent signaling pathways are required for v-src to exert its biological effects. SIGNOR-47152 0.65 PDGFB protein P01127 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity binding 9606 11331882 t miannu Pdgf-b activates both pdgfr-alpha and pdgfr-beta SIGNOR-107397 0.711 hydrogen peroxide smallmolecule CHEBI:16240 ChEBI MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni These findings suggest that c-src mediated bmk1 activation by h(2)o(2) may counteract ischemic cellular damage probably through the activation of mef2c transcription factor. SIGNOR-113758 0.8 DNAJC3 protein Q13217 UNIPROT EIF2AK4 protein Q9P2K8 UNIPROT down-regulates activity binding 9606 BTO:0000567 25329545 t gcesareni € we show that p58IPK is a general inhibitor of the eIF2 kinases in that it also interacts with GCN2 SIGNOR-246204 0.566 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexenyl]methyl]-1-piperazinyl]-N-[4-[[(2R)-4-(4-morpholinyl)-1-(phenylthio)butan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide chemical CHEBI:94128 ChEBI BCL2 protein P10415 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189150 0.8 PTPN11 protein Q06124 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates dephosphorylation Tyr1023 DLVDAEEyLVPQQGF -1 32024694 t lperfetto ...which in turn suggests the importance SHP2 dephosphorylation of pTyr992 in EGFR and pTyr1023 in HER2 to mediate signaling.|More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors. SIGNOR-262957 0.834 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr126 RDAMVRDyVRQTWKL 9606 BTO:0000661 7961936 t lperfetto We show that ZAP-70 has a primary autophosphorylation site at Tyr-292, with a secondary site at Tyr-126. We also show additional phosphorylation at Tyr-69, Tyr-178, Tyr-492, and Tyr-493 upon the addition of the protein tyrosine kinase, p56lck. By comparative two-dimensional phosphopeptide mapping, we show that ZAP-70 isolated from Jurkat T cells also autophosphorylates at Tyr-292 and Tyr-126 SIGNOR-247044 0.2 C1QC protein P02747 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR form complex binding -1 29449492 t lperfetto C1q comprises 18 polypeptide chains; three chains of C1q-A, -B, and -C trimerize to form six collagen-like triple helices connected to six globular (trimeric) ligand-recognition (gC1q) modules (fig. S1B) (1). SIGNOR-263389 0.565 ERCC6 protein Q03468 UNIPROT APEX1 protein P27695 UNIPROT down-regulates activity binding 9606 17567611 t Regulation miannu CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP-DNA substrates, with the latter being more pronounced (up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity. SIGNOR-251932 0.425 PPARGC1A protein Q9UBK2 UNIPROT CYCS protein P99999 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000443 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253097 0.387 COL18A1 protein P39060 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium SIGNOR-254679 0.7 EDNRA protein P25101 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 BTO:0000671 10199825 t gcesareni We studied the ability of et receptors to activate galfa13 using an assay for g protein alfa-chain activation that is based on the fact that an activated (gtp-bound) alfa-chain is resistant to trypsinization compared with an inactive (gdp-bound) alfa-chain. SIGNOR-66856 0.549 FOXO1 protein Q12778 UNIPROT TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18612045 f lperfetto Transcriptional reporter assays performed in both HepG2 and C2C12 cells demonstrate that the MuRF1 promoter is highly responsive to dexamethasone-activated glucocorticoid receptor (GR) and FoxO1 individually, while co-overexpression of GR and FoxO1 leads to a dramatic synergistic increase in reporter activity SIGNOR-235367 0.412 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Thr74 SVLTGKLtTVFLPIV -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263587 0.4 ABL1 protein P00519 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Tyr194 DVQKSKEyFSKQK -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276278 0.392 PRKCB protein P05771 UNIPROT EEF1A1 protein P68104 UNIPROT up-regulates activity phosphorylation Ser53 AAEMGKGsFKYAWVL 10090 20923971 t miannu PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein. SIGNOR-263167 0.2 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000938 10708759 t esanto Autophosphorylated trka binds directly to plc?, Abl, and shc. SIGNOR-75405 0.643 PRKAA1 protein Q13131 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity phosphorylation Ser374 GDTLLGLsDSEVEEL -1 31805502 t miannu MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected. SIGNOR-277494 0.2 CDK1 protein P06493 UNIPROT CENPA protein P49450 UNIPROT down-regulates quantity by destabilization phosphorylation Ser68 LIRKLPFsRLAREIC 9606 BTO:0000567 34758320 t miannu Here, we report that the phosphorylation of CENP-A Ser68 primes the ubiquitin-proteasome-mediated proteolysis of CENP-A during mitotic phase in human cultured cells.the mitotic CENP-A degradation specifically depends on Cdk1 activity. SIGNOR-277576 0.672 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT down-regulates activity phosphorylation Ser338 KGKRGGHsSVSTESE 9606 10521508 t Manara Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization. SIGNOR-260900 0.2 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser483 SMQPDNSsDSDYDLH 9606 9834084 t lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) SIGNOR-62307 0.346 S1PR3 protein Q99500 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257330 0.368 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr401 STTGLSAtPPASLPG 9606 21135229 t lperfetto We show that b-raf is a calcineurin substrate;among calcineurin target residues on b-raf is t401, a site of negative feedback phosphorylation by erk1/2. Blocking calcineurin activity in _ cells prevents dephosphorylation of b-raf t401 and decreases b-raf and erk1/2 activities. SIGNOR-170339 0.2 MAPK11 protein Q15759 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target SIGNOR-65586 0.751 IKBKE protein Q14164 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity phosphorylation 9606 15489227 t miannu Constitutive and interleukin-1-inducible Phosphorylation of p65 NF-{kappa}B at Serine 536 Is Mediated by Multiple Protein Kinases Including I{kappa}B Kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF Family Member-Associated (TANK)-binding Kinase 1 (TBK1). Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro. SIGNOR-217379 0.428 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser389 LKEAEEEsSGGEEED 9606 18649047 t gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. SIGNOR-179542 0.399 CSNK1D protein P48730 UNIPROT PPP5C protein P53041 UNIPROT up-regulates activity phosphorylation Thr362 LFSEDGVtLDDIRKI 9606 BTO:0000007 29141220 t miannu  Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.  SIGNOR-277373 0.337 ATP6AP1 protein Q15904 UNIPROT RAB7A protein P51149 UNIPROT up-regulates activity binding 22467241 t lperfetto We found that Ac45 colocalized with Rab7 in resorbing osteoclasts cultured on bone slices (Fig. 6A). In addition, a co-immunoprecipitation assay revealed that Ac45 directly interacted with Rab7| Therefore, Ac45’s role in extracellular acidification, lysosomal trafficking, and cathepsin K exocytosis may be through the Rab7 pathway. SIGNOR-261484 0.292 CSNK2A1 protein P68400 UNIPROT VDR protein P11473 UNIPROT up-regulates phosphorylation Ser208 SFSNLDLsEEDSDDP 9606 17368182 t lperfetto Casein kinase ii (ckii) phosphorylates vdr both in vitro and in vivo at serine 208 within the hinge domain. This phosphorylation does not affect the ability of vdr to bind dna, but increases its ability to transactivate target promoters SIGNOR-153711 0.339 NFIA protein Q12857 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268894 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PRKAR1A protein P10644 UNIPROT up-regulates phosphorylation Ser83 DSREDEIsPPPPNPV 9606 BTO:0000093 16582606 t lperfetto In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue. SIGNOR-216729 0.304 PTPRG protein P23470 UNIPROT DAB1 protein O75553 UNIPROT down-regulates activity dephosphorylation Tyr198 EDVEDPVyQYIVFEA -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254697 0.2 NatA complex SIGNOR-C415 SIGNOR Protein_acetylation phenotype SIGNOR-PH189 SIGNOR up-regulates 9606 21351257 f miannu About 80% of soluble human proteins are N-terminally acetylated by 1 of 3 major Nα-terminal acetyltransferase complexes, hNatA, hNatB and hNatC, which differ in their subunit composition and substrate specificity. SIGNOR-267229 0.7 SLBP protein Q14493 UNIPROT H2AW protein Q7L7L0 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265409 0.2 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni In this study, we demonstrate that akt also regulates the activity of fkhrl1, a member of the forkhead family of transcription factors. In the presence of survival factors, akt phosphorylates fkhrl1, leading to fkhrl1's association with 14-3-3 proteins and fkhrl1's retention in the cytoplasm. Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252818 0.706 UBE2D1 protein P51668 UNIPROT MPG protein P29372 UNIPROT up-regulates activity binding -1 25207814 t miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. We observed that PP2Ac was ubiquitinated in the presence of UbcH5a-c and UbcH6, similar to results obtained with MID1-catalyzed ubiquitination of alpha4 (Figure 2E) SIGNOR-271927 0.2 CAMKK2 protein Q96RR4 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates activity phosphorylation Thr200 EHQVLMKtVCGTPGY 7615569 t llicata Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation. SIGNOR-250718 0.61 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 BTO:0000007 22724072 t PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65 SIGNOR-270345 0.2 TRIP12 protein Q14669 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20208519 t miannu ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. SIGNOR-266781 0.594 RBPJ protein Q06330 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000165 10066785 t gcesareni ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA SIGNOR-243178 0.59 PTH protein P01270 UNIPROT PTH1R protein Q03431 UNIPROT up-regulates binding 9606 18981475 t gcesareni Here we show that binding of pth to its receptor pth1r induced association of lrp6, a coreceptor of wnt, with pth1r. The formation of the ternary complex containing pth, pth1r, and lrp6 promoted rapid phosphorylation of lrp6, which resulted in the recruitment of axin to lrp6, and stabilization of beta-catenin. SIGNOR-182039 0.767 UTS2R protein Q9UKP6 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257377 0.419 AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR Early Endosome complex SIGNOR-C246 SIGNOR up-regulates activity relocalization 9606 23144738 t lperfetto Rabip4' colocalized with AP-3 on a tubular subdomain of early endosomes and the extent of colocalization was increased by a dominant negative rab4 mutant. Knock-down of AP-3 had an ever more dramatic effect and caused accumulation of lysosomes in protrusions at the plasma membrane. The most peripheral lysosomes were localized beyond microtubules, within the cortical actin network. Our results uncover a novel function for AP-3 and rabip4' in regulating lysosome positioning through an interorganellar pathway. SIGNOR-260712 0.2 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000007 11970898 t Immunoblots with phospho-specific antibodies confirmed that PTP1B suppresses phosphorylation of the Jak2 activation site tyrosines (Y1007/Y1008) and Stat3 in a dose-dependent manner SIGNOR-248404 0.793 MIR9-1HG protein Q13536 UNIPROT FOS protein P01100 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002874 10995546 t Luana CROC-4: a novel brain specific transcriptional activator of c-fos expressed from proliferation through to maturation of multiple neuronal cell types. SIGNOR-261569 0.2 DRAM2 protein Q6UX65 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. SIGNOR-259146 0.31 TNFRSF10B protein O14763 UNIPROT FADD protein Q13158 UNIPROT up-regulates binding 9606 14585074 t amattioni Fadd binds to ligated trailr1 or trail-r2 SIGNOR-98565 0.846 MAPK8 protein P45983 UNIPROT BMF protein Q96LC9 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 12591950 t miannu Activated JNK causes BimL and Bmf phosphorylation in vivo. It is known that UV radiation causes the release of Bim and Bmf from dynein and myosin V motor complexes and that these proteins cause Bax/Bak-dependent apoptosis . The results of this study demonstrate that JNK can engage this apoptotic pathway by phosphorylation of BH3-only proteins, including Bim and Bmf. SIGNOR-250116 0.682 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 11604500 t lperfetto The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding. SIGNOR-111056 0.799 SLC9A8 protein Q9Y2E8 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265598 0.8 RBX1 protein P62877 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271439 0.598 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT up-regulates activity phosphorylation Ser113 LHPYSPLsPKGRPSS 9606 30105797 t done miannu Cyclin B/cyclin-dependent kinase 1 (CDK1) phosphorylates inhibitor of apoptosis stimulating protein of P53 (iASPP) to promote iASPP nucleus localization and its inhibitory effect on p53.  SIGNOR-273586 0.514 PTK6 protein Q13882 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10980601 t gcesareni The phosphorylation of and association with bks by brk was also dependent on the sh2-like domain present within bks.bks is a substrate for the kinase activity of brk and has the characteristics of an adaptor protein. SIGNOR-81489 0.718 PLK1 protein P53350 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates phosphorylation Ser216 IPLMLNDsGSAHSMP 9606 18794143 t lperfetto Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway. SIGNOR-180915 0.451 NEK6 protein Q9HC98 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000007 20595392 t done miannu Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. These results demonstrate that NEK6 interacts with and phosphorylates STAT3, an event that could play an important role in oncogenesis. For the maximal activation of STAT3 signaling, phosphorylation of both Tyr705 and Ser727 is required. Phosphorylation of Tyr705 induces dimerization, nuclear translocation, and DNA binding of the STAT3 protein, whereas phosphorylation of Ser727 is important for transcriptional activation. SIGNOR-273902 0.337 RPS6KA1 protein Q15418 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 7838153 t gcesareni Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii. SIGNOR-34113 0.503 HP protein P00738 UNIPROT HBB protein P68871 UNIPROT down-regulates quantity binding 9606 9315856 t Regulation of binding miannu Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers. SIGNOR-251815 0.767 MAP4K3 protein Q8IVH8 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 9820741 t gcesareni With regard to at least mekk1, serine/threonine kinases such as nik,glkand hpk1 appear also to be important for regulation SIGNOR-61814 0.439 SOX9 protein P48436 UNIPROT DCC protein P43146 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003858 19745029 f miannu Promoter analysis and transfection studies showed that the up-regulation of DCC in OA chondrocytes may be mediated by the transcription factors Sox9 and AP-2. SIGNOR-255188 0.2 PRKCA protein P17252 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 9679146 t gcesareni Pkc phosphorylation of native and recombinant adducin inhibited actin capping measured using pyrene-actin polymerization and abolished activity of adducin in recruiting spectrin to ends and sides of actin filaments SIGNOR-59299 0.2 MTOR protein P42345 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 29789464 f Luana The mTOR complexes are essential to neurogenesis and the establishment of neural circuits. | Activation of mTOR complexes exerts profound effects on all the processes of neurogenesis, including dendrite formation. SIGNOR-265771 0.7 EGR1 protein P18146 UNIPROT HYAL1 protein Q12794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004796 18718911 f miannu In 253J-Lung and HT1376 bladder cancer cell lines, which show high HYAL-1 expression, transcription factors Egr-1, AP-2, and NFκB bind the HYAL-1 promoter. Because both SP1 and Egr-1 have two overlapping binding sites within the promoter (Fig. 5), it appears that although SP1 binding to the methylated HYAL-1 promoter turns off transcription, binding of Erg-1 (and also AP-2) to the unmethylated promoter turns on transcription. SIGNOR-253878 0.2 SMURF1 protein Q9HCE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 22298955 t Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps SIGNOR-195660 0.7 HSD3B1 protein P14060 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity chemical modification 9606 BTO:0000056 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268638 0.8 HOOK3 protein Q86VS8 UNIPROT MSR1 protein P21757 UNIPROT down-regulates binding 9606 BTO:0000801 17237231 t miannu We have identified a microtubule-binding protein, hook3, as a novel interacting partner of sr-a. / by transfecting small interfering rna targeting hook3, total and surface expression, receptor-mediated ligand uptake and protein stability of sr-a were significantly promoted, whereas the protein synthesis and maturation were not altered. We propose for the first time that hook3 may participate in the turnover of the endocytosed scavenger receptor SIGNOR-152314 0.336 RIMS1 protein Q86UR5 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264381 0.802 CRYGD protein P07320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 10521291 f The γ-crystallin proteins are tightly folded in two domains with no free loops. It is possible that the R58H mutation destabilizes the contact between lens-fiber cells, which is critical for the maintenance of lens transparency. Improper folding of CRYGD, the most abundantly expressed γ-crystallin in the lens, could well cause protein aggregation and lens opacification. SIGNOR-253620 0.7 ZMYND8 protein Q9ULU4 UNIPROT ADORA1 protein P30542 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 21620140 t Luana We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.  SIGNOR-266208 0.2 TNF protein P01375 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18647246 f miannu NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. SIGNOR-252407 0.424 TFE3 protein P19532 UNIPROT CLCN7 protein P51798 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276814 0.287 SDHB protein P21912 UNIPROT SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-266272 0.965 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 BTO:0000007 18204439 t lperfetto Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation. SIGNOR-252959 0.713 SSTR4 protein P31391 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256959 0.251 STUB1 protein Q9UNE7 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding -1 12150907 t miannu In this study, we found that CHIP promotes Parkin-mediated Pael-R ubiquitination and subsequent degradation. In vitro ubiquitination assays suggested that only a combination of both Parkin and its cofactor CHIP function as a ubiquitin ligase, which is able to sufficiently ubiquitinate Pael-R in vivo (Figure 6).  SIGNOR-272888 0.2 Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273454 0.7 CDK2 protein P24941 UNIPROT DLG1 protein Q12959 UNIPROT up-regulates phosphorylation Ser443 FLGQTPAsPARYSPV 9606 19066288 t llicata We also show that dlg1 is phosphorylated by both cdk1 and cdk2 on ser158 and ser442. These phosphorylated sites together affect the nuclear localisation of the protein, and implicate the role of phosphorylation on ser158 and ser442 in its putative nuclear functions as a tumour suppressor. phosphorylation on ser158 and ser442 enhances nuclear expression of dlg1 SIGNOR-182765 0.284 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser301 SSSPNNLsPTGWSQP 9606 16407412 t lperfetto Using mass spectrometry, we identified raf-1 phosphorylation on three sp motif sites: s289/s296/s301. These sites were phosphorylated by extracellular signal-regulated kinase (erk)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous erk activity. Functionally, erk-1 expression sustains raf-1 activation in a manner dependent on raf-1 phosphorylation on the identified sites, and s289/296/301a substitution markedly decreases the in vivo activity of raf-1 s259a. SIGNOR-244685 0.2 DCAF7 protein P61962 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181; BTO:0003484 16887337 f Giorgia HAN11 and mDia1 repressed DYRK1A-dependent GLI1 transcriptional activity. The studies of SZ95 cells suggest that HAN11 reduces GLI1-dependent transcription by decreasing the nuclear pool of GLI1. SIGNOR-260634 0.263 STAT3 protein P40763 UNIPROT S100A9 protein P06702 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18809714 f miannu Accumulation of myeloid-derived suppressor cells (MDSCs) associated with inhibition of dendritic cell (DC) differentiation is one of the major immunological abnormalities in cancer and leads to suppression of antitumor immune responses. The molecular mechanism of this phenomenon remains unclear. We report here that STAT3-inducible up-regulation of the myeloid-related protein S100A9 enhances MDSC production in cancer. SIGNOR-261931 0.378 N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester chemical CHEBI:94306 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000785 31016515 t Gianni We explored the anti-tumor effect and the molecular mechanism of cay10603, a potent HDAC6 inhibitor in Burkitt's lymphoma cells. SIGNOR-262205 0.8 NR1I2 protein O75469 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000003 18540626 f miannu Among approximately 40 kinds of phytochemicals, tangeretin and ginkgolides A and B markedly induced the PXR-dependent transcriptional activity and also the activity of the human MDR1 promoter. The expression levels of MDR1 mRNA as well as of CYP3A4 mRNA, another gene regulated by PXR, were significantly increased by these phytochemicals. SIGNOR-254834 0.467 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser114 HISPAQGsPKPPPAA -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277880 0.2 ITGAM protein P11215 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 12393465 f apalma CD11b, another marker for differentiation, was also less expressed in patients with t(8;21) in comparison to patients without t(8;21) SIGNOR-255662 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t lperfetto In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-244647 0.2 ATM protein Q13315 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1083 ESERGSGsQSSVPSV 9606 18442975 t llicata Ser-1083 phosphorylation is ir-inducible, depends on atm and nijmegen breakage syndrome 1 (nbs1), and is required for intra-s phase checkpoint. SIGNOR-178479 0.736 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation Ser467 SVRCSSMs 9534 9346908 t lperfetto Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-beta (TGF-beta) type I receptor, TbetaRI. Phosphorylation sites on Smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. These results indicate that receptor-dependent phosphorylation of Smad2 on serines 465 and 467 is required in mammalian cells to permit association with Smad4 and to propagate TGF-_ signals. SIGNOR-235995 0.821 MC1R protein Q01726 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256813 0.467 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Ser88 LMCFSIDsPDSLENI 9534 BTO:0000298 26816343 t miannu We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation. SIGNOR-277202 0.2 TRIM25 protein Q14258 UNIPROT KLF5 protein Q13887 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 21542805 t miannu  The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked.  SIGNOR-271908 0.49 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 t AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity. gcesareni Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition. SIGNOR-175776 0.672 PDPK1 protein O15530 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser226 LIDSMANsFVGTRSY 9606 15175348 t gcesareni The identified pdk1 phosphorylation sites in mek1 and mek2 are ser222 and ser226, respectively, and are known to be essential for full activation. SIGNOR-125176 0.258 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation Ser63 GILARRPsYRKILKD 9606 8663317 t lperfetto Camk ii phosphorylates only ser63 (corresponding to ser133 of creb), which is essential for the activation, and not ser72 (corresponding to ser142 of creb), which is a negative regulation site SIGNOR-42565 0.298 NMDA receptor_2A complex SIGNOR-C347 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30037851 t miannu NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS).  SIGNOR-264218 0.8 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 15276472 t gcesareni Once activated, calcineurin directly dephosphorylates members of the nuclear factor of activated t-cells (nfat) transcription factor family in the cytoplasm, promoting their translocation into the nucleus. SIGNOR-127248 0.82 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258030 0.8 NRL protein P54845 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253818 0.379 AURKA protein O14965 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser405 FDDTGKSsLGDMFSP 9606 BTO:0001938 31028180 t lperfetto Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone. SIGNOR-272965 0.546 Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR 43S_pre_initiation_complex complex SIGNOR-C453 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269159 0.2 CIITA protein P33076 UNIPROT HLA-DOB protein P13765 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11823510 f Class II transactivator is required for maximal expression of HLA-DOB in B cells|HLA-DO, encoded by the HLA-DOA and HLA-DOB genes, has been shown to function as a modulator of Ag presentation. DNA microarray comparisons between B cells wild-type and mutant for the master regulator of MHC class II transcription, class II transactivator (CIITA), identified HLA-DOA and HLA-DOB as being up-regulated by CIITA. SIGNOR-254015 0.314 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Ser253 QEALQKLsDVTLVPV 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275646 0.2 MRPS23 protein Q9Y3D9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261435 0.677 ERCC2 protein P18074 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269312 0.867 PRKCG protein P05129 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser42 AKKKSKIsASRKLQL 9606 BTO:0000887 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134632 0.2 CDKN1A protein P38936 UNIPROT RB1 protein P06400 UNIPROT up-regulates activity 9606 10439039 f gcesareni P21 may inhibit cell cycle progression by preventing the phosphorylation of prb. SIGNOR-69925 0.709 ITGB1BP1 protein O14713 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257663 0.27 HOXA7 protein P31268 UNIPROT KRT10 protein P13645 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11435435 f miannu Antisense HOXA7 expression activated transglutaminase 1, involucrin, and keratin 10 message and protein levels, demonstrating that endogenous HOXA7 down-regulates multiple differentiation-specific keratinocyte genes. SIGNOR-254472 0.2 SETDB1 protein Q15047 UNIPROT SETDB1/NLK/CHD7 complex SIGNOR-C189 SIGNOR form complex binding 10090 21952300 t FFerrentino The non-canonical WNT ligand WNT5A activates the histone methyltransferase SET domain bifurcated 1 (SETDB1)42. SETDB1 forms a complex with chromodomain helicase DNA-binding 7 (CHD7) and NEMO-like kinase (NLK) to inhibit the ability of PPARγ to transcriptionally activate its downstream metabolic target genes in the MSC cell line ST2 and in 3T3‑L1 cells42,43. SIGNOR-253522 0.535 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001289 21489980 f miannu Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1. SIGNOR-254893 0.2 CAMK2G protein Q13555 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275795 0.273 VRK1 protein Q99986 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 17938195 t gcesareni We show that histone h3 is phosphorylated by vaccinia-related kinase 1 (vrk1). Direct phosphorylation of thr3 and ser10 in h3 by vrk1 both in vitro and in vivo was observed. Loss of vrk1 activity was associated with a marked decrease in h3 phosphorylation during mitosis. SIGNOR-265371 0.2 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT up-regulates phosphorylation Tyr735 LKGPTCQyRAAQSGP 9606 BTO:0000661 11741929 t lperfetto Hck, and to a lesser extent lck, phosphorylated the adam15. Deletion and point mutation analysis of the adam15 cytoplasmic domain confirmed the importance of the proline-rich motifs for grb2 and lck binding and indicated the regulatory nature of tyr(715) and tyr(735). These data demonstrate selective, phosphorylation-dependent interactions of adam15 with src family ptks and grb2, which highlight the potential for integration of adam functions and cellular signaling. SIGNOR-112923 0.359 GPAA1 protein O43292 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32432756 f miannu GPAA1 may contribute to the malignant progression of childhood ALL via activating c-myc. Luciferase reporter gene assay demonstrated that overexpression of c-myc remarkably attenuated the Luciferase activity of the wild-type GPAA1 vector without attenuating that of the mutant vector or empty vector, further demonstrating that GPAA1 can be targeted by c-myc. SIGNOR-261240 0.2 KIF1C protein O43896 UNIPROT RAB6B protein Q9NRW1 UNIPROT up-regulates quantity relocalization -1 20360680 t miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. SIGNOR-266878 0.2 CSNK1D protein P48730 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 24715453 t milica LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-230738 0.408 ULK2 protein Q8IYT8 UNIPROT ENO1 protein P06733 UNIPROT down-regulates activity phosphorylation Ser282 QLADLYKsFIKDYPV 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274037 0.2 AHR protein P35869 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 17012224 t The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 . SIGNOR-253642 0.5 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 21695114 t gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins SIGNOR-174539 0.2 RB1 protein P06400 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 21524151 f lperfetto Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-267284 0.7 RAD50 protein Q92878 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 21763684 t gcesareni One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase. SIGNOR-175053 0.809 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI HCAR2 protein Q8TDS4 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). SIGNOR-268772 0.8 VARLITINIB chemical CID:42642648 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189900 0.8 AKAP12 protein Q02952 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity relocalization 14657015 t lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. SIGNOR-271835 0.2 MAP3K8 protein P41279 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 15466476 t lperfetto Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases. SIGNOR-244904 0.563 INSR protein P06213 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t lperfetto The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-24782 0.409 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 18930133 t lperfetto Using a functional genomic approach, we have identified two protein serine/threonine phosphatases, ppm1a and ppm1b, as ikkbeta phosphatases. Overexpression of ppm1a or ppm1b results in dephosphorylation of ikkbeta at ser177 and ser181 and termination of ikkbeta-induced nf-kappab activation SIGNOR-181663 0.409 FZD8 protein Q9H461 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000971 21078818 t amattioni Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate Wnt–Beta-catenin signaling. SIGNOR-169638 0.749 EGR2 protein P11161 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. SIGNOR-256041 0.313 HECTD3 protein Q5T447 UNIPROT RAF1 protein P04049 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 28636940 t miannu  By western blot, we observed robust degradation of endogenous native CRAF in untransformed HEK293 cells treated with control siRNA 24 hr after the addition of AUY922, but this was substantially reduced in cells in which HECTD3 was knocked down, confirming that endogenous CRAF is a bona fide degradation target of HECTD3  SIGNOR-272328 0.2 PRKCD protein Q05655 UNIPROT TBL1XR1 protein Q9BZK7 UNIPROT up-regulates activity phosphorylation Ser123 AAASQQGsAKNGENT 9606 18374649 t Manara In addition, we describe that the functions and the specificity of these two highly- related exchange factors is tightly regulated by signal-induced phosphorylation events at the level of target gene promoters, as exemplified by the role of TBLR1 phosphorylation at Ser 123 by PKCδ upon retinoic acid or estrogen stimulation. SIGNOR-260903 0.2 PCM1 protein Q15154 UNIPROT NIN protein Q8N4C6 UNIPROT up-regulates relocalization 9606 12403812 t miannu Rna silencing of pcm-1 leads to reduced assembly of centrin, pericentrin, and ninein at the centrosome SIGNOR-95077 0.413 WNK4 protein Q96J92 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser371 VRRVPGSsGHLHKTE 16990453 t lperfetto Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1 SIGNOR-264641 0.515 amitriptyline chemical CHEBI:2666 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8100134 t miannu Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Competition between [‘H]QNB and the antidepressant compounds (Table 1) showed that at the ml subtype the most potent drugs were amitriptyline > dothiepin > doxepin = nortriptyline; at the m2 receptor, amitriptyline > imipramine > nortriptyline = dothiepin; at the m3 recep- tor, amitriptyline > dothiepin > nortriptyline; at the m4 receptor, amitriptyline > dothiepin > doxepin = nortrip- tyline; and at the m5 receptor, amitriptyline > doxepin > imipramine. SIGNOR-258700 0.8 MAPK1 protein P28482 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates 9606 18481201 f gcesareni In addition, immunoblot and immunostaining analysis revealed that phosphorylation of erk was increased by treatment with sb203580;whereas pd98059 increased the phosphorylation of p38, which implies a seesaw-like balance between erk and p38 phosphorylation. SIGNOR-178639 0.495 MDM2 protein Q00987 UNIPROT DYRK2 protein Q92630 UNIPROT down-regulates quantity by destabilization ubiquitination 19965871 t lperfetto Under normal conditions, nuclear and not cytoplasmic DYRK2 is ubiquitinated by MDM2, resulting in its constitutive degradation.|Upon exposure to genotoxic stress, ATM phosphorylates DYRK2 at Thr-33 and Ser-369, which enables DYRK2 to escape from degradation by dissociation from MDM2 and to induce the kinase activity toward p53 at Ser-46 in the nucleus. SIGNOR-275579 0.559 metaproterenol chemical CHEBI:6792 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257873 0.8 PRKCA protein P17252 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Thr174 KVPVTHEtQEECLGM -1 27368100 t miannu These results suggest that PKC activates JAK2 and thereby STAT3 by directly phosphorylating T174 and S518.  SIGNOR-277262 0.261 AXIN1 protein O15169 UNIPROT CSNK1D protein P48730 UNIPROT up-regulates binding 9606 SIGNOR-C110 12000790 t gcesareni Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45). SIGNOR-87401 0.544 RPS6KB1 protein P23443 UNIPROT PIP5K1C protein O60331 UNIPROT down-regulates quantity by destabilization phosphorylation Thr553 QPRYRRRtQSSGQDG 27780861 t miannu Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation. SIGNOR-277282 0.2 SRC protein P12931 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Tyr68 GQTVDDPyATFVKML 9606 19802004 t lperfetto Tyrosine phosphorylation of cofilin at y68 by v-src leads to its degradation through ubiquitin-proteasome pathway SIGNOR-188352 0.564 AKT1 protein P31749 UNIPROT DLC1 protein Q96QB1 UNIPROT unknown phosphorylation Ser766 VTRTRSLsACNKRVG 10116 16338927 t gcesareni We have demonstrated that Ser-322 is phosphorylated upon insulin stimulation of intact cells and that this site is directly phosphorylated in vitro by PKB and ribosomal S6 kinase, members of the AGC (protein kinases A, G, and C) family of insulin-stimulated protein kinases SIGNOR-252550 0.504 perfluorohexanesulfonic acid chemical CHEBI:132448 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268761 0.8 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 9407116 t lperfetto The src family kinase hck interacts with bcr-abl by a kinase-independent mechanism and phosphorylates the grb2-binding site of bcr SIGNOR-53964 0.2 AKT1 protein P31749 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates phosphorylation Ser159 LLRERKSsAPSHSSQ 9606 11782427 t lperfetto Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation. SIGNOR-252468 0.692 AKT proteinfamily SIGNOR-PF24 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates activity phosphorylation 9606 BTO:0003324 25323588 t miannu Earlier studies found that expression of active Akt increases mitochondrial HK activity and the anti-apoptotic effect of Akt required mitoHK SIGNOR-267577 0.493 MMP25 protein Q9NPA2 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272369 0.7 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1100 QGCRRRHsSETFSST 9606 17360977 t lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 SIGNOR-235675 0.2 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser276 AAQQTKGsYMEVEDN 9615 BTO:0000837 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250826 0.422 ARNTL protein O00327 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT down-regulates activity binding 9606 BTO:0000007 22208286 t miannu Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. SIGNOR-253517 0.375 RET protein P07949 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000944 15994200 t lperfetto The PKB Y315 residue, which is known to be phosphorylated by Src tyrosine kinase, was also a major site of phosphorylation by RET/PTC. RET/PTC-mediated tyrosine phosphorylation results in the activation of PKB kinase activity SIGNOR-252619 0.327 WWTR1 protein Q9GZV5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199208 0.7 STK3 protein Q13188 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181056 0.2 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249070 0.343 STXBP1 protein P61764 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR up-regulates activity transcriptional regulation 9606 BTO:0000938 30267828 t miannu In neuronal exocytosis, Munc18-1 (aSM-protein) and Munc13-1/2 (similar to CATCHRs) arethe relevant proteins responsible for SNARE-complex formation. Munc18-1 associates with syntaxin-1 in its‘closed’ conformation, i.e. with the regulatory Habc-domain folded against the SNARE (H3-)-domain. Opening-up of syntaxin is catalyzed by the Mun-domainwithin Munc13-1/2 and allows assembly with the partnerSNARE SNAP-25 and possibly VAMP2. SIGNOR-263970 0.838 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12857757 t gcesareni We show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. Similar to the loss of presenilin or nicastrin, the inactivation of endogenous maph-1 using small interfering rnas results in the decrease of presenilin levels, accumulation of gamma-secretase substrates (app carboxyl-terminal fragments), and reduction of gamma-secretase products (amyloid-beta peptides and the intracellular domains of app and notch). SIGNOR-103611 0.967 GALR3 protein O60755 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256862 0.435 LPAR4 protein Q99677 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257170 0.2 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22575959 t gcesareni Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6 SIGNOR-197414 0.295 NEUROD1 protein Q13562 UNIPROT MGAT5B protein Q3V5L5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 21771782 f miannu By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression. SIGNOR-253825 0.253 F10 protein P00742 UNIPROT F2 protein P00734 UNIPROT up-regulates activity cleavage 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263539 0.445 SRC protein P12931 UNIPROT FCRL3 protein Q96P31 UNIPROT up-regulates activity phosphorylation Tyr692 HEELTVLySELKKTH -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274007 0.2 PTGER1 protein P34995 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256811 0.442 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser222 LIDSMANsFVGTRSY -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-39054 0.782 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-104811 0.85 SRGAP3 protein O43295 UNIPROT WASF1 protein Q92558 UNIPROT up-regulates binding 9606 12447388 t miannu Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo. SIGNOR-95967 0.563 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267512 0.8 BRD7 protein Q9NPI1 UNIPROT BRD2 protein P25440 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000192 12600283 f miannu BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent. SIGNOR-253763 0.417 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16874298 t lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo SIGNOR-148323 0.61 CAD protein P27708 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI up-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267420 0.8 AL/b2 integrin complex SIGNOR-C169 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257712 0.451 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Ser686 LEELHEKsQEVIWGL -1 12852856 t lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction SIGNOR-103348 0.693 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr426 ASAASFEyTILDPSS 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251349 0.808 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 31152168 t miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway) SIGNOR-269199 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 19364816 t gcesareni Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21cip1.|Phosphopeptide analysis of in vitro ERK2-phosphorylated p21(Cip1) revealed two phosphorylation sites, Thr57 and Ser130. SIGNOR-244618 0.2 RABEPK protein Q7Z6M1 UNIPROT M6PR protein P20645 UNIPROT up-regulates activity relocalization 9230071 t lperfetto P40 is a very potent transport factor in that the pure, recombinant protein can stimulate, significantly, an in vitro transport assay that measures transport of mannose 6-phosphate receptors from endosomes to the trans-Golgi network. The functional importance of p40 is confirmed by the finding that anti-p40 antibodies inhibit in vitro transport. Finally, p40 shows synergy with Rab9 in terms of its ability to stimulate mannose 6-phosphate receptor transport. These data are consistent with a model in which p40 and Rab9 act together to drive the process of transport vesicle docking. SIGNOR-253091 0.368 DAPK1 protein P53355 UNIPROT TPM1 protein P09493 UNIPROT up-regulates activity phosphorylation Ser283 HALNDMTsI 9606 BTO:0000007 17895359 t miannu We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling. SIGNOR-262845 0.279 MAPK14 protein Q16539 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity phosphorylation Thr1392 CSAKNALtPSSKKPV 10090 BTO:0002572 16138080 t lperfetto We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes SIGNOR-140082 0.466 ETFB protein P38117 UNIPROT ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 t miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. SIGNOR-269452 0.945 HOXC13 protein P31276 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 f miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. SIGNOR-254184 0.391 PRKACA protein P17612 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 10116 BTO:0001009 12459461 t miannu Thr138 as the exclusive site of SNAP-25 phosphorylation by protein kinase A in vivo. PMA or forskolin treatment alone resulted in dramatic phosphorylation of SNAP-25 Ser187 and/or Thr138 without appreciable neurotransmitter release. SIGNOR-250052 0.329 PIP4K2A protein P48426 UNIPROT 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) smallmolecule CHEBI:58456 ChEBI up-regulates quantity chemical modification 9606 9367159 t Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K SIGNOR-268864 0.8 SRC protein P12931 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr322 GDGPAVDyENQDVAS 9606 12540842 t lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src. SIGNOR-247337 0.412 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK2 protein O96017 UNIPROT up-regulates activity 9606 19151762 f lperfetto Cell cycle progression is monitored constantly to ensure faithful passage of genetic codes and genome stability. We have demonstrated previously that, upon DNA damage, TTK/hMps1 activates the checkpoint kinase CHK2 by phosphorylating CHK2 at Thr68 SIGNOR-242605 0.7 TLN1 protein Q9Y490 UNIPROT ITGB7 protein P26010 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257633 0.581 AKT proteinfamily SIGNOR-PF24 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates activity phosphorylation Ser571 RMRSRSRsFSRHRSC 9606 BTO:0000759 17554339 t lperfetto Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin. SIGNOR-155532 0.2 Calcineurin complex SIGNOR-C155 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-252315 0.274 IL1B protein P01584 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32446778 f doi: 10.1016/j.cytogfr.2020.05.003 miannu Interleukin-6 (IL-6) deserves a more extensive discussion in view of its involvement in the coronavirus-induced cytokine storm. The production of this cytokine is increased by IL-1β and tumor necrosis factor (TNF- α) SIGNOR-260855 0.522 MTOR protein P42345 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000007 20508131 f The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. SIGNOR-255944 0.7 DGC complex SIGNOR-C217 SIGNOR NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265447 0.355 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246272 0.571 RAB32 protein Q13637 UNIPROT AP-3 complex complex SIGNOR-C247 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260698 0.289 AURKA protein O14965 UNIPROT CETN2 protein P41208 UNIPROT up-regulates phosphorylation Ser170 LRIMKKTsLY 9606 BTO:0000150 21731694 t llicata Our studies show that aurora a phosphorylates centrin at serine 170 in vitro and that the serine 170 phosphorylation affects the stability of centrin by regulating its interaction with apc/c. finally we demonstrated that phosphorylation of centrin serine 170 is an absolute requirement for aurora a-mediated centriole amplification. SIGNOR-174686 0.503 NRAS protein P01111 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. It was also described that ras interacts with pi3k in a direct manner.llysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175228 0.714 TNF protein P01375 UNIPROT TNFRSF1A protein P19438 UNIPROT up-regulates activity binding 9606 17151142 t miannu TNF-α has two distinct plasma membrane receptors known as p55 and p75. These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253591 0.924 ANXA1 protein P04083 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 27426034 f miannu Our study demonstrates that ANXA1 can be phosphorylated by PKC and is subsequently translocated to the nucleus of BV-2 microglial cells after OGD/R, resulting in the induction of pro-inflammatory cytokines. we set out to examine the relationship between the different subcellular distributions of ANXA1 and the upregulation of inflammatory cytokines. When BV-2 microglial cells were transfected with ANXA1-S27A constructs following by OGD/R treatment, the pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, were found to be expressed at lower levels than those of control groups SIGNOR-261939 0.408 HES1 protein Q14469 UNIPROT CTNND2 protein Q9UQB3 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001033 21106062 f miannu Coordinated regulation of δ-catenin expression by both the activating transcription factor E2F1 and repressive transcription factor Hes1 in prostate cancer progression. SIGNOR-251877 0.351 TBPL2 protein Q6SJ96 UNIPROT TAF3/TRF3 complex SIGNOR-C23 SIGNOR form complex binding 9606 BTO:0000887;BTO:0001103;BTO:0001760 18851836 t lperfetto We recently identified taf3 as a subunit specifically associated with trf3 to form a complex that is required for myogenic differentiation SIGNOR-181614 0.677 KRAS protein P01116 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner. SIGNOR-175213 0.772 ADRA1D protein P25100 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257080 0.574 CDKN2AIP protein Q9NXV6 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 16803988 t miannu In the nucleoplasm, carf interacts with p53 and enhances its function. SIGNOR-147360 0.389 CDK5RAP2 protein Q96SN8 UNIPROT TUBG1 protein P23258 UNIPROT up-regulates activity binding 9606 BTO:0002181 17959831 t Giulio Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome. SIGNOR-260310 0.643 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9534 7791754 t fspada Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33440 0.621 EXOC1 protein Q9NV70 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270776 0.865 PAK1 protein Q13153 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation 9606 15037762 t gcesareni Kinases targeted sequentially to the neck, cla4/pak and cdc5/polo, are responsible for stepwise phosphorylation and down-regulation of swe1. SIGNOR-123528 0.302 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser44 PGTALVGsQKEPSEV 9606 10617144 t fspada In this study, we showed that the pkc-mediated phosphorylation of hmg-i exerted a very potent inhibition on the binding of this protein to the at-rich promoter regions of both pkc g and ng genes. The purified hmg-i can be phosphorylated by pkc a,b, g, and d but is poorly phosphorylated by pkc e and z. We have mapped two major sites of phosphorylation by pkc at ser44 and ser64 SIGNOR-73606 0.265 ZNRF1 protein Q8ND25 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys39 MADELSEkQVYDAHT 9606 BTO:0000007 28593998 t miannu The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. ZNRF1 mediates CAV1 polyubiquitination at lysine 39 and promote CAV1 degradation to modulate TLR4-mediated immune response. SIGNOR-272327 0.37 LRRC4C protein Q9HCJ2 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 t miannu A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles SIGNOR-264050 0.371 KDM6B protein O15054 UNIPROT M1_polarization phenotype SIGNOR-PH54 SIGNOR down-regulates 9606 22378047 f lperfetto IL-4-induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing JMJD3-IRF4 axis to inhibit IRF5-mediated M1 polarization. SIGNOR-249563 0.7 PRKCD protein Q05655 UNIPROT DBI protein P07108 UNIPROT up-regulates phosphorylation Thr42 ATVGDINtERPGMLD 9606 18194441 t gcesareni Acyl coenzyme a-binding protein (acbp) is phosphorylated following protein kinase c activation. SIGNOR-160393 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 t miannu Here, we show that protein kinase A (PKA) phosphorylates the PP2Cβ, which was inhibited by PKA-specific inhibitor, H89. Mutation analysis of serine residues in PP2Cβ revealed that Ser-195 in PP2Cβ is phosphorylated by PKA. Importantly, PKA inhibition by H89 abrogated the Forskolin-induced destabilization of PP2Cβ against ubiquitin-dependent proteosomal degradation pathway. SIGNOR-276494 0.2 KDM3A protein Q9Y4C1 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9606 16603237 t miannu Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.  SIGNOR-276845 0.2 CTNNA1 protein P35221 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23431053 t milica The trimeric complex of alfa-catenin, 14-3-3, and yap sequesters yap at ajs and prevents yap dephosphorylation/activation. SIGNOR-201173 0.357 PRKCG protein P05129 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202788 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24168260 f miannu NF-κB, which can be activated by mitogen-activated protein kinases (MAPKs) (12), is responsible for the transcription of inflammatory factors and profibrotic cytokines, which promote an inflammatory response and fibrosis SIGNOR-260446 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PBK protein Q96KB5 UNIPROT unknown phosphorylation Thr9 EGISNFKtPSKLSEK 9606 15541388 t lperfetto Topk-thr-9 was phosphorylated by cdk1/cyclin b and topk significantly associates with mitotic spindles. SIGNOR-216896 0.562 Zalospirone chemical CID:163925 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258864 0.8 CDK2 protein P24941 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser51 GVVSESDsPVKRPGR 9606 BTO:0000567 12851383 t lperfetto Thus, phosphorylation of serine 51 on hligi plays a critical role in regulating the interaction between hligi and rfc, which is required for efficient dna replication and repair. SIGNOR-103246 0.463 histamine smallmolecule CHEBI:18295 ChEBI HRH3 protein Q9Y5N1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257514 0.8 S1PR2 protein O95136 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257349 0.457 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1256 KGCSNEPyFGSLTAL 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187851 0.414 RPS12 protein P25398 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262440 0.769 GSK2126458 chemical CID:25167777 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252645 0.8 KANSL1 protein Q7Z3B3 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. SIGNOR-267172 0.7 MAPK1 protein P28482 UNIPROT LIMA1 protein Q9UHB6 UNIPROT down-regulates quantity by destabilization phosphorylation Ser604 FQSTSVKsPKTVSPP 9606 23188829 t miannu Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. SIGNOR-263055 0.2 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257972 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RAD9A protein Q99638 UNIPROT unknown phosphorylation Ser328 VLPSISLsPGPQPPK 9606 23028682 t lperfetto The forced activation of cyclin a-cdk2 in these cells by the overexpression of cyclin a,triggered rad9 phosphorylation at serine 328 and thereby promoted the interaction of rad9 with bcl-xl and the subsequent initiation of the apoptotic program. SIGNOR-217268 0.407 CYP26A1 protein O43174 UNIPROT all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI down-regulates activity chemical inhibition 9606 9716180 t Gianni The RA-induced CYP26 was shown to be highly specific for the hydroxylation of all-trans-RA and did not recognize the 13-cis and 9-cis isomers. This substrate specificity is promising for finding retinoids that are not recognized by this enzyme and, therefore, could be more effective in growth inhibition of susceptible cancer cells. SIGNOR-266425 0.8 ASDURF protein L0R819 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270922 0.2 F11 protein P03951 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261857 0.479 beta-alanine smallmolecule CHEBI:16958 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 9606 BTO:0000007 9009272 t inferred from family member miannu For each mutant GlyR we examined the agonist efficacies of taurine and beta-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where beta-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human alpha-1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and beta-alanine act as full agonists of huma nalpha-1 GlyRs when expressed in this system. SIGNOR-267795 0.8 GART protein P22102 UNIPROT 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI down-regulates quantity chemical modification 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267298 0.8 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1C protein Q8TCG5 UNIPROT down-regulates activity binding 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267116 0.8 HTR1E protein P28566 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256705 0.433 PZP protein P20742 UNIPROT MMP9 protein P14780 UNIPROT down-regulates activity binding -1 9344465 t lperfetto Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261802 0.353 AKT proteinfamily SIGNOR-PF24 SIGNOR ACLY protein P53396 UNIPROT unknown phosphorylation Ser455 PAPSRTAsFSESRAD 10116 BTO:0000443 12107176 t gcesareni Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo substrate for protein kinase B. SIGNOR-245259 0.2 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val53 SHVTGKGvTVETVFS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263590 0.4 CGA protein P01215 UNIPROT TSH complex SIGNOR-C412 SIGNOR form complex binding 9606 BTO:0001379 8196184 t scontino TSH is a heterodimer composed of common alpha subunit and unique beta subunit encoded by genes located on different chromosomes. It is known that the expression of these subunit genes is regulated in different mechanism by several extracellular factors. SIGNOR-267046 0.672 NEK2 protein P51955 UNIPROT PPP1CC protein P36873 UNIPROT down-regulates phosphorylation Thr318 TPPRGMItKQAKK 9606 10880350 t gcesareni Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. SIGNOR-78603 0.497 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Thr663 IATVIVItLVMLKKK -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261793 0.497 SNAI1 protein O95863 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity transcriptional regulation 9606 19055748 f lperfetto Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status. SIGNOR-252260 0.753 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RHOA protein P61586 UNIPROT up-regulates activity phosphorylation Thr100 ENIPEKWtPEVKHFC 9534 BTO:0000298 26816343 t miannu We have recently reported that Rac1 is phosphorylated on threonine 108 (108T) by extracellular signal-regulated kinases (ERK) in response to epidermal growth factor (EGF) stimulation. Here, we provide evidence that RhoA is phosphorylated by ERK on 88S and 100T in response to EGF stimulation. SIGNOR-277203 0.2 TGFb proteinfamily SIGNOR-PF5 SIGNOR Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f inferred from 70% family members lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-Œ±, TGF-Œ≤, tumor necrosis factor (TNF)-Œ±, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-270216 0.7 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Pro) smallmolecule CHEBI:29177 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269493 0.8 ANK2 protein Q01484 UNIPROT PPP2R5A protein Q15172 UNIPROT up-regulates quantity relocalization 9606 BTO:0003324 19840192 t miannu Ankyrin-B is targeted to the M-line via its interaction with the C-terminal domain of the large sarcomeric protein obscurin. Obscurin is targeted to the M-line via its N-terminal interactions with myomesin and titin. This population of ankyrin-B recruits B56α, a regulatory subunit of protein phosphatase 2A, to the M-line where the phosphatase may regulate the phosphorylation status of contractile and signalling proteins. SIGNOR-266729 0.285 GRK4 protein P32298 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t gcesareni ...expression of GRK4ƒŽ‚ drastically increased the basal level of32P incorporation into B2R.[ƒ‚€‚]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-249674 0.29 CRP protein P02741 UNIPROT NOS3 protein P29474 UNIPROT down-regulates quantity by destabilization 17942113 f miannu C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. we found that CRP decreased the eNOS dimer/monomer ratio further supporting eNOS uncoupling. SIGNOR-252217 0.472 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI HR protein O43593 UNIPROT up-regulates activity chemical activation 29981745 t lperfetto Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2-OGDDs) that regulate gene expression by altering chromatin structure. |2-OG is a central intermediate of the Krebs cycle, where it is produced by isocitrate dehydrogenase (IDH) isoenzymes 2 and 3. SIGNOR-273463 0.8 JUN protein P05412 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 12200429 f miannu Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. SIGNOR-254536 0.2 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates phosphorylation Ser390 KEAEEESsGGEEEDE 9606 18649047 t gcesareni We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2. SIGNOR-179546 0.399 NMUR2 protein Q9GZQ4 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257010 0.251 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 27629041 t miannu Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival SIGNOR-260174 0.691 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 11691836 t lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding SIGNOR-249393 0.653 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser68 PPQTSGLsPSRLSKS 9606 20516213 t lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-217145 0.472 SRC protein P12931 UNIPROT SH3GL1 protein Q99961 UNIPROT unknown phosphorylation Tyr315 QPSCKALyDFEPEND 9606 16054026 t llicata These results identified y315 of endophilin a2 as a major phosphorylation site by fak/src complex. tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of tyr315 phosphorylation promoted endocytosis of mt1-mmp. SIGNOR-139154 0.631 INTS6 protein Q9UL03 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261463 0.844 DNAJB9 protein Q9UBS3 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates activity binding -1 12356756 t miannu When BAP was added to BiP (2:1 molar ratio of BAP:BiP), it increased the ATPase activity of BiP by about 2-fold, which was similar to the increase observed when the J domain of ERdj4 was added to BiP (Fig.5). When both BAP and the J domain were added to BiP, the rate of ATP hydrolysis by BiP was stimulated by about 4-fold over basal levels, indicating that both BAP and ERdj4 positively regulate the ATPase activity of BiP SIGNOR-261044 0.552 Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266029 0.7 FLT3 protein P36888 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001545 17851558 t miannu Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML. SIGNOR-260124 0.416 DBP protein Q10586 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 8383844 f inferred from family member miannu Contransfection experiments of aldolase B/CAT constructs and of expression vectors for different transcription factors were carried out in human hepatoma Hep G2 cells. We found that DBP and HNF-1 are strong transactivators of the aldolase B promoter while C/EBP and vHNF-1 are only weak activators SIGNOR-270225 0.2 LATS1 protein O95835 UNIPROT PRPS1 protein P60891 UNIPROT down-regulates quantity by destabilization phosphorylation Ser285 EDKMKHCsKIQVIDI -1 34465890 t miannu  Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness. SIGNOR-276505 0.2 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates activity phosphorylation Ser173 VKKNPHHsQWGDMKL 9606 BTO:0000018 16540648 t llicata Defects in ATR-dependent XPA phosphorylation increases the cell sensitivity to UV irradiation. | The XPA-deficient cells complemented with XPA-S196A mutant, in which Ser196 was substituted with an alanine, displayed significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Moreover, substitution of Ser196 with aspartic acid for mimicking the phosphorylation of XPA increased the cell survival to UV irradiation. SIGNOR-250584 0.5 NR4A3 protein Q92570 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000815;BTO:0002552 30455429 f miannu NR4A3 exhibits p53-independent anti-proliferative functions. Ectopic expression of NR4A3 inhibits the growth of MDA-MB-231 and H1299 cancer cell lines. SIGNOR-256201 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244144 0.2 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Ser378 RICMRNFsRSDHLTT 10090 BTO:0000944 8662759 t llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. SIGNOR-250856 0.472 CCNE2 protein O96020 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR form complex binding 9606 19665013 t lperfetto The eukaryotic cell cycle is controlled by different cyclins and their associated kinases (murray and hunt, 1993). In mammalian cells, levels of cycline and its associated kinase, cdk2, rise in late g1/early s-phase when dna replication is initiated SIGNOR-187454 0.932 CSNK1D protein P48730 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser314 SREQSTDsGLGLGCY 9606 24715453 t lperfetto LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP) SIGNOR-234438 0.351 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tailother studies demonstrated that tyr191 within the p190yap motif is one of two major phosphorylation sites in cd28-stimulated jurkat t cells, and the only tyrosine residue within the cd28 cytoplasmic tail that is essential for delivery of costimulatory signals SIGNOR-45516 0.682 STK38 protein Q15208 UNIPROT RAB11FIP5 protein Q9BXF6 UNIPROT up-regulates activity phosphorylation Ser307 FTHKRTYsDEANQMR 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263035 0.2 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Ser696 KKRARRGsSSDEEGG -1 14657015 t lperfetto Following receptor activation, gravin binding to the receptor increases, a process dependent upon PKA-catalyzed phosphorylation of two canonical PKA sites (Ser696–698 and Ser772) located within the AKAP domain of gravin. SIGNOR-271843 0.2 TRPM6 protein Q9BX84 UNIPROT TRPM6 protein Q9BX84 UNIPROT down-regulates activity phosphorylation Thr1851 FNQVKPQtIPYTPRF 9606 18258429 t Manara Autophosphorylation of Threonine1851 in the Kinase Domain Is Essential for the Inhibitory Effect of RACK1 SIGNOR-260922 0.2 SIRT6 protein Q8N6T7 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates activity binding 9606 BTO:0000007 25083875 t miannu SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids. SIGNOR-268158 0.377 AURKA protein O14965 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser94 SLLSRSSsGYFSFDT 9606 BTO:0002181 23912711 t miannu  We observed that BimEL is phosphorylated by Aurora A early in mitosis and reversed by PP2A after mitotic exit. Aurora A phosphorylation stimulated binding of BimEL to the F-box protein beta-transducin repeat containing E3 ubiquitin protein ligase and promoted ubiquitination and degradation of BimEL.  SIGNOR-276248 0.381 L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 24657844 t miannu Recently, we structurally and biochemically characterized the enzyme human L-asparaginase 3 (hASNase3), which possesses L-asparaginase activity and belongs to the N-terminal nucleophile superfamily of enzymes. l-Asparaginases (EC 3.5.1.1; l-asparagine amidohydrolase; l-ASNase2) are enzymes that primarily catalyze the conversion of l-asparagine (l-Asn) to l-aspartic acid (l-Asp) and ammonia, although some of them are able to also hydrolyze l-glutamine (l-Gln) to l-glutamic acid (l-Glu) and ammonia. SIGNOR-267536 0.8 AKT1 protein P31749 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor. SIGNOR-252542 0.737 MAPK3 protein P27361 UNIPROT SPHK1 protein Q9NYA1 UNIPROT up-regulates phosphorylation Ser225 VGSKTPAsPVVVQQG 9606 14532121 t gcesareni Activation of sphingosine kinase 1 by erk1/2-mediated phosphorylation. SIGNOR-118550 0.594 Food intake phenotype SIGNOR-PH152 SIGNOR vitamin D smallmolecule CHEBI:27300 ChEBI up-regulates quantity 9606 30080183 f lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin. Vitamin D can also be obtained from nutrition. SIGNOR-270565 0.7 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT up-regulates activity phosphorylation Tyr310 LPNQEENyVTPIGDG BTO:0000007 12540842 t lperfetto To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 80€“60% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2. SIGNOR-249372 0.346 PKA proteinfamily SIGNOR-PF17 SIGNOR PIK3CG protein P48736 UNIPROT down-regulates activity phosphorylation Thr1024 YLALRHHtNLLIILF 9606 BTO:0002181 21474070 t miannu Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production.  SIGNOR-276321 0.2 ETS1 protein P14921 UNIPROT TBX22 protein Q9Y458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 25373698 t miannu TBX22 is an X-linked gene, which encodes a T-box-containing transcription factor. Loss-of-function mutation in the X-linked TBX22 promoter disrupts an ETS-1 binding site and leads to cleft palate. We first link the transcription factor ETS-1 to TBX22 pathway during embryonic palatogenesis. SIGNOR-265565 0.2 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser146 PALEVSDsESDEALV 9606 10618498 t lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability SIGNOR-73887 0.436 MEF2A protein Q02078 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates quantity by expression transcriptional regulation 14630949 f lperfetto Neither GEF nor MEF2A alone significantly activated GLUT4 promoter activity, but increased promoter activity 4- to 5-fold when expressed together. SIGNOR-271692 0.368 TOM40 complex complex SIGNOR-C421 SIGNOR ATF5 protein Q9Y2D1 UNIPROT down-regulates activity relocalization 31387448 t lperfetto Central to the mtUPR is the transcription factor ATF5. When stress causes protein import and/or electron transport chain dysfunction ATF5 accumulates in the nucleus to transcribe mitochondrial chaperones and protease genes |Under normal conditions, ATF5 is imported into and sequestered within mitochondria. SIGNOR-267685 0.2 AGT protein P01019 UNIPROT AGTR1 protein P30556 UNIPROT up-regulates activity binding 10116 BTO:0004578 17346243 t AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells) SIGNOR-252293 0.85 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DHPS protein P49366 UNIPROT up-regulates activity phosphorylation Ser233 KNHIPVFsPALTDGS 9606 BTO:0002524 32989218 t miannu The Ser-233 phosphorylation of DHPS by ERK1/2 is important for its function in cell proliferation. SIGNOR-277815 0.2 RPL38 protein P63173 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262461 0.864 HNF4G protein Q14541 UNIPROT HAS2 protein Q92819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003723 23896584 t Luana Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G. SIGNOR-261626 0.342 TSPAN12 protein O95859 UNIPROT NDP protein Q00604 UNIPROT up-regulates 9606 19837033 f Genetic Interaction gcesareni Tspan12 genetically interacts with norrin or lrp5 SIGNOR-188661 0.572 cabazitaxel chemical CHEBI:63584 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 21770474 t miannu Among these, larotaxel (XRP9881, formerly RPR109881A)[3,4] and cabazitaxel (XRP6258, TXD258, RPR116258A)[5] share a mechanism of action unique to taxanes, promoting tubulin assembly and stabilizing microtubules against cold-induced depolymerization SIGNOR-259340 0.8 GSK3B protein P49841 UNIPROT TSC2 protein P49815 UNIPROT up-regulates activity phosphorylation 10116 BTO:0003293 16959574 t lperfetto Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation. SIGNOR-149380 0.725 HERC2 protein O95714 UNIPROT XPA protein P23025 UNIPROT down-regulates ubiquitination 9606 20304803 t miannu Herc2 may ubiquitinate xpa and thus target it for proteolytic degradation SIGNOR-164595 0.39 ACOT4 protein Q8N9L9 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271806 0.8 P2RY6 protein Q15077 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257398 0.2 PRKCA protein P17252 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl. SIGNOR-17905 0.545 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 26194464 t MARCO ROSINA TGF-b ligands bind to TGF-b type II receptor (TbRII), which transphosphorylates and activates TGF-b type I receptor (TbRI). SIGNOR-255031 0.842 GSK3B protein P49841 UNIPROT STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization phosphorylation Thr385 ILTSNQKtLTPEKGQ 9606 BTO:0002181 31843895 t miannu GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation. SIGNOR-276765 0.291 ruxolitinib chemical CHEBI:66919 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258277 0.8 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 20186153 t gcesareni Akt activation is achieved through a series of phosphorylation steps, the first being akt phosphorylation at thr-450 by jnk kinases. Pp-1 acts as a major phosphatase to dephosphorylate akt at thr-450 and thus modulate its functions. SIGNOR-163965 0.391 NFYA protein P23511 UNIPROT NFY complex SIGNOR-C1 SIGNOR form complex binding 9606 9885213 t lperfetto Nf-y is one of the best characterized ccaat binding proteins, and its unique structure and evolutionary conservation suggest that it plays a crucial role in transcription of eukaryotic genes.It Is a ubiquitous heteromeric transcription factor, composed of three subunits, nf-ya, nf-yb, and nf-yc, all necessary for dna binding. SIGNOR-63013 0.963 EP300 protein Q09472 UNIPROT ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 f lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. SIGNOR-254097 0.2 BRAF protein P15056 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29731393 f miannu Oncogenic proteins that regulate proliferation, such as KRAS, BRAF, and MYC increase the transcription of NRF2 SIGNOR-267362 0.2 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Ser29 VSHWQQQsYLDSGIH -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275995 0.46 HMGCS2 protein P54868 UNIPROT acetoacetyl-CoA smallmolecule CHEBI:15345 ChEBI down-regulates quantity chemical modification 29597274 t lperfetto Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS, EC 2.3.3.10) catalyzes the condensation reaction between acetyl-CoA and acetoacetyl-CoA in ketone body synthesis SIGNOR-267659 0.8 FOXP3 protein Q9BZS1 UNIPROT T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR up-regulates 9606 15785758 f mrosina Viewed as a whole, the available data demonstrate essential involvement of Foxp3 in the development and function of CD4 + CD25 + T reg cells. SIGNOR-254970 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR AQP5 protein P55064 UNIPROT up-regulates activity phosphorylation Ser156 STDSRRTsPVGSPAL 9606 BTO:0000007 26569106 t lperfetto AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation. SIGNOR-272087 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0000298 phosphorylation:Tyr177 8402896 t gcesareni BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Mutation of Y177 to phenylalanine (Y177F) abolishes GRB-2 binding and abrogates BCR-ABL-induced Ras activation SIGNOR-248199 0.2 IL1A protein P01583 UNIPROT MC1R protein Q01726 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000847 9767234 f miannu MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252387 0.2 KAT2A protein Q92830 UNIPROT H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269601 0.2 NFKBIA protein P25963 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity binding 9606 SIGNOR-C13 1340770 t lperfetto Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b SIGNOR-17688 0.732 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. SIGNOR-249028 0.298 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 24173284 t lperfetto The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A SIGNOR-120836 0.774 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser327 DPEMEEDsYDSFGEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250933 0.309 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser212 DETERAYsFCGTIEY 9606 15568999 t lperfetto Msk1 can autophosphorylate on at least six sites: ser-212, ser-376, ser-381, ser-750, ser-752 and ser-758. Of these sites, the n-terminal t-loop residue ser-212 and the 'hydrophobic motif' ser-376 are phosphorylated by the c-terminal kinase domain of msk1, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain of msk1 and therefore for the phosphorylation of msk1 substrates in vitro. SIGNOR-131387 0.2 H2AZ1 protein P0C0S5 UNIPROT Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR form complex binding -1 24311584 t miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. However, no structural differences between H2A.Z.1 and H2A.Z.2 have been reported. In the present study, the crystal structures of nucleosomes containing human H2A.Z.1 and H2A.Z.2 were determined. SIGNOR-263715 0.2 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 4188963 t dermatitis gcesareni SIGNOR-251705 0.8 TAF2 protein Q6P1X5 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269574 0.542 LCK protein P06239 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT 10880360 t lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. SIGNOR-249373 0.637 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499-2 UNIPROT down-regulates phosphorylation Ser579 YQSTIPQsPSPAPDD 9606 10828059 t The effect has been demonstrated using Q08499-5 llicata The pde4d2 isoform is inhibited by erk2 phosphorylation SIGNOR-77563 0.357 AKT1 protein P31749 UNIPROT SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21619873 t gcesareni Akt, a member of the ser-ine/threonine-specific protein kinase, was found to phosphorylate osx and dlx5 SIGNOR-252514 0.431 BRAF protein P15056 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 f These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. SIGNOR-259373 0.7 NPY protein P01303 UNIPROT NPY5R protein Q15761 UNIPROT up-regulates binding 9606 11825645 t gcesareni Npy expression significantly increases whereas the gene expression of its receptors npy1r, npy2r, and npy5r initially decreases. SIGNOR-114746 0.735 CDK1 protein P06493 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Thr317 RGALVRGtPVRGAIT 9606 9315091 t lperfetto Phosphorylation of sam68 by purified cdc2. SIGNOR-51275 0.524 STON2 protein Q8WXE9 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 26903854 t miannu  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. SIGNOR-264113 0.553 GRM6 protein O15303 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264084 0.329 GRK2 protein P25098 UNIPROT OXTR protein P30559 UNIPROT down-regulates activity phosphorylation 9534 BTO:0000298 16179383 t miannu Recent experiments in COS-7 cells transfected with OTR have demonstrated that a rapid GRK2-mediated phosphorylation of the agonist-occupied OTR is a key first step leading to its desensitization, and that it precedes and is required for β-arrestin-dependent internalization SIGNOR-270329 0.2 FCAR protein P24071 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 9606 30766540 f lperfetto IgA-mediated immune effector responses such as phagocytosis, antibody-dependent cell-mediated cytotoxicity, respiratory burst and cytokine release are mediated through FcalphaRI (CD89), an IgA-specific receptor that is expressed on monocytes, eosinophils, neutrophils and macrophages SIGNOR-264861 0.7 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Ser409 LRLDPTLsVDDLANS 9606 BTO:0000972 phosphorylation:Ser213 TRKLMEFsEHCAIIL 9155023 t lperfetto Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. In contrast, phosphorylation of Ser409 and Ser416, located in a segment corresponding to the substrate recognition T-loop region in a three-dimensional structural model of protein kinases, is enhanced by receptor dimerization and can occur via an intermolecular mechanism. Phosphorylation of Ser409 is essential for TbetaRII kinase signaling, while phosphorylation of Ser416 inhibits receptor function. SIGNOR-246743 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE11A protein Q9HCR9 UNIPROT up-regulates activity phosphorylation Ser117 GNLQRRAsQKELRKS -1 18312413 t miannu The N-terminus has two phosphorylation sites for cyclic nucleotide monophosphate-dependent protein kinases (Ser117, Ser168). Phosphorylation of both by cAMP-dependent protein kinase decreased the EC50 value for cGMP from 72 to 23 μm. Effect of phosphorylations at Ser117 and Ser162. Here, serine phosphorylation by the catalytic subunit of cAK, albeit not known whether at position 117, 162 or both, increased cGMP affinity about threefold. SIGNOR-276153 0.2 PRKACA protein P17612 UNIPROT DSP protein P15924 UNIPROT down-regulates activity phosphorylation Ser2849 RSGSRRGsFDATGNS 9606 BTO:0000567 7525582 t miannu HeLa cells treated with forskolin indicated that stimulation of protein kinase A in transfected cells could decrease the interaction of DP.AN.SerC23 with keratin IF networks. phosphorylation of Ser-C23 could destabilize interactions that occur either directly through this 20 residue sequence or that are dependent on its correct conformation SIGNOR-250353 0.331 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser106 SQKTYQGsYGFRLGF 9606 23201157 t gcesareni Ser-106 phosphorylation of p53 decreases its interaction with mdm2 and prolongs the half-life of p53 SIGNOR-199939 0.774 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr830 PLEEQCEyLSYDASQ 9606 20431062 t lperfetto Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk. SIGNOR-165047 0.5 DOK1 protein Q99704 UNIPROT AX/b2 integrin complex SIGNOR-C171 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257683 0.299 EID3 protein Q8N140 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 10090 23720823 f miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene. SIGNOR-266641 0.7 SHOC2 protein Q9UQ13 UNIPROT MRAS protein O14807 UNIPROT up-regulates binding 9606 10783161 t gcesareni Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf. SIGNOR-77082 0.685 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 t lperfetto Recently, Liu et al. [3] identified CyclinE/CDK2 to be the kinase phosphorylating OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) by elegantly combining genetics and biochemistry. Knockout of all five G1 cyclins (D1, D2, D3, E1 and E2) in mESCs (coined Q-KO cells) and consequent inactivation of CDK2/4/ 6 leads to perturbation of the pluripotent state and to the adaption of the trophectoderm cell fate. This was attributed to reduced phosphorylation of OCT4 (as well as SOX2 and NANOG) leading to an increase of protein turnover [3]. SIGNOR-264437 0.323 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr371 LLAKLEEtKEYQEPE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276210 0.386 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275942 0.2 RAB4A protein P20338 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity binding 9606 20534812 t Giulio Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4 SIGNOR-261280 0.672 KLF15 protein Q9UIH9 UNIPROT RBP3 protein P10745 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253816 0.267 LCK protein P06239 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Tyr194 DVQKSKEyFSKQK -1 20178744 t miannu Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation. SIGNOR-276277 0.2 MRPL50 protein Q8N5N7 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262338 0.681 HCK protein P08631 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9534 12235133 t Src family kinase Hck induces phosphorylation of WASp-Tyr(291). Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. SIGNOR-251268 0.566 CKM complex complex SIGNOR-C406 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273140 0.343 SIRT7 protein Q9NRC8 UNIPROT H3-4 protein Q16695 UNIPROT up-regulates activity deacetylation Lys38 PATGGVKkPHRYRPG 30653310 t lperfetto Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. SIGNOR-275882 0.2 ADX-47273 chemical CID:11383075 PUBCHEM GRM5 protein P41594 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189338 0.8 RNF8 protein O76064 UNIPROT RAD18 protein Q9NS91 UNIPROT up-regulates binding 9606 19396164 t gcesareni Rnf8 depletion also significantly reduced the accumulation of rad18 to chromatin fraction after ir SIGNOR-185593 0.422 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3. All four sites are followed by a proline residue. We have shown that purified cyclin b-cdk1 (cyclindependent kinase 1) phosphorylates these sitesalanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase. SIGNOR-216809 0.376 NDUFA4 protein O00483 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267752 0.53 AKT proteinfamily SIGNOR-PF24 SIGNOR IRAK1 protein P51617 UNIPROT down-regulates activity phosphorylation Thr100 LRARDIItAWHPPAP 9606 BTO:0000007 11976320 t gcesareni CaMKKc and Akt overexpression increases IRAK1 phosphorylation at Thr100, and point mutation of this site abrogates the inhibitory effect of Akt on IRAK1-mediated NF-kappaB activation. SIGNOR-248008 0.2 NCOA1 protein Q15788 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255063 0.46 CSNK1E protein P49674 UNIPROT CSNK1E protein P49674 UNIPROT down-regulates activity phosphorylation Thr407 SRIPASQtSVPFDHL 9606 BTO:0000007 10542239 t llicata Amino acids Ser-323, Thr-325, Thr-334, Thr-337, Ser-368, Ser-405, Thr-407, and Ser-408 in the carboxyl-terminal tail of CKIepsilon were identified as probable in vivo autophosphorylation sites. A recombinant CKIepsilon protein with serine and threonine to alanine mutations eliminating these autophosphorylation sites was 8-fold more active than wild-type CKIepsilon using IkappaBalpha as a substrate. T SIGNOR-250814 0.2 MTA1 protein Q13330 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001938 19805145 t miannu MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism SIGNOR-271892 0.2 CD28 protein P10747 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000782 18006698 t gcesareni Cd28 can bind directly to pi3k by a well-characterized ymnm binding motif in its cytoplasmic domain. SIGNOR-159322 0.373 LTC4S protein Q16873 UNIPROT glutathionate(1-) smallmolecule CHEBI:57925 ChEBI down-regulates quantity chemical modification 9606 27365393 t miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). SIGNOR-277259 0.8 PLK1 protein P53350 UNIPROT PKMYT1 protein Q99640 UNIPROT unknown phosphorylation Thr495 LLSLFEDtLDPT 9606 12738781 t lperfetto These results suggest that Ser-426 is a major phosphorylation site by Plk1, and Thr-495 is a second major site.  SIGNOR-249208 0.712 FER protein P16591 UNIPROT FER protein P16591 UNIPROT up-regulates activity phosphorylation Tyr714 RQEDGGVySSSGLKQ 9534 10998246 t P94fer undergoes autophosphorylation in-trans in vivo and that oligomerization mediates this process. the N-terminal sequences of the FER tyrosine kinases direct their different cellular autophosphorylation states, thereby dictating their different cellular functions. SIGNOR-251133 0.2 APLNR protein P35414 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256681 0.422 MAPKAPK2 protein P49137 UNIPROT HSPA1L protein P34931 UNIPROT up-regulates activity phosphorylation Ser241 DFDNRLVsHFVEEFK -1 31642047 t done miannu  We demonstrate that MK2 phosphorylates HspA1L solely on Ser241, a residue within the N-terminal nucleotide-binding domain of the enzyme. This phosphorylation event enhances the chaperone activity of HspA1L in vitro and renders male germ cells more resistant to heat stress-induced apoptosis. SIGNOR-273674 0.2 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1693 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273070 0.635 PHF10 protein Q8WUB8 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270598 0.684 PAK1 protein Q13153 UNIPROT SYN1 protein P17600 UNIPROT up-regulates activity phosphorylation Ser605 AGPTRQAsQAGPVPR 10116 BTO:0001009 12237306 t miannu Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release SIGNOR-250235 0.353 CHD8 protein Q9HCK8 UNIPROT NEUROD4 protein Q9HD90 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268918 0.2 RNF4 protein P78317 UNIPROT NFYA protein P23511 UNIPROT up-regulates activity binding 9606 15496512 t miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252229 0.2 FOXO proteinfamily SIGNOR-PF27 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-256644 0.7 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190985 0.8 ERCC1 protein P07992 UNIPROT ERCC4/ERCC1 complex SIGNOR-C50 SIGNOR form complex binding 9606 16338413 t miannu Human ercc1/xpf interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. SIGNOR-142989 0.953 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in alzheimer's disease (ad). Gsk-3beta phosphorylated tau at many sites, with ser199, thr205, and ser396 being the most favorable sites in cells. SIGNOR-164655 0.733 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-202807 0.8 CDON/SPAG9 complex SIGNOR-C21 SIGNOR MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 22337877 t lperfetto Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts SIGNOR-235557 0.36 RAB1A protein P62820 UNIPROT C9orf72 protein Q96LT7 UNIPROT up-regulates activity binding 9606 27334615 t lperfetto Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology. SIGNOR-261282 0.483 GAL protein P22466 UNIPROT GALR2 protein O43603 UNIPROT up-regulates binding 9606 10601261 t gcesareni Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm). SIGNOR-73125 0.86 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates activity phosphorylation Ser1143 PMGSSHAsQVCSETP 9606 BTO:0002181 11114888 t llicata Of the four potential phosphoacceptor sites in the BRCA1 (1005–1313) fragment (Ser 1143, Ser 1239, Ser 1280, Ser 1298), Ala substitutions at two sites, Ser 1143 and Ser 1280, reduced the in vitro phosphorylation of GST–BRCA1 (1005–1313) by ATR, whereas substitution of Ser 1239 or Ser 1298 with Ala had little or no effect (Fig. 2C; data not shown). A Ser 1143/Ser 1280 double mutant was a poor substrate for ATR, suggesting that these are the two major in vitro phosphorylation sites on this BRCA1 fragment. | Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication. SIGNOR-250581 0.796 UBE2D2 protein P62837 UNIPROT TRIM9 protein Q9C026 UNIPROT up-regulates activity binding 9606 BTO:0000142 20085810 t miannu Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N SIGNOR-271420 0.41 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1623 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273097 0.749 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26582 0.2 GOT1 protein P17174 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-267509 0.8 MAPK14 protein Q16539 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr300 TPVVSVAtPTLPGQG 9606 9858528 t The effect has been demonstrated using Q06413-3 lperfetto Our studies showed that p38 specifically phosphorylates serine 387 and threonines 293 and 300 within the mef2c transactivation domain SIGNOR-62796 0.688 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Thr202 HDHTGFLtEYVATRW 10116 7535768 t We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively SIGNOR-248462 0.781 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr218 PPRDFAAyRS 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail SIGNOR-45520 0.682 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 10090 BTO:0004052 23996074 t irozzo In this work, we have identified and mapped the protein-protein interaction site between DOT1L and MLL fusion proteins, AF9 and ENL.The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). It is known that the recruitment of DOT1L results in hypermethylation of H3K79 on the prominent MLL fusion downstream target loci Hoxa9 and Meis1 SIGNOR-255869 0.2 TGFBI protein Q15582 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 26387839 t lperfetto BIGH3 binds molecules of the ECM, including fibronectin, laminin and different collagens ( Hashimoto et al., 1997 ; Hanssen et al., 2003) and serves as a ligand for several integrins|BIGH3 has been shown to interact with α3β1, αvβ3, αvβ5, α1β1, α6β4 and α7β1 integrin heterodimers SIGNOR-253266 0.426 PDPK1 protein O15530 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates phosphorylation Thr305 TDAATMKtFCGTPEY 9606 BTO:0000887;BTO:0001103;BTO:0001760 9512493 t gcesareni The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma) SIGNOR-55937 0.641 GAD1 protein Q99259 UNIPROT gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267552 0.8 MAPKAPK2 protein P49137 UNIPROT LIMK1 protein P53667 UNIPROT up-regulates phosphorylation Ser323 KDLGRSEsLRVVCRP 9606 16456544 t lperfetto Mk2 activated limk1 by phosphorylation at ser-323. SIGNOR-144333 0.364 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr115 GTIAKSGtKAFMEAL 9606 24117238 t lperfetto Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity. SIGNOR-202812 0.259 CSNK2A1 protein P68400 UNIPROT CAPZA1 protein P52907 UNIPROT up-regulates phosphorylation Ser9 ADFDDRVsDEEKVRI 9606 15831458 t lperfetto We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments. SIGNOR-135422 0.2 WWP1 protein Q9H0M0 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates activity ubiquitination 9606 15221015 t lperfetto Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. SIGNOR-227466 0.724 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity precursor of -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-268105 0.8 OPRL1 protein P41146 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256722 0.449 GRM5 protein P41594 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264348 0.7 CDK2 protein P24941 UNIPROT PTPN12 protein Q05209 UNIPROT down-regulates activity phosphorylation Ser19 QRVQAMKsPDHNGED 9606 BTO:0000815 28842430 t miannu In the present study, we found that S19 site phosphorylation of PTPN12 by CDK2 discharged its antitumor activity by down-regulation of its inhibitory role in cell migration, but not affecting its other regulatory functions. SIGNOR-277366 0.388 EZH2 protein Q15910 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates activity 10090 15520282 f We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts SIGNOR-255719 0.7 SYK protein P43405 UNIPROT HCLS1 protein P14317 UNIPROT up-regulates phosphorylation Tyr397 EDEPEGDyEEVLEPE 9606 BTO:0000776 9104825 t llicata Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis. SIGNOR-47342 0.658 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR3 protein P32745 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257583 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates activity phosphorylation Thr193 VKLSNIPtIKRFLEP 9534 12646569 t lperfetto Mutational analysis show that the putative mitochondrial targeting signal resides within the C-terminal 20 amino acid residues of the protein and that the targeting signal requires activation by phosphorylation at the C-terminal-most protein kinase A (PKA) site at Ser-189 or protein kinase C (PKC) site at Thr-193. SIGNOR-264795 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation -1 9525907 t inferred from 70% family members miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-270170 0.2 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser274 TSPSPISsPTFSPIE 9606 23442801 t lperfetto It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation SIGNOR-201515 0.26 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS2 protein Q9NRM7 UNIPROT up-regulates 9606 23075495 f gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-199199 0.8 LETM1 protein O95202 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 10090 29123128 t lperfetto Others have suggested that LETM1 plays an essential role in mitochondrial K+ homeostasis by mediating the mitochondrial K+/H+ exchange SIGNOR-262542 0.8 MMP10 protein P09238 UNIPROT HAPLN1 protein P10915 UNIPROT down-regulates quantity by destabilization cleavage Leu40 QAENGPHlLVEAEQA -1 7694569 t miannu Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix. SIGNOR-256332 0.327 pazopanib chemical CHEBI:71219 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258262 0.8 PRKACA protein P17612 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD -1 9016641 t miannu PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1. SIGNOR-250336 0.443 NTRK3 protein Q16288 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 BTO:0000938 10092678 t gcesareni We demonstrate that the phosphotyrosine binding domain of frs-2 directly binds the trk receptors at the same phosphotyrosine residue that binds the signaling adapter shc, suggesting a model in which competitive binding between frs-2 and shc regulates differentiation versus proliferation. SIGNOR-65958 0.725 GRK2 protein P25098 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10852916 t llicata We found that grk-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and pld2. These findings suggest that gpcrs may be able to indirectly stimulate pld2 activity via their ability to regulate grk-promoted phosphorylation of synuclein. SIGNOR-78333 0.2 GSK3B protein P49841 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates activity phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 t lperfetto The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. SIGNOR-261795 0.435 LPAR3 protein Q9UBY5 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256890 0.443 PPP1R3B protein Q86XI6 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR up-regulates binding 9606 BTO:0000759 36551183 t miannu In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2) SIGNOR-271736 0.705 PTPMT1 protein Q8WUK0 UNIPROT 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI down-regulates quantity chemical modification 10090 21641550 t lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. SIGNOR-267026 0.8 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0002881 19427855 f Luana Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2 SIGNOR-264966 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 GPLITPGsGSIYSSP 9606 BTO:0000567 35469017 t miannu  CDK1–cyclin B1 mediates KIND2 phosphorylation at mitotic entry. SIGNOR-276716 0.2 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249626 0.909 afatinib chemical CHEBI:61390 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 24643470 t miannu This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. SIGNOR-259295 0.8 zotepine chemical CHEBI:32316 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0000298 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258557 0.8 MYC protein P01106 UNIPROT FUT3 protein P21217 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f miannu We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-254612 0.255 HIF1A protein Q16665 UNIPROT KDM1A protein O60341 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271573 0.267 CBLB protein Q13191 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000782 11087752 t miannu Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells.Here it is shown that Cbl-b interacts with and induces ubiquitin conjugation to the p85 regulatory subunit of phosphatidylinositol 3-kinase, an upstream regulator of Vav. SIGNOR-272583 0.504 MAP3K5 protein Q99683 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates phosphorylation Ser98 GGRRPGTsPALLQGT 9606 17325029 t lperfetto P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway. SIGNOR-153440 0.581 AKT proteinfamily SIGNOR-PF24 SIGNOR FANCA protein O15360 UNIPROT unknown phosphorylation Ser1149 CLRSRDPsLMVDFIL -1 11855836 t FANCA is phosphorylated at Ser1149 by Akt. The biological significance of FANCA phosphorylation and its regulation by Akt remains unclear at this time. SIGNOR-251476 0.2 CSNK1G2 protein P78368 UNIPROT LYN protein P07948 UNIPROT up-regulates quantity by stabilization phosphorylation Ser13 SKGKDSLsDDGVDLK 9606 BTO:0000007 33004926 t miannu Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. we concluded that S-palmitoylated CK1γ encounters N-myristoylated Lyn and specifically phosphorylates the Ser-13 residue at the Golgi during intracellular protein traffic, as shown schematically in Fig. 8. Phosphorylated dual-lipid-modified Lyn and S-palmitoylated CK1γ are then transported from the Golgi to the plasma membrane. SIGNOR-275397 0.2 GSK3B protein P49841 UNIPROT CDH1 protein P12830 UNIPROT up-regulates activity phosphorylation Ser847 SEAASLSsLNSSESD -1 10671552 t Phosphorylation of the E-cadherin Cytoplasmic Domain by CKII and GSK-3β Increases the Binding to β-catenin. pre-phosphorylation by CKII at Ser-855 and/or Ser-853 of E-cadherin is required before GSK-3β can phosphorylate at Ser-849. SIGNOR-251225 0.569 MAPK14 protein Q16539 UNIPROT NFATC4 protein Q14934 UNIPROT down-regulates activity phosphorylation Ser168 QGGGAFFsPSPGSSS 10029 BTO:0001131 11997522 t miannu P38 MAP kinase phosphorylates Ser168 and Ser170 of NFATc4. Mutational replacement of Ser168,170 with Ala promotes NFATc4 nuclear localization and increases NFATc4-mediated transcription activity. SIGNOR-250107 0.407 MYT1 protein Q01538 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005949 30312684 t miannu Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. Examination of the gene expression changes in cells expressing Myt1 or Myt1l suggests that both repress expression of the YAP1 transcriptional coactivator, which functions primarily in the Hippo signaling pathway. Expression of YAP1 and its target genes is reduced in Myt-expressing cells, and there is an inverse correlation between YAP1 and MYT1/MYT1L expression in human brain cancer datasets. Together, our data suggest that Myt1 and Myt1l directly repress expression of YAP1, a protein which promotes proliferation and GBM growth. SIGNOR-266777 0.2 CSNK2B protein P67870 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Ser29 VSHWQQQsYLDSGIH 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-251065 0.593 AKT1 protein P31749 UNIPROT PALLD protein Q8WX93 UNIPROT unknown phosphorylation Ser1118 VRRPRSRsRDSGDEN 9606 20471940 t llicata Akt1, but not akt2, phosphorylates palladin at ser507 in a domain that is critical for f-actin bundling. SIGNOR-252510 0.413 C5AR2 protein Q9P296 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263461 0.7 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L6 protein O14933 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271319 0.639 Nalorphine chemical CHEBI:7458 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258814 0.8 S100A8 protein P05109 UNIPROT Calprotectin complex complex SIGNOR-C293 SIGNOR form complex binding 9867828 t lperfetto Using the two-hybrid system we analyzed the dimerization of MRP8 (S100A8) and MRP14 (S100A9), two S100 proteins expressed in myeloid cells. It is reported that the MRP8-MRP14 heteromer is the clearly preferred complex in both man and mouse. SIGNOR-262832 0.721 MAPKAPK2 protein P49137 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k SIGNOR-166622 0.307 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization ubiquitination Lys572 VVRPKLPkPPTDPLG 10090 35670107 t lperfetto TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels SIGNOR-272541 0.2 DGCR8 protein Q8WYQ5 UNIPROT RNF168 protein Q8IYW5 UNIPROT up-regulates activity binding 9606 BTO:0002181 34188037 t miannu  Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs.  SIGNOR-277309 0.2 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 18326031 t lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. SIGNOR-161278 0.611 CXCL5 protein P42830 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000584 34237033 f miannu  We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. SIGNOR-277733 0.7 (E)-3-tosylacrylonitrile chemical CHEBI:85928 ChEBI PTPN1 protein P18031 UNIPROT down-regulates chemical inhibition 9606 Other t The anti-inflammatory compound BAY 11-7082 is a potent inhibitor of Protein Tyrosine Phosphatases. gcesareni SIGNOR-190254 0.8 PTGS2 protein P35354 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0001103 20219869 t apalma Furthermore, COX-2 inhibition reduced MyoD expression in regenerating muscle, suggesting a role for COX-2 in modulating muscle differentiation, as well as growth SIGNOR-256214 0.266 HDAC4 protein P56524 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 10737771 t gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. SIGNOR-76237 0.685 PCGF2 protein P35227 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266813 0.771 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser377 PPFNPNVsGPNDLRH -1 12023960 t miannu The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6. SIGNOR-250296 0.341 SMARCB1 protein Q12824 UNIPROT CSF1 protein P09603 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 16267391 f miannu Ini1/hsnf5/baf47 is involved in activation of the csf1 promoter. SIGNOR-141047 0.2 PGAM proteinfamily SIGNOR-PF78 SIGNOR 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266516 0.8 PAX3 protein P23760 UNIPROT MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 23384562 f gcesareni Direct molecular regulation of the myogenic determination gene myf5 by pax3, with modulation by six1/4 factors, is exemplified by the -111 kb-myf5 enhancer. SIGNOR-200862 0.482 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation 9606 BTO:0000149 24342355 t inferred from 70% family members lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity SIGNOR-270118 0.2 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Thermogenesis phenotype SIGNOR-PH192 SIGNOR up-regulates 9606 24692351 f scontino TH plays a significant role in energy expenditure through both central and peripheral actions. TH maintains basal metabolic rate, facilitates adaptive thermogenesis, modulates appetite and food intake, and regulates body weight. SIGNOR-267491 0.7 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr243 LDDSTGGtPLTPAAR 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274084 0.533 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258570 0.8 TNFRSF17 protein Q02223 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates 9606 10903733 f inferred from 70% of family members miannu Overexpression of bcma activates the p38 mapk SIGNOR-269917 0.267 acetyl-CoA smallmolecule CHEBI:15351 ChEBI malonyl-CoA smallmolecule CHEBI:15531 ChEBI up-regulates quantity precursor of 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267108 0.8 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Phe634 VHHQKLVfFAEDVGS -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261771 0.497 regorafenib chemical CHEBI:68647 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259214 0.8 CALM3 protein P0DP25 UNIPROT PPP3CB protein P16298 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266338 0.587 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254726 0.31 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. SIGNOR-183688 0.633 AKT proteinfamily SIGNOR-PF24 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates binding 9606 15048128 t gcesareni Pkb inhibits smad3 by preventing its phosphorylation, binding to smad4 and nuclear translocation. [...] Regulation of smad3 by pkb occurs through a kinase-activity-independent mechanism, resulting in a decrease in smad3-mediated transcription and protection of cells against tgf-beta-induced apoptosis. SIGNOR-252345 0.2 DDX21 protein Q9NR30 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268824 0.427 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser248 SVQSDIWsMGLSLVE -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-39058 0.782 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr286 EELAMDVyDEVDRRE 9606 16317044 t fspada Conversely, a gfp-pkl phosphorylation mutant, y286/392/592f (gfp-pkl triple yf) (brown et al., 2005), was not phosphorylated during adhesion and the addition of ptp-pest had no effect, suggesting one or more of these tyrosine residues are dephosphorylated by ptppest. Taken together, these data strongly suggest pkl as a direct substrate for ptp-pest. SIGNOR-142711 0.349 SOX8 protein P57073 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000410 32550913 t miannu We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance.. Our results showed that SOX8 targets FOXK1, thereby regulating its transcription, which has significant impacts on senescence, glycolysis and chemoresistance in ovarian cancer. SIGNOR-273613 0.291 Caspase 3 complex complex SIGNOR-C221 SIGNOR STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 t lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. SIGNOR-256445 0.606 GRK2 protein P25098 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15843435 t llicata Grk2 phosphorylates glutathione s-transferase (gst)-ezrin, but not an ezrin fusion protein lacking threonine 567 (t567), in vitro. These results suggest that t567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of grk2-mediated phosphorylation. SIGNOR-135622 0.2 EIF3K protein Q9UBQ5 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266390 0.922 PKN2 protein Q16513 UNIPROT MEFV protein O15553 UNIPROT down-regulates activity phosphorylation Ser242 SGKMRPRsLEVTIST 10090 BTO:0004732 27270401 t no miannu PKNs bind to human pyrin and phosphorylate S208 and S242. Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. SIGNOR-275463 0.354 PIP3 smallmolecule CHEBI:16618 ChEBI MAPKAP1 protein Q9BPZ7 UNIPROT up-regulates activity chemical activation 9606 26293922 t gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation SIGNOR-252429 0.8 PD173074 chemical CHEBI:63448 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205725 0.8 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 24265311 t lperfetto Herein, we demonstrate we demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. We have identified the major phosphatase responsible for dephosphorylation of ser-4 to be protein phosphatase 4 catalytic subunit. SIGNOR-203281 0.2 ATG13 protein O75143 UNIPROT ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR form complex binding 9606 23863160 t lperfetto In mammals, two protein complexes, namely the ULK1-Atg13-FIP200 (200kDa focal adhesion kinase family-interacting protein) complex and the Beclin–Vps34 complex, function jointly to produce the phagophore membrane, the initial phase of autophagosome formation. SIGNOR-209884 0.917 FADD protein Q13158 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity binding 9606 11717445 t amattioni Fadd recruits caspase-8 through homotypic interactions of death-effector domains (deds), leading to caspase-8 activation and apoptosis. In turn, fadd recruits the zymogen form of the apoptosis-initiating protease caspase-8, through homophilic interaction of death effector domains. SIGNOR-112061 0.93 Caspase 3 complex complex SIGNOR-C221 SIGNOR RAD51 protein Q06609 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0002882 11684015 t lperfetto The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin SIGNOR-271708 0.473 GRB2 protein P62993 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 BTO:0001271 8402896 t GRB2 binds BCR-ABL with SH2 domain gcesareni We demonstrate that bcr-abl exists in a complex with grb-2 in vivo. Binding of grb-2 to bcr-abl is mediated by the direct interaction of the grb-2 sh2 domain with a phosphorylated tyrosine, y177, within the bcr first exon. SIGNOR-39049 0.568 IKK-complex complex SIGNOR-C14 SIGNOR CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000661 15870263 t gianni In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IkappaB kinase gamma (IKKgamma) and can be induced by IKK catalytic subunits. SIGNOR-266435 0.621 POLR2K protein P53803 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266150 0.858 WWTR1 protein Q9GZV5 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-199211 0.7 P4HB protein P07237 UNIPROT Collagen proteinfamily SIGNOR-PF103 SIGNOR up-regulates quantity by stabilization binding 9606 9545296 t miannu We also show that PDI associates independently with the C-propeptide of monomeric procollagen chains prior to trimer formation, indicating a role for this protein in coordinating the assembly of heterotrimeric molecules. This demonstrates that PDI has multiple functions in the folding of the same protein, that is, as a catalyst for disulfide bond formation, as a subunit of P4-H during proline hydroxylation, and independently as a molecular chaperone during chain assembly. SIGNOR-269731 0.2 ATF4 protein P18848 UNIPROT CARS1 protein P49589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269416 0.2 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser616 PSVASSVsEEYFEVR -1 24554596 t lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. SIGNOR-264767 0.38 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr412 NQVFLGFtYVAPSVL 9823 BTO:0004712 23486913 t lperfetto Collectively, these results indicate that Arg, Leu, and Gln act coordinately to stimulate proliferation of pTr cells through activation of the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway SIGNOR-201538 0.96 CASP6 protein P55212 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp326 YDPEMEEdSYDSFGE -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261745 0.367 MAPK8 protein P45983 UNIPROT MFN2 protein O95140 UNIPROT down-regulates quantity phosphorylation Ser27 HMAEVNASPLKHFVT 9606 BTO:0001938 22748923 t Barakat We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation. SIGNOR-274138 0.436 COL4A6 protein Q14031 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254670 0.7 SMAD6 protein O43541 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 22298955 t Create a non-functional complex with smad4 and competes with R-smad. lperfetto On the other hand, Smad6 competes with R-Smad and forms a non-functional complex with Smad4, which will inhibit BMP signaling in bone formation. Smad6 is involved in a negative feedback loop regulating BMP signaling and is required to limit BMP signaling during endochondral bone formation. SIGNOR-195648 0.563 AURKB protein Q96GD4 UNIPROT PLEKHG6 protein Q3KR16 UNIPROT up-regulates phosphorylation Thr544 SPSTRPStPSLEGSQ 9606 24482237 t lperfetto In this study we report that aurora b-mediated phosphorylation of myogef at thr-544 creates a docking site for plk1, leading to the localization and activation of myogef at the central spindle. SIGNOR-204534 0.256 PDE6G protein P18545 UNIPROT PDE6A protein P16499 UNIPROT down-regulates activity binding 9606 20940301 t Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B SIGNOR-260010 0.863 SIRT7 protein Q9NRC8 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity deacetylation Lys3016 VLMRLQEkLKGVEEG 30944854 t lperfetto Here, we report that sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. |Upon DNA damage, ATM is activated via a series of highly organized machineries, including acetylation by the histone acetyltransferase TIP60 at lysine 3016 SIGNOR-275890 0.365 ITGB1 protein P05556 UNIPROT A10/b1 integrin complex SIGNOR-C167 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253186 0.683 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 17151142 t These data indicate that myogenic activation of p38 requires TNF-alpha receptor-mediated signaling SIGNOR-253592 0.929 DDHD2 protein O94830 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269655 0.8 NME1 protein P15531 UNIPROT LPAR1 protein Q92633 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255163 0.412 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1420 YVVHGPAsVPLGYVP 9606 16513652 t gcesareni We find that ckiepsilon binds to lrp5 and lrp6 in vitro and in vivo and identify three ckiepsilon-specific phosphorylation sites in lrp6. Two of the identified phosphorylation sites, ser1420 and ser1430, influence wnt signaling in vivo, SIGNOR-145049 0.264 SRC protein P12931 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates activity phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000132 19718473 t lperfetto Integrin-dependent translocation of LASP-1 to the cytoskeleton of activated platelets correlates with LASP-1 phosphorylation at tyrosine 171 by Src-kinase SIGNOR-271706 0.255 THOC7 protein Q6I9Y2 UNIPROT TREX complex complex SIGNOR-C444 SIGNOR form complex binding 9606 33191911 t miannu The TREX complex is found in all eukaryotes and contains the multi-subunit THO complex, the DEXD-box RNA helicase UAP56/DDX39B (yeast Sub2), and an RNA export adapter such as ALYREF (yeast Yra1). The human THO complex comprises six subunits, THOC1, −2, –3, −5, –6, and −7, of which four have known counterparts in the yeast Saccharomyces cerevisiae (Sc): THOC1 (yeast Hpr1), −2 (yeast Tho2), −3 (yeast Tex3), and −7 (yeast Mft1) . In this study we focus on the conserved TREX complex (Heath et al., 2016; Xie and Ren, 2019): THO–UAP56/DDX39B–ALYREF, and hereafter refer to UAP56/DDX39B as UAP56. SIGNOR-268507 0.912 frovatriptan chemical CHEBI:134991 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation -1 9986723 t miannu As far as the selectivity against the 5-HT1A receptor, compound 10 shows similar selectivity as VML-251 (4) but has slightly lower selectivity as compared to sumatriptan (1), naratriptan (2), and rizatriptan (3). Although none of the 5-HT1D receptor agonists in the current study demonstrate as good selectivity versus the 5-HT1B receptor, the N-methyl-5-tert-butyltryptamine (10) remains the most selective (4-fold). SIGNOR-259073 0.8 Fanconi anemia core complex complex SIGNOR-C300 SIGNOR FANCD2 protein Q9BXW9 UNIPROT up-regulates activity ubiquitination 9606 17396147 t lperfetto Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263249 0.767 MAPK3 protein P27361 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser8 MESEMLQsPLLGLGE 9606 BTO:0000007 SIGNOR-C3 21071439 t lperfetto We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169530 0.477 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity phosphorylation Tyr567 IRVDTPHyPRWITKE -1 11812791 t Src, Fyn, or Lyn are the essential kinases that tyrosine phosphorylate and inactivate PKC δ. Lyn phosphorylates tyrosine residue 565 in vitro SIGNOR-251407 0.545 HIF1A protein Q16665 UNIPROT PKG proteinfamily SIGNOR-PF77 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0000972 8089148 f inferred from family member miannu Hypoxia-inducible factor 1 (HIF-1) activates erythropoietin gene transcription in Hep3B cells subjected to hypoxia. HIF-1 activity is also induced by hypoxia in non-erythropoietin-producing cells, suggesting a more general regulatory role. We now report that RNAs encoding the glycolytic enzymes aldolase A (ALDA), phosphoglycerate kinase 1 (PGK1), and pyruvate kinase M were induced by exposure of Hep3B or HeLa cells to inducers of HIF-1 (1% O2, cobalt chloride, or desferrioxamine). Sequences from the ALDA, PFKL, and PGK1 genes containing HIF-1 binding sites mediated hypoxia-inducible transcription in transient expression assays. SIGNOR-270291 0.477 CAMK2A protein Q9UQM7 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser2137 RDLRRLYsVDAQGFL 10090 BTO:0003695 38001892 t miannu  we also discovered that a novel CaMKII-phosphorylated site, S2137, underwent dephosphorylation by calcineurin.  SIGNOR-277871 0.274 CTDSPL2 protein Q05D32 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 20932329 f Regulation of transcription miannu CTD small phosphatase like 2 (CTDSPL2) can increase ε- and γ-globin gene expression in K562 cells and CD34+ cells derived from umbilical cord blood. SIGNOR-251778 0.2 PLD1 protein Q13393 UNIPROT phosphatidic acid smallmolecule CHEBI:16337 ChEBI up-regulates chemical modification 9606 9873061 t gcesareni The primary known function of phospholipase d (pld) is to generate phosphatidic acid (pa) via the hydrolysis of phosphatidylcholine. . phospholipase d (pld) hydrolyzes phospholipids to generate phosphatidic acid (pa). SIGNOR-62882 0.8 SSTR5 protein P35346 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256969 0.282 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Thr638 TRGQPVLtPPDQLVI 9606 15277524 t lperfetto Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function SIGNOR-127257 0.2 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD -1 19661060 t miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276228 0.2 PPP2R5B protein Q15173 UNIPROT KIF20A protein O95235 UNIPROT up-regulates activity dephosphorylation Ser878 RILRSRRsPLLKSGP 9606 BTO:0000567 27939310 t miannu We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878. SIGNOR-262660 0.2 SAV1 protein Q9H4B6 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 9606 21084559 t miannu Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. SIGNOR-256183 0.893 PTK6 protein Q13882 UNIPROT PTK6 protein Q13882 UNIPROT up-regulates activity phosphorylation Tyr447 RLSSFTSyENPT 9606 12121988 t lperfetto Mutation of a C-terminal tyrosine (Tyr-447) increases enzyme activity and SH2 domain accessibility, consistent with a role for this residue in autoinhibition. | These results suggest that the Y447F and W44A mutations disrupt the normal intramolecular regulation of Brk and increase the catalytic activity of Brk. SIGNOR-249152 0.2 MTOR protein P42345 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000132 SIGNOR-C2 21592956 t lperfetto Protein kinase B (PKB, Akt) is a Ser/Thr kinase involved in the regulation of cell survival, proliferation, and metabolism and is activated by dual phosphorylation on Thr(308) in the activation loop and Ser(473) in the hydrophobic motif. It plays a contributory role to platelet function, although little is known about its regulation. In this study, we investigated the role of the mammalian target of rapamycin complex (mTORC)-2 in Akt regulation using the recently identified small molecule ATP competitive mTOR inhibitors PP242 and Torin1. SIGNOR-244417 0.929 MORF4L2 protein Q15014 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269300 0.667 DHFR protein P00374 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI down-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268257 0.8 ABL2 protein P42684 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Tyr78 RAIDFSPyLEPLGAP 9606 BTO:0000007 19563810 t gcesareni The y79 amino acid residue of c/ebpbeta was phosphorylated by c-abl or arg. The phosphorylation of c/ebpbeta resulted in an increased c/ebpbeta stability and a potentiation of c/ebpbeta transcription activation activity in cells SIGNOR-186427 0.276 AMPK complex SIGNOR-C15 SIGNOR KLC2 protein Q9H0B6 UNIPROT up-regulates phosphorylation Ser582 PRMKRASsLNFLNKS 9606 21725060 t lperfetto Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582 SIGNOR-216468 0.29 RNF5 protein Q99942 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys362 RAGMVPSkVPTSMVL 9606 BTO:0000007 20483786 t miannu In this study, we showed that the E3 ubiquitin ligase RING-finger protein 5 (RNF5) interacted with VISA at mitochondria in a viral infection-dependent manner. Domain mapping experiments indicated that the C-terminal transmembrane domain of VISA was required for its interaction with RNF5. RNF5 targeted VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection, whereas knockdown of RNF5 reversed virus-induced downregulation of VISA at the early phase.  SIGNOR-271488 0.463 AUTS2 protein Q8WXX7 UNIPROT DOCK1 protein Q14185 UNIPROT up-regulates activity binding 10090 BTO:0001909 25533347 t miannu Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development.  AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These results suggest that FL-AUTS2 can activate Rac1 via interaction with P-Rex1 and the Elmo2/Dock180 complex to regulate actin dynamics in N1E-115 cells. SIGNOR-266820 0.2 RAB1A protein P62820 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity binding 9606 BTO:0000007 27479033 t Giulio Hemagglutinin (HA)-Rab1A is associated with mTOR and Raptor, not Rictor (Figure S2A), and is bound more with Myc-Raptor than Myc-mTOR (Figures S2B and S2C).|Rab1A Is an mTORC1 Activator and a Colorectal Oncogene SIGNOR-261286 0.319 MAPK3 protein P27361 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser425 TKGSGLGsPTSSFNS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-184577 0.588 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 APPSPAWsEPEPEAG 10090 37029927 t miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. SIGNOR-277795 0.2 NLGN3 protein Q9NZ94 UNIPROT NRXN2 protein Q9P2S2 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264152 0.827 CDH15 protein P55291 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265854 0.626 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Ser65 FLMECRNsPVTKTPP 9606 BTO:0000007 11691836 t lperfetto The 4E-BPs inhibit translation in a reversible manner. Hypophosphorylated 4E-BPs interact avidly with eIF4E, whereas 4E-BP hyperphosphorylation, elicited by stimulation of cells with hormones, cytokines, or growth factors, results in an abrogation of eIF4E-binding activity.|These results are at variance with reports that have characterized the 4E-BP1/eIF4E interaction utilizing recombinant 4E-BP1 proteins phosphorylated in vitro with ERK, and harboring alanine substitutions at Thr 37, Thr 46, Thr 70, and Ser 83 |phosphorylation of either Thr 46 or Ser 65 was reported to result in a decrease in eIF4E binding SIGNOR-249390 0.653 MAPK3 protein P27361 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser172 YRDPSCLsPASSLSS 9606 10652349 t Translocation from Nucleus to Cytoplasm esanto We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats. SIGNOR-74564 0.52 RPS6KA1 protein Q15418 UNIPROT L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. SIGNOR-248948 0.493 PTPN14 protein Q15678 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation Tyr128 SKAQQGLyQVPGPSP 9606 BTO:0000586 22710723 t lperfetto We show that p130 crk-associated substrate (p130cas) is a direct substrate of ptpn14 and that ptpn14 specifically regulates p130cas phosphorylation at tyrosine residue 128 (y128) in colorectal cancer (crc) cells. We engineered crc cells homozygous for a p130cas y128f knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation SIGNOR-197923 0.4 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252874 0.702 AURKA protein O14965 UNIPROT NSD2 protein O96028 UNIPROT up-regulates quantity by stabilization phosphorylation Ser56 SKAQLSSsLQEGVMQ 35389552 t lperfetto Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. SIGNOR-275512 0.2 F2RL2 protein O00254 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257234 0.2 TAF4 protein O00268 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263921 0.882 PRKD1 protein Q15139 UNIPROT PIP4K2A protein P48426 UNIPROT down-regulates phosphorylation Thr376 KAAHAAKtVKHGAGA 9606 16563698 t lperfetto We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases. SIGNOR-145370 0.2 BBC3 protein Q9BXH1 UNIPROT BCL2 protein P10415 UNIPROT down-regulates activity binding 9606 BTO:0001938 11463392 t lperfetto Puma localizes to the mitochondria, interacts with bcl-2, and function to induce cytochrome c release SIGNOR-109506 0.654 RECQL4 protein O94761 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 9606 27287744 f RECQL4 is important for genome stability and DNA damage repair. SIGNOR-258951 0.7 ITGA11 protein Q9UKX5 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253187 0.699 PKA proteinfamily SIGNOR-PF17 SIGNOR PPM1B protein O75688 UNIPROT down-regulates quantity by destabilization phosphorylation Ser195 MIQRVNGsLAVSRAL 9606 BTO:0000007 23756813 t miannu Collectively, these data suggest that PKA destabilizes PP2Cβ upon inflammatory stimuli via phosphorylation of Ser-195 in PP2Cβ. SIGNOR-277825 0.2 ZNF318 protein Q5VUA4 UNIPROT AR protein P10275 UNIPROT down-regulates activity binding 9606 16469430 t Monia Using different promoters and cells, we confirmed that AR-mediated transactivation was repressed by TZF in a dose-dependent manner (Fig. 1A and B). Endogenous ARmediated transactivation was also inhibited by expression of TZF; These results indicate that amino acid residues 512–663 are essential for the repressive effect of TZF on AR-mediated transactivation. SIGNOR-261187 0.376 SP1 protein P08047 UNIPROT LORICRIN protein P23490 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 12200429 f miannu Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. SIGNOR-254538 0.2 FGR protein P09769 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 t We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn. this interaction is weakened by phosphorylation of Tyr-222, through an allosteric mechanism that ultimately causes the detachment of fully phosphorylated HS1 from c-Fgr. SIGNOR-251144 0.443 STK10 protein O94804 UNIPROT MSN protein P26038 UNIPROT up-regulates activity phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 19255442 t llicata Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration. SIGNOR-184433 0.391 BRD8 protein Q9H0E9 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269304 0.649 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260885 0.2 MAPK3 protein P27361 UNIPROT ETS1 protein P14921 UNIPROT up-regulates phosphorylation Thr38 CADVPLLtPSSKEMM 9606 11948414 t gcesareni We found that hgf/sf activates the erk1 map kinase, leading to the phosphorylation of the threonine 38 residue of ets1 SIGNOR-116494 0.664 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257975 0.8 NEK9 protein Q8TD19 UNIPROT NEK7 protein Q8TDX7 UNIPROT up-regulates activity phosphorylation Ser195 SKTTAAHsLVGTPYY 9606 BTO:0000007 12840024 t lperfetto Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity SIGNOR-103030 0.706 STXBP4 protein Q6ZWJ1 UNIPROT STX4 protein Q12846 UNIPROT up-regulates activity binding 10029 BTO:0000246 15753124 t miannu Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4. SIGNOR-262634 0.796 C5AR2 protein Q9P296 UNIPROT SELL protein P14151 UNIPROT down-regulates quantity by repression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263467 0.2 NTN4 protein Q9HB63 UNIPROT NEO1 protein Q92859 UNIPROT up-regulates activity binding 9606 BTO:0001484 28245592 t miannu Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins. SIGNOR-268170 0.546 ARRB2 protein P32121 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000971 12488444 t miannu Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination. SIGNOR-272592 0.44 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t The effect has been demonstrated using Q08499-2 gcesareni These straddle the target residue, ser(579), for erk2 phosphorylation of pde4d3. Mutation of either or both of these docking sites prevented erk2 from being co-immunoprecipitated with pde4d3, ablated the ability of epidermal growth factor to inhibit pde4d3 through erk2 action in transfected cos cells, and attenuated the ability of erk2 to phosphorylate pde4d3 in vitro. SIGNOR-270174 0.2 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 17259970 t milica Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity. SIGNOR-152917 0.523 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser119 GAAAAPPsPAWSEPE 10090 37029927 t miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. SIGNOR-277796 0.2 PTPA protein Q15257 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473) SIGNOR-252607 0.2 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT up-regulates activity phosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 11870224 t Eph receptor activation leads to tyrosine phosphorylation of three major autophosphorylation sites. these residues function to regulate kinase activity, their phosphorylation being required for full intrinsic enzyme activity. these tyrosines (EphA3 Y596, Y602 and Y779) as the prominent autophosphorylation sites of EphA3 SIGNOR-251117 0.2 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1197 STAENAEyLRVAPQS 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-235951 0.2 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser366 EPIQMENsMGTLRTS 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251207 0.29 MAPK1 protein P28482 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t gcesareni Activated following phosphorylation at thr-182 by p38-alpha/mapk14, p38-beta/mapk11, erk2/mapk1, erk3/mapk6, and erk4/mapk4. SIGNOR-58127 0.487 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 19029990 f lperfetto STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others. SIGNOR-249498 0.53 CD79A protein P11912 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268188 0.647 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB1 protein Q9Y5G3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265703 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2V1 protein Q13404 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271321 0.569 TNFSF13 protein O75888 UNIPROT TNFRSF13B protein O14836 UNIPROT up-regulates binding 9606 10956646 t gcesareni Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys. SIGNOR-81308 0.704 RAB7A protein P51149 UNIPROT NTRK1 protein P04629 UNIPROT down-regulates activity binding 10116 16306406 t Sara Endogenous TrkA and Rab7 form a complex. Inhibition of Rab7 potentiates the signaling of TrkA in response to brief stimulations with NGF SIGNOR-261305 0.48 PTPRJ protein Q12913 UNIPROT FLT1 protein P17948 UNIPROT down-regulates dephosphorylation 9606 12771128 t gcesareni Vegf acts by binding to two high affinity receptor tyrosine kinases: vegf receptor (vegfr)* 1 also called flt-1, and vegfr-2, also called flk-1/kdr a dominant-negative mutant of high cell densityenhanced ptp 1 (dep-1)//cd148 as well as reduction of its expression by rna interference partially restore vegfr-2 phosphorylation and map kinase activation. SIGNOR-101272 0.366 PRKAA1 protein Q13131 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Ser801 KLRRRTFsLTEVRGQ -1 28992084 t miannu We found that the strong direct substrate KIF4A is phosphorylated by AMPK at Ser801.Using in vitro kinase assays, we found that active AMPK and Aurora B phosphorylated KIF4A at Ser801 and Thr799 respectively in a time-dependent manner (Figure 5D). KIF4A is phosphoregulated by AMPK and Aurora B. Although AMPK phosphorylation increased the ATPase activity of KIF4A, Aurora B phosphorylation resulted in a stronger increase (Figure 5I), which might be consistent with the more powerful kinase function of Aurora B during mitosis. SIGNOR-265991 0.2 SMARCD1 protein Q96GM5 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270722 0.747 mTORC2 complex SIGNOR-C2 SIGNOR MYC protein P01106 UNIPROT up-regulates 9606 24856037 f miannu MTORC1 and mTORC2 converge on c-Myc to control metabolic reprogramming in cancer. mTORC1 and mTORC2 conspire to link growth factor receptor–PI3K signaling with c-Myc-dependent metabolic reprogramming by controlling both c-Myc levels and activity SIGNOR-256171 0.358 MTCP1 protein P56278 UNIPROT AKT3 protein Q9Y243 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81677 0.349 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Thr185 TRNKVRKtFVGTPCW 9606 17190791 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1) SIGNOR-151663 0.491 GRPEL2 protein Q8TAA5 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267700 0.506 GRIA1 protein P42261 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264947 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2G1 protein P62253 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271349 0.706 JAK3 protein P52333 UNIPROT JAK1 protein P23458 UNIPROT up-regulates activity phosphorylation Tyr1034 AIETDKEyYTVKDDR -1 12559972 t Phosphorylation by recombinant JAK3 of a peptide substrate corresponding to the JAK1 activation loop (KAIETDKEYYTVKD) SIGNOR-251363 0.523 fluoxymesterone chemical CHEBI:5120 ChEBI AR protein P10275 UNIPROT up-regulates activity chemical activation 9606 10077001 t miannu The anabolic steroids, oxandrolone and fluoxymesterone, have high inhibition constants for binding, yet induce the N/C interaction and stabilize AR at relatively low ligand concentrations and are AR agonists in vivo. SIGNOR-259264 0.8 GSK3B protein P49841 UNIPROT AURKA protein O14965 UNIPROT down-regulates quantity by destabilization phosphorylation Ser283 GWSVHAPsSRRTTLC 9606 38442201 t miannu EEF1A2 bridged the interactions between the SKP1-CUL1-FBXW7 (SCF) ubiquitin ligase complex, the kinase GSK3β, and Aurora-A, thereby facilitating the phosphorylation of Aurora-A in a degron site that was recognized by FBXW7. SIGNOR-277919 0.547 GRIN1 protein Q05586 UNIPROT NMDA receptor_2D complex SIGNOR-C350 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264126 0.654 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser276 VHPATPIsPGRASGM 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. SIGNOR-138961 0.604 CNOT1 protein A5YKK6 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268300 0.892 RNA Polymerase II complex SIGNOR-C391 SIGNOR precursor messenger RNA smallmolecule CHEBI:139356 ChEBI up-regulates quantity chemical modification 9606 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. SIGNOR-266176 0.8 AEP complex complex SIGNOR-C117 SIGNOR MEIS1 protein O00470 UNIPROT up-regulates quantity by expression 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-256144 0.388 PTEN protein P60484 UNIPROT AR protein P10275 UNIPROT up-regulates activity dephosphorylation Ser83 QQQQQETsPRQQQQQ 9606 24480624 f miannu Furthermore, PTEN depletion increased AR protein instability, and this effect was further enhanced by p300 silencing in LAPC4 cells .|Our data demonstrate that loss of PTEN increases AR phosphorylation at Ser81 and that Ser81 phosphorylation acts as a molecular beacon that is required for the binding of p300, a key event that subsequently leads to AR acetylation, inhibition of AR ubiquitination and AR stabilization (XREF_FIG). SIGNOR-277077 0.591 HBB protein P68871 UNIPROT APOB protein P04114 UNIPROT up-regulates quantity by stabilization 9606 8611031 f Regulation of binding miannu Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Crosslinked apo B was shown to resist lysosomal degradation, thereby causing accumulation of oxidized LDL in macrophages SIGNOR-251754 0.278 ILK protein Q13418 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr696 ARQSRRStQGVTLTD -1 12030846 t miannu MYPT1 was phosphorylated by ILK and phosphorylation sites in the N- and C-terminal fragments of MYPT1 were detected. From sequence analyses, three sites were identified: a primary site at Thr(709), and two other sites at Thr(695) and Thr(495). ILK produced an intermediate level of inhibition SIGNOR-262886 0.573 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser5 sVSSGGAG 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165562 0.845 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity deubiquitination 9606 25481026 t miannu Here we show that PLpro also inhibits IRF3 activation at a step after phosphorylation and that this inhibition is dependent on the de-ubiquitination (DUB) activity of PLpro. We found that PLpro is able to block the type I IFN induction of a constitutively active IRF3, but does not inhibit IRF3 dimerization, nuclear localization or DNA binding. However, inhibition of PLpro’s DUB activity by mutagenesis blocked the IRF3 inhibition activity of PLpro, suggesting a role for IRF3 ubiquitination in induction of a type I IFN innate immune response. SIGNOR-260249 0.2 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity precursor of 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269686 0.8 ERBB2 protein P04626 UNIPROT BBC3 protein Q9BXH1 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr58 PTLLPAAyLCAPTAP 9606 BTO:0000093 24236056 t miannu HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. SIGNOR-276473 0.284 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser268 SDEFRPRsKSQSSSN -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251288 0.648 CSNK1A1 protein P48729 UNIPROT ERG protein P11308 UNIPROT down-regulates quantity by destabilization phosphorylation Ser38 TEMTASSsSDYGQTS -1 26344095 t miannu Using in vitro kinase assays, we further demonstrated that deletion of degron 1 largely abolished CKI-mediated phosphorylation of ERG (Figure S5B), indicating that serine residues within degron 1 are the major CKI phosphorylation sites. SIGNOR-276936 0.2 pazopanib chemical CHEBI:71219 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258260 0.8 MAPK1 protein P28482 UNIPROT NCOA6 protein Q14686 UNIPROT up-regulates activity phosphorylation Ser884 NKDVTLTsPLLVNLL -1 11773444 t miannu In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα. SIGNOR-265882 0.2 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 18467333 t gcesareni Additionally, the pim kinases phosphorylate mdm2 in vitro and in cultured cells at ser166 and ser186, two previously identified targets of other signaling pathways, including akt. SIGNOR-178615 0.394 AKT1 protein P31749 UNIPROT STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr387 TMKRRDEtMQPAKPS 9606 23431053 t gcesareni Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt. SIGNOR-252537 0.403 1-[4-[[2-(2-amino-5-pyrimidinyl)-7-methyl-4-(4-morpholinyl)-6-thieno[3,2-d]pyrimidinyl]methyl]-1-piperazinyl]-2-hydroxy-1-propanone chemical CHEBI:93753 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192601 0.8 SHH protein Q15465 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887 17688959 f lperfetto Most importantly, we report that shh induces mapk/erk and phosphoinositide 3-kinase (pi3k)-dependent akt phosphorylation and that activation of both signaling pathways is essential for shh's signaling in muscle cells. However, the effect of shh on akt phosphorylation is more robust than that on mapk/erk, and data suggest that shh influences these pathways in a manner similar to igf-i. SIGNOR-244446 0.479 DNA_damage stimulus SIGNOR-ST1 SIGNOR ERCC8 protein Q13216 UNIPROT up-regulates 24086043 f lperfetto TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. SIGNOR-275690 0.7 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276128 0.649 NLGN2 protein Q8NFZ4 UNIPROT MAGI2 protein Q86UL8 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu S-SCAM is a member of the membrane-associated guanylate kinase (MAGUK) family of PDZ-domain-containing proteins that include the synaptic organising molecule PSD-95. The PDZ domain of S-SCAM binds to the C-terminal tail of NL2, forming a ternary complex at the cell membrane (Figure 2b). The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265444 0.409 FOXJ1 protein Q92949 UNIPROT SPAG6 protein O75602 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000939 23822649 t miannu FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1). SIGNOR-266935 0.455 PYY protein P10082 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 7592911 t gcesareni Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid. SIGNOR-29767 0.661 CASP8 protein Q14790 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261760 0.373 MAPK8IP2 protein Q13387 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 t gcesareni Both jip1 and jip2 selectively bind the mapkk isoform mkk7. SIGNOR-70857 0.672 STK3 protein Q13188 UNIPROT PIK3CA protein P42336 UNIPROT down-regulates activity phosphorylation Thr1061 KMDWIFHtIKQHALN -1 38060450 t miannu MST1/2 and HGK inhibit catalytic activity of p110α through phosphorylation at T1061  SIGNOR-277922 0.2 HBA1 protein P69905 UNIPROT Hemoglobin complex SIGNOR-C209 SIGNOR form complex binding 9606 18179859 t miannu AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin SIGNOR-255274 0.702 P2RY14 protein Q15391 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256723 0.387 STK24 protein Q9Y6E0 UNIPROT RAB8A protein P61006 UNIPROT up-regulates activity phosphorylation Thr72 AGQERFRtITTAYYR -1 32227113 t lperfetto In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease SIGNOR-260265 0.277 MAPK11 protein Q15759 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Thr1609 LGPYEAVtPLTKAAD -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK SIGNOR-264447 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP3 inflammasome complex SIGNOR-C225 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263127 0.7 ELF1 protein P32519 UNIPROT IL2RA protein P01589 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 7862168 f 2 miannu The interleukin 2 receptor alpha-chain (IL-2R alpha) gene is rapidly and potently induced in T cells in response to mitogenic stimuli. Previously, an inducible enhancer between nucleotides -299 and -228 that contains NF-kappa B and CArG motifs was identified. We now report the characterization of a second essential positive regulatory element located between nucleotides -137 and -64 that binds Elf-1 and HMG-I(Y). Transcription from the IL-2R alpha promoter was inhibited when either the Elf-1 or the HMG-I(Y) binding site was mutated. Coexpression of both proteins activated transcription of the -137 to -64 element in COS-7 cells. SIGNOR-240193 0.2 BLVRA protein P53004 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation Thr500 WDGVTTKtFCGTPDY 9606 17227757 t llicata Human biliverdin reductase, a previously unknown activator of protein kinase c ?II the phosphorylation of thr500 was confirmed by immunoblotting of hbvr.pkc betaii immunocomplex. SIGNOR-152181 0.309 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266523 0.8 MFF protein Q9GZY8 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto These proteins include the classical mitochondrial fusion (MFN1, MFN2, and OPA1) and fission proteins (DRP1, MFF, FIS1, etc.) as well as several other proteins that are directly or indirectly involved in these processes (e.g. YME1L, OMA1, INF2, GDAP1, MIC13, etc. SIGNOR-272983 0.7 C1QBP protein Q07021 UNIPROT C1QA protein P02745 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263402 0.389 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263808 0.8 WDR62 protein O43379 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity relocalization 10090 30566428 t lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis SIGNOR-271715 0.2 TIMP1 protein P01033 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252272 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR MDM4 protein O15151 UNIPROT up-regulates activity phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2. SIGNOR-178063 0.2 USH1C protein Q9Y6N9 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. SIGNOR-262576 0.701 USF2 protein Q15853 UNIPROT B2M protein P61769 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12480693 f miannu Here we show that upstream stimulatory factor 1 (USF1) and USF2 bind to the E box and regulate beta(2)m transactivation. SIGNOR-254656 0.2 PTPN13 protein Q12923 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates activity dephosphorylation 9606 19734941 t miannu Since a previous report showed PTPN13 may dephosphorylate ErbB2 directly, we also examined levels of phospho-ErbB2 (tyr 1248), and we also observed a small effect in the presence of wild-type PTPN13 (XREF_FIG).|The fact that both ErbB2 and H-RasV12 were potentiated by PTPN13 loss and PTPN13 inhibited MAP kinase signaling downstream of multiple oncogenes (ErbB2, EGFR, H-RasV12), suggest that the phosphatase target that inhibits MAP kinase signaling may not only be limited to ErbB2 tyrosine 1248. SIGNOR-277087 0.337 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1665 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248819 0.851 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259013 0.33 PRKACA protein P17612 UNIPROT CUL5 protein Q93034 UNIPROT up-regulates activity phosphorylation Ser730 MKMRKKIsNAQLQTE 9534 BTO:0000298 10898738 t miannu Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor. SIGNOR-250352 0.325 YBX1 protein P67809 UNIPROT ABCB1 protein P08183 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10644769 f miannu these results indicate a role for both NF-Y and Sp1 in the transcriptional activation of the MDR1 gene by genotoxic stress, and indicate that YB-1, if involved, is not sufficient to mediate this activation. SIGNOR-253873 0.389 HSP90AA1 protein P07900 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 18591668 t lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. SIGNOR-179271 0.388 AARS1 protein P49588 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI down-regulates quantity chemical modification 9606 32314272 t miannu Alanyl-tRNA synthetase 1 (AARS1) gene encodes a ubiquitously expressed class II enzyme that catalyzes the attachment of alanine to the cognate tRNA. AARS1 mutations are frequently responsible for autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N). SIGNOR-270446 0.8 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257470 0.8 ELOVL7 protein A1L3X0 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267895 0.8 LAMA1 protein P25391 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 t lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. SIGNOR-253232 0.557 OXTR protein P30559 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256793 0.417 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9576626 t tpavlidou Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm SIGNOR-56901 0.936 RPS6KB1 protein P23443 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser560 LARLGCSsCLDYFTT 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180775 0.2 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR2 protein O95136 UNIPROT up-regulates chemical activation 9606 23450633 t gcesareni S1p action on yap in 293a (or hacat) cells is mediated by s1p2 rather than s1p1 or s1p3 (of ? Ve known s1p receptors) and lpa receptors 1 and 3 (of six). SIGNOR-192117 0.8 tamoxifen chemical CHEBI:41774 ChEBI ESR1 protein P03372 UNIPROT down-regulates activity chemical inhibition 9606 20512796 t miannu Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. SIGNOR-258587 0.8 PGM1 protein P36871 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI down-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267931 0.8 WDR83 protein Q9BRX9 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates binding 9606 15118098 t gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. SIGNOR-124473 0.494 Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR BRCA2 protein P51587 UNIPROT up-regulates 18985065 f lperfetto Once monoubiquitinated, the ID complex becomes associated with chromatin and is redistributed to DNA-damage sites, forming foci that are visible by immunofluorescence and colocalizing with other DNA-repair molecules, notably BRCA1, BRCA2 and γH2AX. SIGNOR-263270 0.787 ABL1 protein P00519 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Tyr143 SPAGRSIyNSFYVYC 9606 BTO:0000142 20823226 t llicata Here we show that the nonreceptor tyrosine kinase c-abl phosphorylates tyrosine 143 of parkin, inhibiting parkin's ubiquitin e3 ligase activity and protective function. SIGNOR-167853 0.2 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates activity dephosphorylation Ser1981 SLAFEEGsQSTTISS 9606 18265945 t lperfetto More recently, Shreeram et al.  have also shown that Wip1 dephosphorylates human ATM at Ser367 as well as Ser1981.|Thus, overexpression of Wip1 in an oncogenic context could contribute to tumor promotion by inhibiting both p53 and ATM functions. SIGNOR-276954 0.498 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates activity binding 9606 19703466 t GTP-bound, active WT Gαi1 acts to inhibit AC, resulting in a decreased concentration of intracellular cAMP. SIGNOR-256498 0.54 DNM1 protein Q05193 UNIPROT SYP protein P08247 UNIPROT up-regulates activity binding 9606 10823955 t miannu The GTPase dynamin I is required for synaptic vesicle (SV) endocytosis. Our observation that dynamin binds to the SV protein synaptophysin in a Ca2+-dependent fashion suggested the possibility that a dynamin/synaptophysin complex functions in SV recycling. SIGNOR-264119 0.337 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148595 0.368 ROCK2 protein O75116 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates activity phosphorylation Thr853 PREKRRStGVSFWTQ -1 12220642 t lperfetto Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited. SIGNOR-249164 0.781 IQGAP1 protein P46940 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity binding 15695813 t lperfetto Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.  SIGNOR-261888 0.807 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2E3 protein Q969T4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271364 0.6 NFIB protein O00712 UNIPROT NFIC protein P08651 UNIPROT down-regulates activity binding 9606 BTO:0000567 9099724 t 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. SIGNOR-240880 0.366 NARS2 protein Q96I59 UNIPROT asparagine smallmolecule CHEBI:22653 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270462 0.8 IKBKE protein Q14164 UNIPROT IRF1 protein P10914 UNIPROT down-regulates activity phosphorylation Ser215 DLYNFQVsPMPSTSE 9606 BTO:0000007 24396068 t miannu We demonstrated that IKK-ε phosphorylated the transcription factor IFN regulatory factor 1 (IRF-1) at amino acid (aa) 215/219/221 in primary CD4(+) T cells and blocked its transcriptional activity.  SIGNOR-276480 0.354 Caspase 3 complex complex SIGNOR-C221 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-256477 0.7 TRAF6 protein Q9Y4K3 UNIPROT ULK1 protein O75385 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0000007 23524951 t lperfetto AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. SIGNOR-273000 0.538 PRKD2 protein Q9BZL6 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser172 GQLVRNDsLWHRSDS 34010649 t lperfetto The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-275941 0.2 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR IGFBP5 protein P24593 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136601 0.315 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 19584320 t gcesareni In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-186633 0.491 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252855 0.909 DUOX1 protein Q9NRD9 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264719 0.7 MRAP2 protein Q96G30 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252365 0.5 risperidone chemical CHEBI:8871 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258527 0.8 CYLD protein Q9NQC7 UNIPROT BCL3 protein P20749 UNIPROT down-regulates deubiquitination 9606 BTO:0001286 16713561 t gcesareni Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation. SIGNOR-146774 0.521 CASP1 protein P29466 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp348 GTGGLEPdLARGRWA 9606 BTO:0005111 32122970 t miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. SIGNOR-272192 0.2 NSD2 protein O96028 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 BTO:0001130 19481544 t miannu In this study, we discovered that nsd2 specifically interacts with the dna-binding domain of androgen receptor (ar) via its hmg domain, and the nuclear translocation of both nsd2 and ar is enhanced in the presence of ligand / the histone methyltransferase, nsd2, enhances androgen receptor-mediated transcription. SIGNOR-186045 0.2 S1PR2 protein O95136 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256871 0.37 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AKAP12 protein Q02952 UNIPROT up-regulates activity phosphorylation Thr767 ESFKRLVtPRKKSKS 9606 BTO:0000007 23063527 t lperfetto Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis. SIGNOR-271840 0.288 CDK1 protein P06493 UNIPROT STIP1 protein P31948 UNIPROT down-regulates activity phosphorylation Ser189 LLGVDLGsMDEEEEI 10090 BTO:0000944 14754904 t miannu Inactivation and phosphorylation mimicking of potential phosphorylation sites in mSTI1 altered the nuclear translocation. Mimicking of phosphorylation at the mSTI1 CKII phosphorylation site (S189E) promoted nuclear localization of mSTI1-EGFP. Mimicking phosphorylation at the cdc2 kinase phosphorylation site (T198E) promoted cytoplasmic localization of mSTI1-EGFP at the G1/S-phase transition,whereas removal of this site (T198A) promoted the nuclear localization of mSTI1-EGFP under the same conditions. SIGNOR-262729 0.266 STUB1 protein Q9UNE7 UNIPROT CBX4 protein O00257 UNIPROT down-regulates quantity by destabilization ubiquitination Lys280 GMQAVKIkSGEVAEG 9606 BTO:0002181 32111827 t miannu The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.  SIGNOR-277514 0.2 KIF20B protein Q96Q89 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272528 0.7 MLL/SET subcomplex complex SIGNOR-C87 SIGNOR MLL1 complex complex SIGNOR-C89 SIGNOR form complex binding 9606 24680668 t miannu The mixed lineage leukemia-1 (mll1) enzyme is a histone h3 lysine 4 (h3k4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human set1 family of enzymes that include mll1_Mll4 and setd1a,b. Dimethylation of h3k4 requires a sub-complex including wrad (wdr5, rbbp5, ash2l, and dpy-30), which binds to each set1 family member forming a minimal core complex that is required for multiple lysine methylation. SIGNOR-204819 0.733 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr317 PPTPGNTyQIPRTFP 9606 BTO:0000007 19881549 t lperfetto Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis SIGNOR-236306 0.698 E2F1 protein Q01094 UNIPROT DHFR protein P00374 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253853 0.524 3-(9-Fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione chemical CID:10029385 PUBCHEM GSK3B protein P49841 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000183 31562256 t miannu Indeed, we demonstrated that the selective GSK3 inhibitor LY2090314 significantly reduced cell proliferation in control pancreatic cancer cell lines SIGNOR-262539 0.8 CALM1 protein P0DP23 UNIPROT GEM protein P55040 UNIPROT up-regulates activity binding 10116 14701738 t miannu Inhibition of voltage-gated calcium channels by Gem requires GTP and calmodulin binding, but not phosphorylation of serine 261 or 289. Calmodulin binding in the C-terminal extension of Gem is required for maximal inhibition of HVA Ca2+ channels by ectopically expressed Gem, as determined by measurement of electrical activity in primary neurons and by Ca2+-evoked secretion in PC12 cells. SIGNOR-261716 0.335 OFD1 protein O75665 UNIPROT IFT88 protein Q13099 UNIPROT up-regulates activity binding 9606 BTO:0001086 20230748 t Regulation of binding miannu Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length. SIGNOR-251973 0.419 EGR1 protein P18146 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9867871 f miannu The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments. SIGNOR-253897 0.294 CDK1 protein P06493 UNIPROT OSBP2 protein Q969R2 UNIPROT up-regulates activity phosphorylation 30925160 t lperfetto CK1a1, JNK1 and CDK1 had the highest site-specific activity for ORP4L, while CDK1, GSK3a, CK1a1 and GSK3b showed the highest specificity for the site when corrected for background activity with ORP4L-S4A. Because of the complexity of the serine/proline-rich site, we did not determine which serine(s) in ORP4L were phosphorylated by candidate kinases.|We conclude that phosphorylation of a unique serine/proline motif in the ORD induces a conformation change in ORP4L that enhances interaction with vimentin and cholesterol extraction from membranes. SIGNOR-264878 0.2 SLC24A4 protein Q8NFF2 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264392 0.8 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser150 PELCGPGsPPVLTPG 9606 15952796 t lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation SIGNOR-138171 0.302 ISCU protein Q9H1K1 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262128 0.713 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT unknown phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 t Manara We have shown that PKCδ binds and phosphorylates K protein. These observations broaden the range of K protein interactions. PKCδ targets Ser302, which is located in the middle of what appears to be a highly interactive KI domain SIGNOR-260877 0.348 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 19029298 t llicata We show that pkd1-ser916 autophosphorylation does not necessarily correlate with pkd1 activity. Rather, autophosphorylation at ser916 is required for subsequent autophosphorylation at ser748. SIGNOR-182480 0.2 AMPK complex SIGNOR-C15 SIGNOR SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr101 IVLNKGKtIFRFSAT 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275769 0.322 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser187 NSHPFPHsPNSSYPN 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248798 0.484 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002861 18682241 t flangone We also find that SMADs bind with the NANOG promoter and that SMAD2/3 activity enhances NANOG promoter activity. SIGNOR-242044 0.543 NF1 protein P21359 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-267847 0.405 ACACB protein O00763 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267106 0.8 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser713 KKKFRTPsFLKKSKK -1 8810272 t lperfetto Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC. SIGNOR-248952 0.287 ABCA1 protein O95477 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity binding 9606 15347662 t miannu The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein. SIGNOR-252100 0.786 MAPK1 protein P28482 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 t lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-71033 0.53 ITGB6 protein P18564 UNIPROT Av/b6 integrin complex SIGNOR-C179 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253210 0.866 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 12270934 f lperfetto We further show that activation of mek1 significantly enhances the transactivation of the c/ebpalpha minimal promoter during the early phase of the differentiation process. SIGNOR-244773 0.2 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 16293724 t lperfetto This leads to the inactivation and release of glycogen synthase kinase 3beta from its complex with axin, thereby relieving the inhibitory phosphorylation of beta-catenin and activating its signaling pathway. SIGNOR-227889 0.893 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFS2 protein O75306 UNIPROT up-regulates activity phosphorylation Ser364 KVDDAKVsPPKRAEM 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275600 0.2 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr699 DPEGGVDyKNIHLEK 9606 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127536 0.2 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR ID1 protein P41134 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18025157 f We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wild-type RARα/RXR. In contrast, PML-RARα transactivated the promoter more than 12-fold in an ATRA-dependent fashion. SIGNOR-255728 0.2 ARFGAP1 protein Q8N6T3 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 22363216 t The effect has been demonstrated using Q8N6T3-2 flangone The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes SIGNOR-196264 0.591 HIPK2 protein Q9H2X6 UNIPROT ZBTB4 protein Q9P1Z0 UNIPROT down-regulates activity phosphorylation Thr983 AAPPAPPtPPPPTLP -1 19448668 t miannu The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4. SIGNOR-262882 0.384 PAK proteinfamily SIGNOR-PF13 SIGNOR SYN1 protein P17600 UNIPROT unknown phosphorylation 10116 12237306 t inferred from 70% family members miannu Recombinant PAK2 could also phosphorylate the Ser9 and Ser551 residues. SIGNOR-269974 0.2 PRKACA protein P17612 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT down-regulates activity phosphorylation Thr108 SPRAWRRPtIESHHVAI 10116 10187789 t In vitro, CaMKK is phosphorylated by PKA and this is associated with inhibition of enzyme activity. The major site of phosphorylation is threonine 108, although additional sites are phosphorylated with lower efficiency. SIGNOR-256115 0.2 HOXA9 protein P31269 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 14701735 f irozzo Here we demonstrate that MLL-ENL immortalizes cells mainly through inducing a reversible block on myeloid differentiation that is dependent on upregulation of Hoxa9 and Meis1 and that enforced expression of these two genes is sufficient to substitute for MLL-ENL function. SIGNOR-255864 0.7 RIMS2 protein Q9UQ26 UNIPROT RAB3C protein Q96E17 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264378 0.569 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Thr516 GASKRLQtICMSGTG 9606 20448038 t lperfetto Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation. SIGNOR-165237 0.376 GATA6 protein Q92908 UNIPROT HES1 protein Q14469 UNIPROT up-regulates quantity by expression 9606 BTO:0000195 24317510 f lperfetto Many GATA6-dependent genes lacked nearby binding sites but several strongly dependent, synexpressed and GATA6-bound genes encode TFs such as MYC, HES1, RARB and CDX2. SIGNOR-253153 0.28 MAPK3 protein P27361 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser676 SNGRRKRsPTQSFRF 9606 15657420 t lperfetto The formation of rsk-nfatc4-dna transcription complex is also apparent upon adipogenesis. Bound rsk phosphorylates ser(676) and potentiates nfatc4 dna binding by escalating nfat-dna association. Ser(676) is also targeted by the erk map kinase, which interacts with nfat at a distinct region than rsk. Thus, integration of the erk/rsk signaling pathway provides a mechanism to modulate nfatc4 transcription activity. SIGNOR-133276 0.292 RASGEF1A protein Q8N9B8 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183823 0.421 BRCA1 protein P38398 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 22832221 f gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. SIGNOR-198467 0.816 MAPK1 protein P28482 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates phosphorylation Ser359 SALSYLQsPITTSPS 9606 10617468 t lperfetto Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein. SIGNOR-73621 0.802 FGFR1 protein P11362 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr327 PLLREETyDVPPAFA 9606 12601080 t lperfetto Five tyrosine phosphorylation sites were identified in p130cas on tyr-128, tyr-249, tyr-306, tyr-327, and tyr-410. These tyrosine residues are all located in the substrate domain of p130cas that mediates binding to the sh2 domain of the adaptor molecule crk. Fgf-1-transduced fibroblasts demonstrated a > 10-fold increase in migration, an observation correlated with increased tyrosine phosphorylation of p125fak and p130cas. SIGNOR-98500 0.258 POU3F2 protein P20265 UNIPROT POU3F2 protein P20265 UNIPROT up-regulates activity binding 9606 11029584 t miannu These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits. SIGNOR-221824 0.2 ILK protein Q13418 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA -1 11313365 t miannu ILK Phosphorylates PKB/Akt on Serine 473 To become fully activated, PKB/Akt requires phosphorylation at two sites, threonine 308 and serine 473, in a phosphatidylinositol (PI) 3-kinase-dependent manner. SIGNOR-252596 0.775 MAD2L2 protein Q9UI95 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates activity binding -1 11459826 t miannu The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1 SIGNOR-264902 0.534 Elongator complex complex SIGNOR-C466 SIGNOR TUBA3D protein P0DPH8 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. α-Tubulin Acetylation Promotes Radial Migration and Branching of Cortical Projection Neurons SIGNOR-269715 0.253 MAD2L1BP protein Q15013 UNIPROT TRIP13 protein Q15645 UNIPROT up-regulates activity binding 9606 BTO:0000567 25092294 t miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). SIGNOR-265971 0.478 PBX1 protein P40424 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265803 0.273 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser465 HNPISSVs 9606 9335504 t llicata The c terminus of smad1, which is phosphorylated directly by the bmp type i receptor at the ssvs sequence in contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. SIGNOR-52670 0.634 TRIM2 protein Q9C040 UNIPROT NEFL protein P07196 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 18687884 t miannu Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. SIGNOR-271776 0.437 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000746 27777311 f We observed GR binding on or near Cebpβ, Cebpδ, Klf5, Klf9, Cebpα, and Pparγ gene loci at 4 h but not at 0 h of adipogenesis. Thus, at least one of the mechanisms by which GR promotes adipogenesis in culture is by directly activating the expression of multiple adipogenic TFs. SIGNOR-256120 0.398 PKG proteinfamily SIGNOR-PF77 SIGNOR 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266507 0.8 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT unknown phosphorylation Ser120 GRNIIHGsDSVESAE -1 8810265 t miannu For autophosphorylated rNm23-H1, phosphorylation was observed at serine 44 and on a fragment containing serines 120, 122, and 125.The biochemical function of Nm23 serine phosphorylation is unknown. SIGNOR-250300 0.2 AP1S1 protein P61966 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR form complex binding 9606 21097499 t lperfetto Key components of this system are the heterotetrameric adaptor protein (AP)4 complexes, AP-1 (gamma-beta1-mi1-sigma1), AP-2 (α-beta2-mi2-sigma2), AP-3 (delta-beta3-mi3-sigma3), and AP-4 (epsilon-beta4-mi4-sigma4) (subunit composition shown in parentheses) SIGNOR-260684 0.864 CSNK2A1 protein P68400 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser608 ENTEDQYsLVEDDED -1 14729945 t miannu Protein kinase CK2 phosphorylates p85α on Ser608 when p85α is free but not when it is complexed with p110α.  SIGNOR-276005 0.247 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204716 0.537 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1185 FGMTRDIyETDYYRK -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106510 0.2 MLNR protein O43193 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257132 0.419 LMO3 protein Q8TAP4 UNIPROT ASCL1 protein P50553 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21573214 f miannu Overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. SIGNOR-254825 0.366 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR2B protein P31323 UNIPROT down-regulates activity chemical inhibition 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258762 0.8 ATR protein Q13535 UNIPROT PARP1 protein P09874 UNIPROT down-regulates activity phosphorylation Ser179 FRPEYSAsQLKGFSL 9606 BTO:0000018 33811702 t miannu Specifically, ATR binds to and phosphorylates PARP1 at Ser179 after the ionophore treatments. This site-specific phosphorylation inactivates PARP1, inhibiting ionophore-induced necrosis. SIGNOR-277551 0.362 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-268102 0.8 Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR protein polypeptide chain smallmolecule CHEBI:16541 ChEBI up-regulates quantity chemical modification 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  SIGNOR-270818 0.8 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 12576312 t lperfetto Vasodilator-stimulated phosphoprotein activation of serum-response element-dependent transcription occurs downstream of rhoa and is inhibited by cgmp-dependent protein kinase phosphorylation. Three phosphorylation sites have been identified in vasp: ser157, ser239, and thr278, all of which can be phosphorylated by either pka or pkg in vitro SIGNOR-98139 0.732 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SCNN1B protein P51168 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 t inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-270050 0.2 sertindole chemical CHEBI:9122 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258843 0.8 SMARCE1 protein Q969G3 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270612 0.832 PTPN11 protein Q06124 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr771 ADIESSNyMAPYDNY -1 7545675 t Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides SIGNOR-248669 0.743 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser428 EPAPVLSsPPPADVS 9606 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain. SIGNOR-216781 0.456 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Thr260 QPWNSDStLNSRQLE 9606 19468302 t llicata Tandem mass spectrometry analysis of a purified hscyk-4 fragment (hscyk-4n) phosphorylated by plk1 in vitro identified four major sites (s157, s170, s214, and s260 plk1 phosphorylation of hscyk-4 localizes ect2 at the midzone and stimulates rhoa-dependent contractile ring assembly at the equatorial cortex. SIGNOR-185758 0.651 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2280 LSPSKSerPAKLN -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259121 0.46 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Phosphofructokinase catalyzes the rate-limiting, ATP-mediated phosphorylation of F6P to FBP. PFK is a homo- or heterotetramer with a molecular mass of approximately 380 kDa, and the enzyme is allosterically regulated, among other metabolites, by 2,3-DPG.35. SIGNOR-266466 0.8 clofarabine chemical CHEBI:681569 ChEBI POLB protein P06746 UNIPROT down-regulates activity chemical inhibition 9606 1707752 t miannu Effects of 2-Chloro-9-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)adenine on K562 Cellular Metabolism and the Inhibition of Human Ribonucleotide Reductase and DNA Polymerases by Its 5′-Triphosphate.The effect of Cl-F-ara-ATP on human DNA polymerases alpha, beta, and gamma isolated from K562 cells grown in culture was determined and compared with those of Cl-dATP and 9-beta-D-arabinofuranosyl-2-fluoroadenine triphosphate (F-ara-ATP). Cl-F-ara-ATP was a potent inhibitor of DNA polymerase alpha.Cl-F-ara-ATP was not a potent inhibitor of DNA polymerase beta, DNA polymerase gamma, or DNA primase. SIGNOR-258358 0.8 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser932 CDSGVETsFRKLSFT 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-70473 0.85 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser345 ELLCLRRsSLKAYGN -1 1848190 t lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. SIGNOR-248857 0.355 CKMT1A protein P12532 UNIPROT N-phosphocreatine smallmolecule CHEBI:17287 ChEBI up-regulates quantity chemical modification 9606 18502307 t miannu Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. SIGNOR-265790 0.8 Aldolase proteinfamily SIGNOR-PF75 SIGNOR D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266482 0.8 SQSTM1 protein Q13501 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 19765191 t P00441:p.Ala5Val (mutation causing interaction)  This study provides a novel molecular mechanism by which mutant SOD1 can be recognized by p62 in an ubiquitin-independent fashion and targeted for the autophagy-lysosome degradation pathway. SIGNOR-262801 0.523 EIF3_complex complex SIGNOR-C401 SIGNOR EIF1 protein P41567 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269152 0.605 IRF3 protein Q14653 UNIPROT SOCS2 protein O14508 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22291912 f miannu SOCS2 induction by LPS was dependent on the type I IFN regulated transcription factors IRF1 and IRF3 as shown by using silencing RNAs for IRFs. SIGNOR-254495 0.368 PRKAA1 protein Q13131 UNIPROT G6PC1 protein P35575 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21892142 f gcesareni Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation SIGNOR-176475 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270400 0.8 MYOCD protein Q8IZQ8 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni A coactivator of srf, myocd, interacts with srf and activates vsmc expression of contractile genes. SIGNOR-174322 0.793 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT down-regulates activity phosphorylation Ser13 FESYGSSsYGGAGGY -1 9295339 t lperfetto We showed previously that UV irradiation increases phosphorylation of the p34 subunit of human replication protein A (RPA) and that this hyperphosphorylation correlated with loss of activity of the DNA replication complex. | we detected phosphorylation of the RPA complex by DNA-PK on RPA-p34 sites Ser-23, Ser-29, and Ser-11, -12, or -13 SIGNOR-248982 0.591 WDR61 protein Q9GZS3 UNIPROT PAF1C complex SIGNOR-C471 SIGNOR form complex binding 9606 BTO:0000567 20178742 t miannu Human PAF1C was affinity purified from a FLAG-hPAF1 HeLa cell line and found to contain homologues (hCTR9, hLEO1, hPAF1, hCDC73 and hRTF1) of the five yeast PAF1C subunits, as well as the SKI8 subunit unique to hPAF1C (Figure 1A).  SIGNOR-269831 0.847 WNT3A protein P56704 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates activity binding 9606 BTO:0000222 10601008 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have a complex and partially overlapping pattern of expression in different regions of the embryo, and many of them (fz1, 3, 7, 8 and 9) have specific expression in the epithelial somites as well as in the newly formed myotomes. SIGNOR-73036 0.792 XAF1 protein Q6GPH4 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 17613533 t gcesareni Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3. SIGNOR-155637 0.57 AHSA1 protein O95433 UNIPROT HSP90AA1 protein P07900 UNIPROT up-regulates activity binding 9606 16696853 t miannu The N-terminal region of Aha1 interacts with the central domain of Hsp90 and stimulates Hsp90 ATPase activity SIGNOR-252211 0.757 mTORC1 complex SIGNOR-C3 SIGNOR Lysosome fusion phenotype SIGNOR-PH231 SIGNOR down-regulates activity 9606 39000072 f miannu The fusion of matured macropinosomes with lysosomes is promoted by TRPML1, and degradation of macropinosomes is inhibited by mTORC1. SIGNOR-277786 0.7 WNK4 protein Q96J92 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates activity phosphorylation Thr50 SHLTHSStFCMRTFG -1 22342722 t Q9BYP7:p.Glu562Lys (mutation causing interaction);Q9BYP7:p.Asp564Ala (mutation causing interaction);Q9BYP7:p.Gln565Glu (mutation causing interaction) lperfetto Threonine 48 was identified as the WNK4 phosphorylation site at mouse NCC|. Thus, WNK4 stimulates NCC in three ways: (1) direct phosphorylation and in turn increasing NCC protein abundance; (2) facilitating the phosphorylation of NCC by SPAK/OSR1 indirectly, and (3) phosphorylating and activating SPAK/OSR1.|Evidences from early studies using Xenopus oocytes and mammalian cells indicate that WNK4 inhibits NCC and PHAII-causing mutations relieve the inhibition SIGNOR-264631 0.591 GALR3 protein O60755 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257206 0.292 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR2 protein Q9HBW0 UNIPROT up-regulates chemical activation 9606 8276865 t gcesareni Lpa activates its own g protein-coupled receptor(s) leading to stimulation of phospholipase c and inhibition of adenylate cyclase. SIGNOR-37368 0.8 RPL4 protein P36578 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262460 0.858 PRKCA protein P17252 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization phosphorylation Ser423 GRAGPFSsSRCGASV -1 35931119 t miannu Through mass spectrometry, we identified that ULK1 is O-GlcNAcylated at Ser409, which is distinct from the previously reported Thr635/Thr754 sites. It has been demonstrated that PKCα mediates phosphorylation of ULK1 at Ser423, which attenuates its stability by shunting ULK1 to the chaperone-mediated autophagy (CMA) pathway.  SIGNOR-277900 0.2 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr46 NKISADTtDNSGTVN -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276218 0.386 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation Ser25 PELLVVGsRPELGRW 9606 BTO:0000007 21728993 t miannu We demonstrate that laforin is a phosphoprotein, as indicated by two-dimensional electrophoresis, and we identify Ser(25) as the residue involved in this modification. We also show that Ser(25) is phosphorylated both in vitro and in vivo by AMPK. Lastly, we demonstrate that this residue plays a critical role for both the phosphatase activity and the ability of laforin to interact with itself and with previously established binding partners. SIGNOR-277830 0.354 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 YRPKPSSsPVIFAGG 9606 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262915 0.326 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr627 KGDKQVEyLDLDLDS 9606 BTO:0000527;BTO:0000017 9890893 t lperfetto Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689). SIGNOR-236392 0.755 TWIST2 protein Q8WVJ9 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255499 0.2 NUP214 protein P35658 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262075 0.659 ABL1 protein P00519 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0002181 12652307 t miannu C-Abl induces Tyr phosphorylation of PLC-γ1 in vivo. These findings demonstrate that c-Abl phosphorylates PLC-γ1 in vivo predominantly at Tyr 771 and Tyr 1003.c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity. SIGNOR-276001 0.578 eribulin mesylate chemical CHEBI:70710 ChEBI TUBB1 protein Q9H4B7 UNIPROT down-regulates activity chemical inhibition 9606 16940412 t miannu The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. SIGNOR-259345 0.8 CTNNB1 protein P35222 UNIPROT SCRIB protein Q14160 UNIPROT up-regulates activity binding 9606 BTO:0000938 21255999 t miannu Cadherins mediate the localization of vesicles to presynaptic compartments through multiple mechanisms. Cadherin-bound β-catenin then recruits scribble (Scrib) which acts as a scaffold for the further recruitment of proteins that mediate the localization of SVs. SIGNOR-265826 0.432 Stress_granules phenotype SIGNOR-PH124 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 27920254 f miannu Stress granules (SGs) are large macromolecular aggregates that contain translation initiation complexes and mRNAs. Stress granule formation coincides with translational repression, and stress granules actively signal to mediate cell fate decisions by signaling to the translation apparatus to (i) maintain translational repression, (ii) mount various transcriptional responses, including innate immunity, and (iii) repress apoptosis. SIGNOR-260865 0.7 chlorphenamine chemical CHEBI:52010 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 12781173 t Luana Identification of a dual histamine H1/H3 receptor ligand based on the H1 antagonist chlorpheniramine. SIGNOR-257896 0.8 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1668 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248739 0.731 REST protein Q13127 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 10449787 f miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. SIGNOR-220698 0.296 TNFRSF17 protein Q02223 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 10903733 f miannu Overexpression of bcma activates the p38 mapk SIGNOR-79501 0.2 protriptyline chemical CHEBI:8597 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter. SIGNOR-258736 0.8 Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). SIGNOR-262138 0.7 E2F1 protein Q01094 UNIPROT PCNA protein P12004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253856 0.482 TACR3 protein P29371 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257389 0.286 CLK1 protein P49759 UNIPROT RBM17 protein Q96I25 UNIPROT up-regulates activity phosphorylation Ser266 QGLSTALsVEKTSKR 9534 BTO:0001538 23519612 t miannu In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues. SIGNOR-262708 0.321 AMH protein P03971 UNIPROT AMHR2 protein Q16671 UNIPROT up-regulates binding 9606 8119126 t acerquone The results point to anti-m?llerian Hormone (amh) being the most likely candidate ligand for c14. SIGNOR-36215 0.802 STK25 protein O00506 UNIPROT PDCD10 protein Q9BUL8 UNIPROT unknown phosphorylation Thr43 VNLSAAQtLRAAFIK 9606 19370760 t llicata Stk25 phosphorylates ccm3 at serine 39 and threonine 43 SIGNOR-185392 0.781 CSNK2A1 protein P68400 UNIPROT CLTB protein P09497 UNIPROT unknown phosphorylation Ser13 GFFSSSEsGAPEAAE -1 3128543 t llicata To date, the only evidence for a functional distinction of LCa and LCb is the preferential phosphorylation of LCb, which takes place at serine residues and is mediated by coated vesicle-associated casein kinase II. As a first step toward determining the function of light chain diversity, we have mapped the in vitro phosphorylation sites on LCb. We use [32P]ATP to phosphorylate LCb within coated vesicles, followed by sequencing of 32P-labeled chymotryptic peptides thereof, to identify serine residues at positions 11 and 13 as the phosphorylation sites. SIGNOR-250843 0.311 C25H27N5O4S chemical CID:66577011 PUBCHEM KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189711 0.8 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin SIGNOR-188869 0.568 CCR4-NOT complex complex SIGNOR-C439 SIGNOR PUM1 protein Q14671 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268351 0.37 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT up-regulates activity phosphorylation Ser45 LGIRSSKsAGALEEG 9606 BTO:0002524 30631047 t miannu Further analysis using an AMPK consensus phosphorylation motif indicated that 32 of these sites are likely direct AMPK phosphorylation sites. We validated one uncharacterized protein, ARMC10, and demonstrated that the S45 site of ARMC10 can be phosphorylated by AMPK both in vitro and in vivo. Function assay of ARMC10 and ARMC10 phosphorylation at S45. SIGNOR-277792 0.2 AQP5 protein P55064 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity binding phosphorylation:Ser156 STDSRRTsPVGSPAL 18583321 t lperfetto We performed immunoprecipitation and western blotting analysis in transfected cell lines using CDK4 and cyclin D1 antibodies. As expected, cells transfected with AQP5 WT showed an increase of the CDK4/cyclin D1 complex, whereas cells transfected with vector did not|hAQP5 Increases Phosphorylation of Retinoblastoma Protein through Cyclin D1/CDK4 Complex SIGNOR-272089 0.248 PRKAG1 protein P54619 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates binding 9606 16054041 t gcesareni Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139173 0.895 F2RL1 protein P55085 UNIPROT SDC4 protein P31431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254844 0.2 etorphine chemical CHEBI:4912 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258803 0.8 LCK protein P06239 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates activity phosphorylation 9606 10799545 t Phosphorylation of p56 dok and p62 dok is increased following CD2 stimulation and requires Lck. Phosphorylation of Dok proteins by Lck might provide a mechanism by which SH2-containing proteins can be recruited and co-localized with their substrates. SIGNOR-251373 0.589 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-244148 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRP1 inflammasome complex SIGNOR-C224 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263125 0.7 RAF1 protein P04049 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000975 11018021 t lperfetto The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. SIGNOR-244945 0.742 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser126 NPEAESSsKEGELDA -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276123 0.62 POMC protein P01189 UNIPROT MC3R protein P41968 UNIPROT up-regulates activity binding 9606 BTO:0000142 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268705 0.754 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser315 LPNNTSSsPQPKKKP 9606 14640983 t lperfetto We used non-radioactive electrophoretic mobility shift assays to show that c-terminal phosphorylation of p53 protein by cdk2/cyclin a on ser315 or by pkc on ser378 can efficiently stimulate p53 binding to dna in vitro. SIGNOR-217300 0.806 TRIM13 protein O60858 UNIPROT TRIM13 protein O60858 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 31744379 t miannu  In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1).  SIGNOR-272219 0.2 Aldolase proteinfamily SIGNOR-PF75 SIGNOR glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266486 0.8 PTCHD1 protein Q96NR3 UNIPROT VPS35 protein Q96QK1 UNIPROT up-regulates quantity binding 10090 BTO:0000142 29118110 t miannu Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus SIGNOR-266653 0.2 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser347 PVYSPPGsPPPGDPR 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77212 0.593 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity binding 9606 17589504 t lperfetto Here we show that Ambra1 (activating molecule in Beclin1-regulated autophagy), a large, previously unknown protein bearing a WD40 domain at its amino terminus, regulates autophagy and has a crucial role in embryogenesis. We found that Ambra1 is a positive regulator of the Becn1-dependent programme of autophagy SIGNOR-156409 0.782 lurasidone chemical CHEBI:70735 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10030 20404009 t Luana In vitro functional assays demonstrated that lurasidone acts as an antagonist at D2 and 5-HT7 receptors and as a partial agonist at the 5-HT1A receptor subtype. SIGNOR-257839 0.8 COLGALT1 protein Q8NBJ5 UNIPROT COL1A2 protein P08123 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261153 0.414 PTPN6 protein P29350 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates dephosphorylation Tyr402 CSIESDIyAEIPDET 9606 10521452 t gcesareni Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk SIGNOR-71414 0.363 AURKA protein O14965 UNIPROT SOX8 protein P57073 UNIPROT up-regulates activity phosphorylation Ser327 SAPSASAsPTETGPP 9606 BTO:0000410 32550913 t miannu We showed for the first time that Aurora-A interacts directly with SOX8 and phosphorylates the protein at Ser327 to further regulate the SOX8/FOXK1 axis, which modulates cell senescence and glycolysis, ultimately leading to cisplatin resistance. SIGNOR-273548 0.2 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser748 DSEGFEDsFEEEEEE 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265272 0.2 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma After binding of Wnt to the receptor complex, the signal is transduced to cytoplasmic phosphoprotein Dishevelled (Dsh/Dvl), and studies have uncovered that Dsh can directly interact with Fz SIGNOR-255892 0.2 MAPKAPK2 protein P49137 UNIPROT KRT20 protein P35900 UNIPROT up-regulates activity phosphorylation Ser13 RSFHRSLsSSLQAPV -1 20724476 t miannu P38 phosphorylates the type II keratin, K8 at Ser73, whereas MK2 phosphorylates the binding partners K18 at Ser52 and K20 at Ser13. SIGNOR-263071 0.2 ATF5 protein Q9Y2D1 UNIPROT CYP2B6 protein P20813 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18332083 f miannu We induced endoplasmic reticulum stress by means of amino acid limitation or selective chemicals, and assessed the time course response of ATF5 and CYP2B6. We found a post-transcriptional up-regulation of ATF5 and a parallel induction of CYP2B6 mRNA. SIGNOR-253751 0.2 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249641 0.746 MCU protein Q8NE86 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270865 0.72 pipamperone chemical CHEBI:78549 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258572 0.8 USP37 protein Q86T82 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 21596315 t lperfetto USP37 Binds, Deubiquitinates, and Stabilizes Cyclin A SIGNOR-265052 0.569 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser88 DSGFCLDsPGPLDSK 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277341 0.621 CTNNB1 protein P35222 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 10937998 f fspada Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma). SIGNOR-80592 0.549 JNK proteinfamily SIGNOR-PF15 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137631 0.2 PCSK6 protein P29122 UNIPROT INSR protein P06213 UNIPROT up-regulates activity cleavage 9606 BTO:0000666 25527501 t Giorgia Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. SIGNOR-260366 0.2 RARB protein P10826 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16519 0.672 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161553 0.554 CSF1 protein P09603 UNIPROT CSF3R protein Q99062 UNIPROT up-regulates binding 9606 16492764 t gcesareni A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution SIGNOR-144737 0.325 GHSR protein Q92847 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257255 0.251 CRBN protein Q96SW2 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31591562 t miannu CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation. SIGNOR-272214 0.2 POU4F1 protein Q01851 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity binding 9606 9448000 t 2 miannu The POU domain of Brn-3a and Brn-3b was shown to interact with the DNA-binding domain of the ER. Brn-3-ER interactions also affect transcriptional activity of an ERE-containing promoter, such that in estradiol-stimulated cells, Brn-3b strongly activated the promoter via the ERE, while Brn-3a had a mild inhibitory effect. SIGNOR-241275 0.54 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser243 AEKYAKEsLKEEDES -1 8619999 t llicata Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery. SIGNOR-250938 0.386 MMP23B protein O75900 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272390 0.7 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CRKL protein P46109 UNIPROT up-regulates phosphorylation Tyr207 IPEPAHAyAQPQTTT 9606 BTO:0001271 9053848 t lperfetto Tyrosine 207 in crkl is the bcr/abl phosphorylation sitephosphorylation of y207 provides a binding site for the crkl sh2 domain and potentially for other sh2-containing proteins. SIGNOR-46893 0.2 TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT up-regulates quantity by expression transcriptional regulation 17541280 f T-bet is crucially implicated in Th1 differentiation due to its strong promoting activity for IFN-gamma gene transcription SIGNOR-254508 0.485 DNA_damage stimulus SIGNOR-ST1 SIGNOR CHEK1 protein O14757 UNIPROT up-regulates 9606 26527132 f lperfetto Checkpoint kinase 1 (CHK1) is a key component of the ATR-dependent DNA damage response pathway that protects cells from RS by preventing replication fork collapse and activating homologous DNA repair. SIGNOR-242616 0.7 RIMBP3B protein A6NNM3 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264364 0.349 IL1RL1 protein Q01638 UNIPROT IRAK1 protein P51617 UNIPROT up-regulates activity binding 9606 BTO:0000007 16286016 t miannu As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.  SIGNOR-277706 0.593 F2RL1 protein P55085 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254842 0.257 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Tyr259 KGRFAEVyKAKLKQN -1 9169454 t lperfetto Tryptic mapping and amino acid sequencing of in vitro autophosphorylated type ii receptor cytoplasmic domain allowed the localization of the sites of tyrosine phosphorylation to positions 259, 336, and 424. Replacement of all three tyrosines with phenylalanines strongly inhibited the kinase activity of the receptor, suggesting that tyrosine autophosphorylation may play an autoregulatory role for the kinase activity of this receptor. SIGNOR-48859 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120220 0.319 MAP4K1 protein Q92918 UNIPROT LCP2 protein Q13094 UNIPROT down-regulates activity phosphorylation Ser376 PRKQLSESSDDDYDD 9606 BTO:0000661 17353368 t Barakat The serine/threonine kinase HPK-1 phosphorylates serine 376 of SLP-76 and induces the interaction with 14-3-3 proteins SIGNOR-274153 0.773 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates binding 9606 21084559 t gcesareni Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. SIGNOR-169835 0.583 H3-4 protein Q16695 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 t miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263725 0.2 NFIA protein Q12857 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268893 0.2 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 12181443 f lperfetto We show [] that the kinase activity and s473 phosphorylation of akt induced by lpa and s1p requires both mitogen-activated protein (map) kinase kinase (mek) and p38 map kinase. [] among different stimuli tested, platelet-derived growth factor stimulates s473 phosphorylation of akt in a mek- and p38-dependent manner. However, epidermal growth factor, thrombin, and endothelin-1?stimulated Akt s473 phosphorylation require p38 but not mek. SIGNOR-91408 0.418 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr288 IDDNEYAyLKAIIFF 9606 22308320 t lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. SIGNOR-195900 0.37 STK11 protein Q15831 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 14657655 f gcesareni Phospho-gsk3b-specific antibodies also revolved that lkb1 regulates gsk3b phosphorylation at a known inhibitory site, serine-9. This localized phosphorylation is cdc42 and pkc-zeta-dependent. SIGNOR-119892 0.382 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 DGSCSSSsPPLPVLG 9606 15632084 t gcesareni In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3. SIGNOR-132967 0.903 MKRN1 protein Q9UHC7 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys291 TEEENLRkKGEPHHE 9606 BTO:0002552 19536131 t miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. K291 and K292 of p53 are required for MKRN1-mediated degradation and ubiquitination of p53 SIGNOR-271846 0.438 PCSK7 protein Q16549 UNIPROT ELK4 protein P28324 UNIPROT up-regulates phosphorylation 9606 9130707 t gcesareni In contrast, the tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387 SIGNOR-47771 0.2 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1A protein P35348 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258462 0.8 LRRC4 protein Q9HBW1 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 9606 BTO:0000142 25526788 f miannu The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks. SIGNOR-264060 0.7 CDK6 protein Q00534 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 16160006 t gcesareni Phosphorylation on ser-10 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.p27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization. SIGNOR-140401 0.852 ARHGAP11B protein Q3KRB8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260467 0.488 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR TRiC complex SIGNOR-C539 SIGNOR down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24298020 t miannu Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not.The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.COP1 functions as an E3 ligase by forming a supercomplex that also includes heterodimeric substrate receptor DET1, adaptor DDB1, scaffold Cul4A, and RBX1 to recruit the E2 enzyme SIGNOR-272873 0.2 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr371 TQEQYELyCEMGSTF 10090 BTO:0000944 11997497 t Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. SIGNOR-251304 0.514 CALM2 protein P0DP24 UNIPROT SCN8A protein Q9UQD0 UNIPROT down-regulates activity binding 9606 BTO:0000938 11807557 t miannu Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. SIGNOR-266330 0.456 MMP9 protein P14780 UNIPROT PZP protein P20742 UNIPROT down-regulates quantity by destabilization cleavage Leu778 WKAGAFClSEDAGLG -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261785 0.353 P4HB protein P07237 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 32149426 t lperfetto The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. SIGNOR-275573 0.435 MAPK8 protein P45983 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 15538382 t lperfetto Upon treatment of cells with h2o2, the small gtpase ral is activated and this results in a jnk-dependent phosphorylation of foxo4 on threonine 447 and threonine 451. This ral-mediated, jnk-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of foxo4 after h2o2 treatment. SIGNOR-252964 0.708 1-naphthol chemical CHEBI:10319 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258163 0.8 RRAGD protein Q9NQL2 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 t lperfetto Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor SIGNOR-217550 0.641 SRC protein P12931 UNIPROT HSP90AB1 protein P08238 UNIPROT up-regulates phosphorylation Tyr301 DDITQEEyGEFYKSL 9606 17855507 t lperfetto C-src directly phosphorylates hsp90 on tyrosine 300 residue and that this event is essential for vegf-stimulated enos association to hsp90 and thus no release from endothelial cells. SIGNOR-157781 0.577 AURKB protein Q96GD4 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser269 GNLLGRNsFEVRVCA 9606 20959462 t llicata Importantly, the aurora b-mediated phosphorylation on ser(269) or thr(284) significantly compromises p53 transcriptional activity. SIGNOR-168745 0.713 SMARCD2 protein Q92925 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270733 0.743 MAP1LC3C protein Q9BXW4 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates binding 9606 BTO:0000007 19250911 t gcesareni We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. . downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1. SIGNOR-184258 0.54 RET protein P07949 UNIPROT ATF4 protein P18848 UNIPROT down-regulates quantity by destabilization phosphorylation Thr114 TMPDDLLtTLDDTCD 9606 BTO:0002181 25795775 t miannu We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA.  SIGNOR-276449 0.2 BCL2L2 protein Q92843 UNIPROT BAX protein Q07812 UNIPROT down-regulates binding 9606 17452531 t gcesareni Bcl-w may protect largely via its ability to associate with bax because it could efficiently protect xem from tbid and bid, bad, hrk, and bmf bh3 peptides SIGNOR-154518 0.473 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-269996 0.2 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu Dendritic spines are small protrusions found on dendrites of principal neurons of mammalian brain. Serving as postsynaptic compartments for individual excitatory inputs, spines show rapid movements and shape changes that are influenced by synaptic activity. The structural modifications of spines are believed to represent morphological correlates of synaptic plasticity. The form and motility of spines are determined mainly by the actin cytoskeleton SIGNOR-266597 0.7 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207251 0.8 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr566 SLNQEDIyITTESLT 10029 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248421 0.487 17beta-estradiol smallmolecule CHEBI:16469 ChEBI Corticotropin protein P01189-PRO_0000024969 UNIPROT up-regulates 24631756 f lperfetto ACTH and corticosterone responses to the same acute stress stimulus are higher in the pro-estrus phase of the cycle, when the serum concentrations of estrogen are the highest |Moreover, Kirschbaum et al. conducted a double blind study of 32 men, showing that 100 mcg of estradiol/day for two days was sufficient to produce statistically significant increases in ACTH SIGNOR-268726 0.8 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser379 SKILGETsLMRTLCG 9606 BTO:0000007 18644861 t lperfetto Regulation of chk2 ubiquitination and signaling through autophosphorylation of serine 379.Thus, auto-/transphosphorylation of s379 is required for chk2 ubiquitination and effector function SIGNOR-179537 0.2 AKT1 protein P31749 UNIPROT RPS6KA3 protein P51812 UNIPROT down-regulates activity phosphorylation Ser19 KMAVESPsDSAENGQ 9606 BTO:0000815 33574926 t miannu Akt interacts with and phosphorylates RSK2 at S19. SIGNOR-277548 0.267 ATM protein Q13315 UNIPROT KHSRP protein Q92945 UNIPROT up-regulates phosphorylation Ser670 GPGAPPGsQPDYSAA 9606 21329876 t lperfetto The atm kinase directly binds to and phosphorylates ksrp, leading to enhanced interaction between ksrp and pri-mirnas and increased ksrp activity in mirna processing SIGNOR-172127 0.431 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity phosphorylation Tyr368 STKMHGDyTLTLRKG 9534 8385099 t The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor. SIGNOR-252692 0.607 FZD5 protein Q13467 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 10937998 f fspada Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors ccaat/enhancer binding protein alpha (c/ebpalpha) and peroxisome proliferator- activated receptor gamma (ppargamma) SIGNOR-80610 0.2 sorafenib tosylate chemical CHEBI:50928 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259454 0.8 SGI-1776 chemical CID:24795070 PUBCHEM PIM2 protein Q9P1W9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206862 0.8 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258252 0.8 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782 8325880 t gcesareni Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase|The present study shows that the MAP kinase has a 20-fold preference for Ser25 as opposed to Ser38 of Op18, while cdc2 kinases have a 5-fold preference for the Ser38 residue. SIGNOR-37848 0.399 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 9606 20626350 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-166629 0.806 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Thr86 YTLSRAQtVVVEYTH 9606 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96759 0.761 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser939 SFRARSTsLNERPKS 9606 12172553 t gcesareni We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex. SIGNOR-91388 0.723 DNA polymerase gamma complex SIGNOR-C378 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 19837034 f lperfetto DNA Pol gamma, in contrast to the many nuclear DNA polymerases (DNAPs) that have specialized functions, is solely responsible for DNA replication and repair in mitochondria.  SIGNOR-265723 0.7 METTL3 protein Q86U44 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000567 27117702 t miannu Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.  SIGNOR-265955 0.2 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 12464600 t gcesareni Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation. SIGNOR-96067 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates 9606 22298955 f gcesareni Similar synergy is found in notch and bmp crosstalk: activating notch signaling enhanced bmp-induced alp activity and formation of calcified nodules in vitro. SIGNOR-254335 0.359 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 9606 BTO:0000763 12193595 t miannu Phosphorylation of smad2 by erk increases its transcriptional activity /thr220 and ser245, ser250, and ser255 were possible phosphorylation sites. The phosphorylation of peak a peptide by erk1 is consistent with that prediction. SIGNOR-91722 0.716 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT up-regulates activity phosphorylation Ser2246 SSSVHASerPLASSP -1 26051540 t irozzo Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. SIGNOR-259118 0.46 A9/b1 integrin complex SIGNOR-C166 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity by expression 9606 24241034 f lperfetto Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages. SIGNOR-253314 0.308 PCK1 protein P35558 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 30193097 t miannu ¬†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).¬† SIGNOR-266587 0.8 CYP2R1 protein Q6VVX0 UNIPROT vitamin D smallmolecule CHEBI:27300 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 30080183 t lperfetto Vitamin D-binding protein transports vitamin D to the liver, where it undergoes 25-hydroxylation by CYP2R1. CYP27B1 further hydroxylates 25-hydroxyvitamin D at the 1-alpha position, resulting in the formation of the active hormone 1,25-dihydroxyvitamin D. SIGNOR-270569 0.8 CEP41 protein Q9BYV8 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 9606 BTO:0000007 31885126 t miannu We performed these assays in HEK 293T cells and observed CEP41 binds HIF1α under both normoxic and hypoxic conditions. Of note, we found hypoxia induces more expression of HIF1α and increases its binding to CEP41 (Fig 8B and C). Hence, these results suggest CEP41 modulates the activation of HIF1α via a physical interaction SIGNOR-269662 0.2 P2RY6 protein Q15077 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257189 0.2 SMAD3 protein P84022 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. SIGNOR-260432 0.7 PRKACA protein P17612 UNIPROT RGS10 protein O43665 UNIPROT down-regulates activity phosphorylation Ser176 QTAAKRAsRIYNT 9606 11443111 t lperfetto We report in this study the acute functional regulation of rgs10 thru the specific and inducible phosphorylation of rgs10 protein at serine 168 by camp-dependent kinase a. This phosphorylation nullifies the rgs10 activity at the plasma membrane, which controls the g protein-dependent activation of the inwardly rectifying potassium channel. SIGNOR-109173 0.338 CPT1B protein Q92523 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267127 0.8 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT up-regulates activity phosphorylation Tyr256 RETSKVIyDFIEKTG -1 16199863 t Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation. SIGNOR-251437 0.56 SNRPD3 protein P62318 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270662 0.736 BCR protein P11274 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260526 0.59 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 10660596 t gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. SIGNOR-74860 0.895 trimipramine chemical CHEBI:9738 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258741 0.8 PTK2 protein Q05397 UNIPROT ACTN1 protein P12814 UNIPROT down-regulates activity phosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0004055 11369769 t lperfetto The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments. SIGNOR-108329 0.562 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser393 MQVSSSSsSHSLSAS 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-235782 0.2 MTTP protein P55157 UNIPROT APOB protein P04114 UNIPROT up-regulates activity lipidation 9606 23721961 t miannu As ApoB is translated, it is lipidated by microsomal triglyceride transfer protein (MTP). MTP adds triglycerides to the nascent ApoB during its co-translational translocation into the lumen of the endoplasmic reticulum. SIGNOR-252118 0.789 S1PR3 protein Q99500 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257175 0.41 SCRIB protein Q14160 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 19458197 f miannu Our data supports a model by which scribble functions downstream of beta-catenin to cluster synaptic vesicles at developing synapses. SIGNOR-265827 0.7 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249325 0.758 DCAF7 protein P61962 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates activity binding 9534 BTO:0000298 14593110 t miannu Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions. SIGNOR-260631 0.743 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 15766588 t gcesareni Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22. SIGNOR-134524 0.933 MAPK10 protein P53779 UNIPROT SFN protein P31947 UNIPROT down-regulates phosphorylation Ser186 FHYEIANsPEEAISL 9606 15071501 t Ser residues in the reagion between alpha-helices 7 and 8, JNK3 is essential for apoptosis of hippocampal neurons gcesareni Here we demonstrate that activated jnk promotes bax translocation to mitochondria through phosphorylation of 14-3-3, a cytoplasmic anchor of bax. Phosphorylation of 14-3-3 led to dissociation of bax from this protein.Jnk phosphorylates 14-3-3zeta_ at ser-184 and 14-3-3sigma_ at ser-191 SIGNOR-124005 0.2 SOSTDC1 protein Q6X4U4 UNIPROT WNT2 protein P09544 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242724 0.307 PRKDC protein P78527 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG -1 9139719 t lperfetto In this study, we show that efficient phosphorylation of HSSB-p34 by DNA-PK requires Ku as well as DNA. The DNA-PK phosphorylation sites in HSSB-p34 have been mapped at Thr-21 and Ser-33. Kinetic studies demonstrated that a phosphate residue is first incorporated at Thr-21 followed by the incorporation of a second phosphate residue at Ser-33. SIGNOR-248972 0.591 HIPK2 protein Q9H2X6 UNIPROT PDX1 protein P52945 UNIPROT unknown phosphorylation Ser268 LPPGLSAsPQPSSVA 10090 BTO:0000783;BTO:0002284 20637728 t Our results suggest that HIPK2-mediated phosphorylation of PDX1 at Ser-269 might be a regulatory mechanism connecting signals generated by changes in extracellular glucose concentration to downstream effectors via changes in subnuclear localization of PDX1, thereby influencing islet cell differentiation and function SIGNOR-255539 0.358 MK-2461 chemical CID:44137946 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194378 0.8 BAG1 protein Q99933 UNIPROT STUB1 protein Q9UNE7 UNIPROT up-regulates activity binding 9534 BTO:0001538 11676916 t miannu BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association SIGNOR-272587 0.55 TCF7L1 protein Q9HCS4 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001581 16894029 t Luana These experiments showed that Tcf3 is associated with chromatin in the Nanog promoter regions and that the DNA-binding activity of Tcf3 was required for repression. SIGNOR-266081 0.346 FCRL3 protein Q96P31 UNIPROT SYK protein P43405 UNIPROT up-regulates activity binding -1 12051764 t miannu Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2. SIGNOR-274011 0.357 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18521620 t gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). SIGNOR-178803 0.784 NAB2 protein Q15742 UNIPROT GFI1 protein Q99684 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 16923394 f miannu Impairing Egr-2 or Nab-2 induction resulted in sustained expression of Gfi-1, demonstrating that Egr-2 and Nab-2 negatively regulate Gfi-1 expression . Importantly, the Gfi-1 promoter was repressed via the Egr site by coexpression of Egr-2 and Nab-2. Thus, Egr-2 and Nab-2 directly repress the Gfi-1 gene. SIGNOR-256042 0.399 AMPK complex SIGNOR-C15 SIGNOR WDR45 protein Q9Y484 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001938 28561066 t miannu WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes. SIGNOR-268480 0.316 NFE2L2 protein Q16236 UNIPROT SOD2 protein P04179 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493435 t miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254652 0.459 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser487 GQPTSMLsPRHRMSP 9606 BTO:0000801 29170386 t Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. SIGNOR-256097 0.247 CSNK2A1 protein P68400 UNIPROT LIG1 protein P18858 UNIPROT up-regulates activity phosphorylation Ser66 KAARVLGsEGEEEDE 9606 BTO:0000567 12851383 t lperfetto Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23). SIGNOR-103258 0.343 HES1 protein Q14469 UNIPROT NEUROG1 protein Q92886 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265140 0.351 AKT1 protein P31749 UNIPROT YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 15806160 t lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 SIGNOR-252475 0.569 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization 10090 17548510 f Simone Vumbaca Previously, we showed that Pax7 overexpression in adult primary myoblasts down-regulates MyoD and prevents myogenin induction, inhibiting myogenesis. We show that Pax7 prevents muscle differentiation independently of its transcriptional activity, affecting MyoD function. [...] Pax7 expression affects MyoD protein stability SIGNOR-255637 0.61 BACH1 protein O14867 UNIPROT MAFK protein O60675 UNIPROT up-regulates activity binding 10090 BTO:0004475 19011633 t miannu Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes SIGNOR-226409 0.481 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser109 NKFAAHIsPAQGSPK -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277881 0.2 TCOF1 protein Q13428 UNIPROT NBN protein O60934 UNIPROT up-regulates activity relocalization 9606 25064736 t lperfetto We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent. SIGNOR-265085 0.322 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257968 0.8 SIX1 protein Q15475 UNIPROT Six1/Dach complex SIGNOR-C122 SIGNOR form complex binding 10090 14628042 t llicata The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, SIGNOR-238029 0.608 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77204 0.593 MYOD1 protein P15172 UNIPROT SMARCA4 protein P51532 UNIPROT up-regulates binding 9606 SIGNOR-C92 17194702 t miannu Myod targets brg1 to the myogenin promoter during the initiation of myogenesis in tissue culture models for skeletal muscle differentiation /initiation of myogenin transcription is dependent upon myod, the pbx homeodomain factor, and swi/snf chromatin-remodeling enzymes SIGNOR-151685 0.538 PIM1 protein P11309 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation 9606 25280219 t FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells SIGNOR-261557 0.69 WKYMVm chemical CID:457933 PUBCHEM FPR2 protein P25090 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257493 0.8 26S Proteasome complex SIGNOR-C307 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates quantity destabilization 10090 BTO:0003569 9233789 t Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. SIGNOR-270947 0.401 PLK1 protein P53350 UNIPROT USP16 protein Q9Y5T5 UNIPROT up-regulates activity phosphorylation Ser386 HESFLDLsLPVLDDQ -1 26323689 t done miannu Plk1 phosphorylates and activates Usp16. In vitro phosphorylation of Usp16 with single (S330A, S386A, or S486A) or collective 3A (S330A/S386A/S486A) mutation showed that Plk1 phosphorylated Usp16 at all three sites (Fig. S2 D). SIGNOR-274015 0.347 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates quantity by destabilization phosphorylation Ser315 DFRSRTNsNASTVSG 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-249647 0.2 KRAS protein P01116 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 BTO:0003104 10082541 f lperfetto A constitutively active Ras protein [Ras(G12V)] regulates the stable expression of the NFIL3 transcription factor through both the Raf-MAPK and PI3-K pathways. SIGNOR-242757 0.2 MARK2 protein Q7KZI7 UNIPROT UTRN protein P46939 UNIPROT up-regulates phosphorylation Ser1258 TLEERMKsTEVLPEK 9606 BTO:0000887;BTO:0001103 19945424 t lperfetto Par-1b, interacts with the utrophin-dg complex, and positively regulates the interaction between utrophin and dg. Ser1258 within r9 is specifically phosphorylated by par-1b. SIGNOR-161915 0.43 GSK3A protein P49840 UNIPROT PKD2 protein Q13563 UNIPROT unknown phosphorylation Ser76 AGAAASPsPPLSSCS 9606 BTO:0000007 BTO:0000671 16551655 t llicata We report the identification of a new phosphorylation site for pc2 within its n-terminal domain (ser(76)) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (gsk3). SIGNOR-145306 0.2 Sin3B_complex complex SIGNOR-C409 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity binding 9606 21041485 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266973 0.2 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT up-regulates activity phosphorylation Tyr257 APSRQDVyGPQPQVR -1 11382764 t lperfetto Identification of Src phosphorylation sites in the catenin p120ctn.Using selected tyrosine to phenylalanine p120 mutants as dominant negative reagents, it may now be possible to selectively block events postulated to be dependent on p120 tyrosine phosphorylation.combinations of Tyr _ Phe mutations at residues 96, 112, 228, 257, 280, 291, 296, and 302 SIGNOR-246488 0.921 FLT3 protein P36888 UNIPROT XRCC5 protein P13010 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 f fcortellessa We detected an approximately 5-fold decrease in Ku86 expression in early pro-B cells from FLT3/ITD mice compared with the wild-type controls. These data support the finding that FLT3/ITD mutations exert a suppressive role on Ku86 expression. SIGNOR-261684 0.2 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT down-regulates activity phosphorylation Thr526 TNSFSAStGLSDMTA 10090 BTO:0000944 8662759 t llicata Casein kinase II associates with Egr-1 and acts as a negative modulator of its DNA binding and transcription activities in NIH 3T3 cells. | There are three CKII recognition sites (S376XXD, T389XE, and T516XXXD) in fragment 10. SIGNOR-250858 0.472 TERB2 protein Q8NHR7 UNIPROT TTM complex complex SIGNOR-C305 SIGNOR form complex binding 9606 BTO:0000007 30718482 t lperfetto Meiotic specific proteins TERB1, TERB2, and MAJIN form a stable complex that plays a critical role in regulating the recruitment of telomeres to the NE SIGNOR-263304 0.2 ARF6 protein P62330 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272154 0.7 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser909 HQRCLAHsLVGTPNY 9606 BTO:0000007 15688006 t milica We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity. SIGNOR-133551 0.613 JAK2 protein O60674 UNIPROT STAT1 protein P42224 UNIPROT up-regulates phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000567 15322115 t lperfetto Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation. SIGNOR-235709 0.803 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 11847100 t lperfetto c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. SIGNOR-246307 0.525 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser464 DKEGLSEsVRSSCTL 9606 20643644 t Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. SIGNOR-260796 0.2 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190179 0.8 BDKRB2 protein P30411 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256974 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 10464286 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-252815 0.2 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI orotidine 5'-phosphate(3-) smallmolecule CHEBI:57538 ChEBI up-regulates quantity precursor of 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267435 0.8 TJP1 protein Q07157 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 10090 19447104 t miannu NHS-A is a novel interactor of ZO-1 and is expected to have a role at tight junctions. Its recruitment to these junctions is dependent upon their assembly. SIGNOR-253567 0.2 (S,S)-asenapine chemical CHEBI:71257 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258567 0.8 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression 9606 17909097 f inferred from family member gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-270254 0.8 STAT6 protein P42226 UNIPROT RETN protein Q9HD89 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000801 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249536 0.317 TNF protein P01375 UNIPROT SCN9A protein Q15858 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253479 0.253 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO4 protein P98177 UNIPROT up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-168762 0.2 F2R protein P25116 UNIPROT LATS1 protein O95835 UNIPROT down-regulates 9606 BTO:0000007 22972936 f Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization. milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-192045 0.2 4.1 complex complex SIGNOR-C386 SIGNOR SPTB protein P11277 UNIPROT up-regulates activity binding 9606 BTO:0000424 22465511 t lperfetto The junctional complex is focused around a hub or ‘junction’ arising from lateral connections between protein 4.1, actin and beta spectrin (the first of which stabilises the actin spectrin association via direct binding to both proteins [8]). SIGNOR-266041 0.359 MCHR2 protein Q969V1 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257334 0.419 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2279 PVQPNPMsPQQHMLP 9606 17623675 t lperfetto Serine residues (ser-2279, ser-2315, and ser-2366) on the c terminus of p300 were the major signaling targets of egf. Furthermore, the c-terminal serine phosphorylation of p300 stimulated its histone acetyltransferase activity these results also constituted the first report identifying the unique p300 phosphorylation sites induced by erk2 in vivo. SIGNOR-244533 0.2 MCU protein Q8NE86 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270874 0.701 SRC protein P12931 UNIPROT DAPP1 protein Q9UN19 UNIPROT up-regulates activity phosphorylation Tyr139 KVEEPSIyESVRVHT 9606 BTO:0000776 10880360 t lperfetto Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell linesyrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins. SIGNOR-247119 0.575 LAMB2 protein P55268 UNIPROT Laminin-9 complex SIGNOR-C180 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253224 0.548 CDK19 protein Q9BWU1 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Thr2511 VPEHPFLtPSPESPD -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273137 0.305 STAT1 protein P42224 UNIPROT IRF7 protein Q92985 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 16628196 f miannu The activation of STAT1 by IFNs not only induces chemokine production, but also results in the expression of IRF-7 and TLR3, thus amplifying the dsRNA-provoked reaction in a positive-feedback manner during viral infection. SIGNOR-255231 0.491 KDM5C protein P41229 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265354 0.2 PIK3R1 protein P27986 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242646 0.717 SNCA protein P37840 UNIPROT VAMP2 protein P63027 UNIPROT down-regulates quantity binding 9606 BTO:0000938 31110017 t miannu The normal function of the small presynaptic protein α-synuclein (α-syn) is of exceptional interest, not only in the context of neurodegeneration, but also as a cytosolic regulator of neurotransmission. we show that α-syn-VAMP2 interactions are necessary for α-syn-induced synaptic attenuation. Our data connect divergent views and suggest a unified model of α-syn function. the data indicate that α-syn–VAMP2 binding is essential for α-syn function and advocate an “interlocking model” where α-syn multimers on the SV surface interact with VAMP2 on adjacent SVs, helping to maintain physiologic SV clustering. SIGNOR-264104 0.406 DPP6 protein P42658 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity relocalization 8355 BTO:0000964 17130523 t Luisa DPPX-S reduced energy barriers of the voltage-dependent transitions; therefore, this auxiliary subunit may exert a catalytic effect on voltage-dependent gating of Kv4.2 channels. DPPX-S may also accelerate coupled inactivation indirectly SIGNOR-269005 0.558 Enolase proteinfamily SIGNOR-PF74 SIGNOR MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 2005901 t inferred from family member Luana This result suggests that MBP-1 in vivo acts as a sequence-specific repressor. SIGNOR-270308 0.2 HCRTR1 protein O43613 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257128 0.251 GSK3B protein P49841 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159476 0.2 SRC protein P12931 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1125 APSRDPHyQDPHSTA 9606 8845374 t lperfetto The c-terminal autophosphorylation domain of egfr was extensively phosphorylated by c-src./These studies revealed that y1086 was phosphorylated to a significantly higher extent by c-src than by egfr. Additionally, y1101 was identified as a unique c-src phosphorylation site SIGNOR-44247 0.615 RPS6KA5 protein O75582 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 12213813 t lperfetto Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells SIGNOR-262990 0.348 FADD protein Q13158 UNIPROT CASP10 protein Q92851 UNIPROT up-regulates binding 9606 11717445 t gcesareni The death-effector domains ofcasp8and -10 bothinteractwith the death-effector domain offadd. Therefore, caspase-10 is recruited into the fas signaling complex and becomes activated like caspase-8 SIGNOR-112058 0.79 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr720 IPKEPSNyDFVYDCN 9606 15952790 t llicata We previously showed that elmo1 binds directly to the hck sh3 domain and is phosphorylated by hck. In this study, we used mass spectrometry to identify the following sites of elmo1 phosphorylation: tyr 18, tyr 216, tyr 511, tyr 395, and tyr 720. Mutant forms of elmo1 lacking these sites were defective in their ability to promote phagocytosis and migration in fibroblasts. SIGNOR-138158 0.597 ACTL6A protein O96019 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270712 0.824 FGR protein P09769 UNIPROT FGR protein P09769 UNIPROT up-regulates activity phosphorylation Tyr412 RLIKDDEyNPCQGSK -1 8612628 t Autophosphorylation of c-Fgr under basal conditions involves Tyr-400 (homologous of c-Src Tyr-416) but not, to any appreciable extent, Tyr-511. Both Tyr-511 and Tyr-400, however, incorporate phosphate if autophosphorylation is performed in the presence of polycationic peptides, such as polylysine, histones H1 and protamines. Such a double phosphorylation induced by polylysine gives rise to an upshifted form of c-Fgr on SDS-PAGE and correlates with a stimulation of catalytic activity instead of a down-regulation SIGNOR-251143 0.2 P2RY4 protein P51582 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257288 0.2 ULK2 protein Q8IYT8 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity phosphorylation Ser74 EATWESVsMMLQLGG 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274043 0.2 bortezomib chemical CHEBI:52717 ChEBI PSMB1 protein P20618 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 t miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. SIGNOR-259306 0.8 CAMKK1 protein Q8N5S9 UNIPROT CAMK4 protein Q16566 UNIPROT up-regulates phosphorylation 9606 10770941 t lperfetto Ca(2+)/calmodulin-dependent protein kinase kinase (CaM-KK) is a novel member of the CaM kinase family, which specifically phosphorylates and activates CaM kinase I and IV SIGNOR-232181 0.61 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267328 0.8 DIP2A protein Q14689 UNIPROT SOD1 protein P00441 UNIPROT up-regulates activity binding 10090 BTO:0000142 33781892 t miannu DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain. SIGNOR-266591 0.2 ICOS protein Q9Y6W8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9606 18641334 t ICOS ligation in concert with TCR stimulation results in strong PI3K activation in T lymphocytes. The ICOS cytoplasmic tail contains an YMFM motif that binds the p85alpha subunit of class IA PI3K, similar to the YMNM motif of CD28, suggesting a redundant function of the two receptors in PI3K signaling. SIGNOR-272539 0.485 UBA2 protein Q9UBT2 UNIPROT SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR form complex binding -1 15660128 t lperfetto E1 enzymes facilitate conjugation of ubiquitin and ubiquitin-like proteins through adenylation, thioester transfer within E1, and thioester transfer from E1 to E2 conjugating proteins. Structures of human heterodimeric Sae1/Sae2-Mg.ATP and Sae1/Sae2-SUMO-1-Mg.ATP complexes were determined at 2.2 and 2.75 A resolution, respectively. SIGNOR-263004 0.818 AKT1 protein P31749 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t miannu We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh. SIGNOR-252501 0.399 STK24 protein Q9Y6E0 UNIPROT STK38L protein Q9Y2H1 UNIPROT up-regulates phosphorylation Thr442 DWVFLNYtYKRFEGL 9606 BTO:0000007 16314523 t lperfetto Ndr1/ndr2 protein kinase is activated by phosphorylation on the activation loop phosphorylation site ser281/ser282 and the hydrophobic motif phosphorylation site thr444/thr442. Autophosphorylation of ndr is responsible for phosphorylation on ser281/ser282, whereas thr444/thr442 is targeted by an upstream kinase. Here we show that mst3, a mammalian ste20-like protein kinase, is able to phosphorylate ndr protein kinase at thr444/thr442. In vitro, mst3 selectively phosphorylated thr442 of ndr2, resulting in a 10-fold stimulation of ndr activity. SIGNOR-142510 0.447 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR TP53 protein P04637 UNIPROT up-regulates quantity by expression 9606 15044535 f gcesareni These results indicate that nf-kb actions occur upstream of p53 to regulate both p53 levels and activity. SIGNOR-123602 0.495 NBEAL2 protein Q6ZNJ1 UNIPROT VWF protein P04275 UNIPROT up-regulates 9606 BTO:0000132 28082341 f lperfetto Recent in vitro megakaryopoiesis studies using HSCs from GPS patients with NBEAL2 mutations showed normal MK differentiation with defective proplatelet formation and reduced α-granule proteins such as von Willebrand factor (VWF), thrombospondin and P-selectin. SIGNOR-261884 0.275 SLBP protein Q14493 UNIPROT H2AC18 protein Q6FI13 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265396 0.2 PRKCA protein P17252 UNIPROT PRKCA protein P17252 UNIPROT up-regulates phosphorylation Ser657 QSDFEGFsYVNPQFV 9606 15277524 t lperfetto Pkc is frequently autophosphorylated on two c-terminal sites, the turn motif (thr- 638 in human pkc) and the hydrophobic site (ser-657 in human pkc). Thus, it is becoming clear that autophosphorylation of pkc can be a regulated event and that it has significant impact on pkc function SIGNOR-127253 0.2 TP53 protein P04637 UNIPROT NLRC4 protein Q9NPP4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15580302 f miannu Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels. SIGNOR-255439 0.435 GLI2 protein P10070 UNIPROT GLI1 protein P08151 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0002572 16571352 f lperfetto Primary mouse embryonic fibroblasts responded to Shh stimulation with the induction of Hh target genes Gli1, Ptc1, and Hip1.These observations support the previously advanced notion of a functional redundancy or cooperativity between Gli2 and Gli1 in activation of target genes [18] and [43] and indicate a functional cooperation between Gli3 and Gli1. SIGNOR-209629 0.443 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 19933840 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction SIGNOR-216572 0.2 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates phosphorylation Tyr500 TSLGSQSyEDMRGIL 9606 10933394 t llicata Experiments with purified proteins demonstrated that cd19-y513 was lyn's initial phosphorylation and binding site. This led to processive phosphorylation of cd19-y482, which recruited a second lyn molecule, allowing for transphosphorylation and amplification of lyn activation. SIGNOR-80290 0.768 SOSTDC1 protein Q6X4U4 UNIPROT WNT3 protein P56703 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242730 0.281 WNT8A protein Q9H1J5 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131987 0.625 PGAM2 protein P15259 UNIPROT 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity chemical modification 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266515 0.8 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. SIGNOR-181327 0.627 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by destabilization phosphorylation Ser265 PRSSSNAsSVSTRLS 9606 BTO:0001109 28945225 t miannu Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268.  SIGNOR-277325 0.2 GATA3 protein P23771 UNIPROT CD8A protein P01732 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8413295 f miannu Taken together, these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T-cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene. Site-directed mutation of the Ets-1 and GATA-3 sites dramatically reduced enhancer activity. SIGNOR-254079 0.31 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr525 ALRADENyYKAQTHG 9606 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246617 0.2 ATG9A protein Q7Z3C6 UNIPROT YWHAE protein P62258 UNIPROT up-regulates activity binding 9606 25266655 t miannu Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK. SIGNOR-266368 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation 9606 12510059 t inferred from 70% family members gcesareni Insulin also activates jnk, erk, pkc and mtor, which induce the phosphorylation of irs1 on serine residues 307, 612 and 632 and inhibit its functions. Our results indicate that the insulin-stimulated degradation of irs-1 via the phosphatidylinositol 3-kinase pathway is in part dependent upon the ser(312) phosphorylation of irs-1. SIGNOR-269997 0.2 NHP2 protein Q9NX24 UNIPROT TERT protein O14746 UNIPROT up-regulates activity binding 18680434 t lperfetto A complex of four proteins (GAR1, NHP2, NOP10, and the putative pseudouridine synthase dyskerin) associates with snoRNAs to form small nucleolar ribonucleoprotein particles (snoRNPs), and the binding of this complex to the H/ACA domain of TERC may have a role in the biogenesis of the telomerase RNP SIGNOR-263330 0.649 PLK1 protein P53350 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Thr382 PRSINTDtLSKETDS 9606 BTO:0000567 19509060 t lperfetto Here we report that the function of Nedd1 is regulated by Cdk1 and Plk1. During mitosis, Nedd1 is firstly phosphorylated at T550 by Cdk1, which creates a binding site for the polo-box domain of Plk1. Then, Nedd1 is further phosphorylated by Plk1 at four sites: T382, S397, S637 and S426. The sequential phosphorylation of Nedd1 by Cdk1 and Plk1 promotes its interaction with gamma-tubulin for targeting the gammaTuRC to the centrosome and is important for spindle formation. SIGNOR-272993 0.61 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257802 0.8 PLEKHG3 protein A1L390 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260585 0.359 ETF1 protein P62495 UNIPROT Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. SIGNOR-270813 0.972 SARS1 protein P49591 UNIPROT MYC protein P01106 UNIPROT down-regulates activity binding 9606 BTO:0000007 24940000 t Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. SIGNOR-259368 0.2 RBBP8 protein Q99708 UNIPROT SPEN protein Q96T58 UNIPROT down-regulates binding 9606 16287852 t gcesareni We identify the ctip and ctbp corepressors as novel components of the human rbp-jk/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. SIGNOR-141616 0.53 CHUK protein O15111 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR form complex binding 9606 20300203 t gcesareni The kinase(s) responsible for the phosphorylation of the ikb inhibitors remained elusive for many years, until the biochemical purification of a cytoplasmic high-molecular weight complex migrating around 700900 kda and containing two related catalytic subunits, ikkalfa and ikkbeta. SIGNOR-164506 0.778 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM JAK3 protein P52333 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262234 0.8 RXRA protein P19793 UNIPROT PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR up-regulates activity binding 10090 17613434 t irozzo RXR Binding Increases the DNA-Binding Affinity of PML/RARA. Here, we demonstrate that the presence of the RARA heterodimeric partner RXR in the PML/RARA complex is required for leukemogenesis in transgenic mice. RXR greatly facilitates the binding of PML/RARA to DNA, but titration of RXR by PML/RARA could also contribute to transformation. SIGNOR-255804 0.2 TYK2 protein P29597 UNIPROT TYK2 protein P29597 UNIPROT up-regulates activity phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 BTO:0000452 8702790 t lperfetto These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation. SIGNOR-43088 0.2 SRC protein P12931 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000763 14978237 t lperfetto The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation. SIGNOR-235696 0.57 ANO6 protein Q4KMQ2 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 24663380 f francesca Ano6 deficiency significantly reduces ERK/AKT phosphorylation. Our data have also shown that Ano6-KD significantly attenuates ERK phosphorylation, which is implicated in the regulation of cancer cell proliferation by Ano1, suggesting that Ano6 is potentially involved in regulating myoblast proliferation through the ERK signaling pathway. SIGNOR-261214 0.2 APC-c complex SIGNOR-C150 SIGNOR CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 t lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. SIGNOR-265051 0.613 PLK1 protein P53350 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19473992 f lperfetto Plk1-mediated phosphorylation of topors regulates p53 stability. Herein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. SIGNOR-185841 0.588 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser109 KETNRRKsLHPIHQG 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165550 0.645 SKA complex complex SIGNOR-C364 SIGNOR Ndc80 complex complex SIGNOR-C361 SIGNOR up-regulates activity relocalization -1 22483620 t lperfetto The Ska complex is an essential mitotic component required for accurate cell division in human cells. It is composed of three subunits that function together to establish stable kinetochore-microtubule interactions in concert with the Ndc80 network. |We discuss how this symmetric architecture might complement and stabilize the Ndc80-microtubule attachments SIGNOR-265225 0.55 ATAD5 protein Q96QE3 UNIPROT BRD4 protein O60885 UNIPROT up-regulates binding 9606 BTO:0000007 31875566 t miannu ATAD5 Interacts with BRD4 through a Conserved BET Protein-Binding Domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin. SIGNOR-266412 0.354 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Ser2070 DEYNVTPsPPGTVLT 9606 BTO:0000007 12794074 t Ser-2093 is efficiently phosphorylated by GSK-3β and, to a minor extent, residues Thr-2068 and/or Ser-2070 and Thr-2074 of Notch2 are also targets for GSK-3β-dependent phosphorylation. We also find that GSK-3β-dependent phosphorylation of Notch2 is inhibiting transcriptional activation of different Notch target genes. SIGNOR-251254 0.49 PRKACA protein P17612 UNIPROT PIM1 protein P11309 UNIPROT up-regulates activity phosphorylation Ser65 HSHSPRHsLRHSPGS 9606 30017192 t miannu In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia. SIGNOR-256153 0.268 TNFAIP1 protein Q13829 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity binding 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264235 0.354 NFATC3 protein Q12968 UNIPROT GPC6 protein Q9Y625 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 21871017 t miannu NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype. SIGNOR-264024 0.2 MAPK1 protein P28482 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser362 ISSVPTPsPLGPLAG 9606 BTO:0000527 19941816 t lperfetto Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity SIGNOR-161851 0.373 EEF1A1P5 protein Q5VTE0 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269552 0.8 MYOD1 protein P15172 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 10090 7791789 f lperfetto The upregulation of p21 occurred at the levels of mrna and protein, SIGNOR-235831 0.408 CRP protein P02741 UNIPROT GCH1 protein P30793 UNIPROT down-regulates activity 9606 BTO:0004602 17942113 f miannu The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH(4), were significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP-mediated pathway. In the present study, CRP-mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. SIGNOR-252215 0.281 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203576 0.773 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-232153 0.2 NFATC1 protein O95644 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates activity 10358178 f The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms. SIGNOR-252344 0.7 hesperadin chemical CHEBI:70726 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193128 0.8 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA -1 15241418 t llicata Thus, we have shown that Smad3 is phosphorylated by CDK4 and CDK2. Mutation of its CDK phosphorylation sites increases its transcriptional activity and antiproliferative function. | Thr 8 and the four sites in the linker (Thr 178, Ser 203, Ser 207 and Ser 212). Each of the five sites was phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo phosphorylated by both CDK4 and CDK2 in vitro, and only Thr 8, Thr 178 and Ser 212 were phosphorylated by CDK4 and CDK2 in vivo. SIGNOR-250767 0.752 PRKCA protein P17252 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR unknown phosphorylation -1 10366608 t inferred from 70% of family members lperfetto In addition, we identified threonine 830 as a potential PKC phosphorylation site. SIGNOR-269853 0.709 SEC61A2 protein Q9H9S3 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-267728 0.647 SIAH1 protein Q8IUQ4 UNIPROT SNCAIP protein Q9Y6H5 UNIPROT down-regulates ubiquitination 9606 16174773 t lperfetto Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system SIGNOR-140612 0.668 MRPL47 protein Q9HD33 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262349 0.719 CREB1 protein P16220 UNIPROT GDA protein Q9Y2T3 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0000938 BTO:0000142 21715638 t lperfetto In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches. SIGNOR-268968 0.2 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity 9606 BTO:0000150 12167717 f lperfetto PKB induction requires phosphorylation of two critical residues, threonine 308 in the activation loop and serine 473 near the carboxyl terminus. Membrane localization of PKB was found to be a primary determinant of serine 473 phosphorylation. PI3K activity was equally important for promoting phosphorylation of serine 473, SIGNOR-252710 0.788 NTNG2 protein Q96CW9 UNIPROT LRRC4 protein Q9HBW1 UNIPROT up-regulates activity binding 9606 BTO:0000938 19467332 t miannu The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. SIGNOR-264048 0.727 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 9606 10480872 t gcesareni The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation. SIGNOR-70603 0.325 Tiospirone chemical CID:55752 PUBCHEM HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258863 0.8 TFIIA complex SIGNOR-C395 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity relocalization 9606 7724559 t lperfetto The human general transcription factor TFIIA is one of several factors involved in specific transcription by RNA polymerase II SIGNOR-266200 0.656 LE-TGN SNARE complex SIGNOR-C157 SIGNOR M6PR protein P20645 UNIPROT up-regulates activity relocalization 9606 18195106 t lperfetto These findings place the retromer complex upstream of both STX10 function and the GCC185 tethering complex in MPR transport. Together, our data suggest that STX10, STX16, Vti1a, and VAMP3 are important for the trafficking of both CD- and CI-MPRs.|Thus, MPRs must pass through a compartment of pH ≤ 5.5 before returning to the Golgi to carry out their biological function. SIGNOR-253084 0.524 LYN protein P07948 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr52 VQKKPTMyPEWKSTF -1 9692543 t Lyn was found to phosphorylate Lyn-associated and recombinant PKC-delta in vitro and the tyrosine 52 phosphorylated PKC-delta was recruited to associate with the Lyn SH2 domain. SIGNOR-251408 0.545 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274096 0.403 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 BTO:0000007 9724739 t gcesareni MKK4/7, in turn, phosphorylates JNK on residues 183 and 185 (17ƒ‚€“20). Activated JNK phosphorylates its substrates, c-Jun, ATF2, ELK1, and p53 SIGNOR-249654 0.745 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT up-regulates activity deacetylation Lys63 TGGMANVkAAPKIID 9606 BTO:0002806 30327428 t miannu SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR SIGNOR-262293 0.52 UMPS protein P11172 UNIPROT orotate smallmolecule CHEBI:30839 ChEBI down-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267436 0.8 SCN3A protein Q9NY46 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 9606 26043074 f miannu The expression of voltage-gated sodium channels (NaVs) is a key feature for initiation and conduction of action potentials in excitable tissues and cells such as cardiac and skeletal muscle and neurons. SIGNOR-253455 0.7 AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI up-regulates quantity relocalization 9606 25720354 t scontino APCs cell surface receptors facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. It is in these compartments that internalized antigen proteolysis and peptide–MHC class II complex formation takes place. SIGNOR-267862 0.8 CEBPB protein P17676 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12493739 f miannu The C/EBP5 motif, which is located between the TATA-box and the translation start point, is essential for the C/EBP-mediated constitutive and most of the cAMP-stimulated expression as its mutation nearly abolished IL-10 promoter activity. Our results suggest a dominant role of C/EBP transcription factors relative to CREB/ATF in tissue-specific and differentiation-dependent IL-10 transcription SIGNOR-254523 0.361 CCT129202 chemical CID:16202152 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190883 0.8 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191409 0.8 TBX5 protein Q99593 UNIPROT MTSS1 protein O43312 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255254 0.252 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 21779440 t gcesareni The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity SIGNOR-89818 0.672 HOXA10 protein P31260 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000661 21261500 f miannu Overexpression of HOXA9 or HOXA10 in JURKAT cells by lentiviral transduction resulted in decreased expression of MEF2C, indicating repression by these homeodomain proteins. HOXA9/10 inhibits expression of MEF2C via NMYC SIGNOR-254212 0.286 SLIT2 protein O94813 UNIPROT GPC1 protein P35052 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 10364234 t gcesareni Slit family proteins are functional ligands of glypican-1 in nervous tissue and suggest that their interactions may be critical for certain stages of central nervous system histogenesis. SIGNOR-68428 0.593 EML4-ALK fusion protein SIGNOR-FP8 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 21415216 t irozzo We also found that phosphorylation of both the mitogen-activated proteinkinase (MAPK) ERK and STAT3 was markedly increased inthe cells expressing either variant of EML4-ALK[.]. Oncogenic EML4-ALK tyrosine kinase activates ERKand STAT3 signaling pathways SIGNOR-259203 0.2 GSK3B protein P49841 UNIPROT DPYSL5 protein Q9BPU6 UNIPROT up-regulates activity phosphorylation Thr516 TPLADTPtRPVTRHG 9606 BTO:0000938 25040932 t lperfetto The T516 phosphorylation was achieved by the glycogen synthase kinase-3beta (GSK-3beta), which can phosphorylate the wildtype protein but not the non-phosphorylatable mutant. Furthermore, we have shown that T516 phosphorylation is essential for the tubulin-binding property of CRMP5. Therefore, CRMP5-induced growth inhibition is dependent on T516 phosphorylation through the GSK-3beta pathway. SIGNOR-264835 0.416 COPS5 protein Q92905 UNIPROT CD274 protein Q9NZQ7 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0000007 27866850 t Barakat The results suggested that TNF-α upregulates expression of CSN5, which interacts and deubiquitinates PD-L1 for protein stabilization. SIGNOR-274977 0.2 TNFRSF1B protein P20333 UNIPROT TRAF1 protein Q13077 UNIPROT up-regulates 9606 8069916 f gcesareni Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2. SIGNOR-33843 0.714 PLK4 protein O00444 UNIPROT PLK4 protein O00444 UNIPROT up-regulates phosphorylation Ser305 SSTSISGsLFDKRRL 9606 20032307 t llicata Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form. SIGNOR-162559 0.2 RPL22 protein P35268 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262499 0.852 RIPK2 protein O43353 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser435 EMFSGELsWSADSIR 9606 22412986 t lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Phosphorylation of carboxyl serines 451 and 462 appear the primary trigger of irf5 function in nuclear accumulation, transcription, and apoptosis. Rip2 activation of the irf5 aspartic acid substitutions showed a similar positive effect of s451d and s462d function in this assay SIGNOR-196520 0.308 LRRK2 protein Q5S007 UNIPROT SNAPIN protein O95295 UNIPROT down-regulates phosphorylation Thr117 NHSVAKEtARRRAML 9606 BTO:0000938 BTO:0000142 23949442 t lperfetto Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2 SIGNOR-202436 0.524 BKM120 chemical CHEBI:71954 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190392 0.8 WARS1 protein P23381 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270512 0.8 BDKRB2 protein P30411 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256695 0.368 CHD2 protein O14647 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates quantity relocalization 9606 BTO:0001938 26895424 t miannu CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs. SIGNOR-264528 0.2 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser408 GPLPRAPsISTVEPK 26843621 t Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. SIGNOR-253540 0.299 DLK1 protein P80370 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19254573 f fspada Pref-1 inhibits adipocyte differentiation through upregulating sox9 expression. SIGNOR-184277 0.398 ADAM17 protein P78536 UNIPROT HBEGF protein Q99075 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259844 0.582 PRKACA protein P17612 UNIPROT KCNJ3 protein P48549 UNIPROT unknown phosphorylation Ser385 NSKERHNsVECLDGL 9606 19151997 t llicata Using this approach, we identified s385 as an in vitro phosphorylation site. Mutation of this residue to alanine resulted in a reduced sensitivity of kir3.1* currents to h89 and forskolin, confirming an in vivo role for this novel site of the kir3.1 channel subunit in its regulation by pka. SIGNOR-183475 0.332 MRGPRX1 protein Q96LB2 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257433 0.2 ABL1 protein P00519 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation Tyr261 GLVTTLHyPAPKCNK 9606 15735735 t lperfetto The results show that arg is stabilized in response to 0.1 mm h2o2 by autophosphorylation of y-261, consistent with involvement of the arg kinase function in regulating arg levels. The results further demonstrate that c-abl-mediated phosphorylation of arg on y-261 similarly confers arg stabilization SIGNOR-134396 0.504 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-268068 0.8 REN protein P00797 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates quantity cleavage 9606 32201502 t miannu Renin is an aspartic protease that enzymatically cleaves its substrate angiotensinogen, which is produced by the liver, to form an inactive peptide: angiotensin (Ang)I or Ang (1–10). SIGNOR-260225 0.2 PCSK5 protein Q92824 UNIPROT Neurophysin 1 protein P01178-PRO_0000020496 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270336 0.2 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Ser241 SKQARANsFVGTAQY 9606 11481331 t miannu In terms of the modulation of PDK1 activity by reversible phosphorylation, five pS sites have been identified on PDK1 in vivo, but only one of these sites, Ser-241 in the activation loop of PDK1, is essential for activity. It seems likely that PDK1 autophosphorylates itself on this residue. SIGNOR-250268 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-251524 0.2 MC3R protein P41968 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257298 0.251 ATR protein Q13535 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 22735644 t lperfetto  Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.  SIGNOR-267662 0.424 IL6ST protein P40189 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204841 0.668 LATS1 protein O95835 UNIPROT CDC26 protein Q8NHZ8 UNIPROT up-regulates activity phosphorylation Thr7 tRLELKLD 25723520 t lperfetto LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C|Overall, these results suggest that LATS1/2 are novel kinases involved in APC/C phosphorylation and indicate a direct regulatory link between LATS1/2 and APC/C|Here, we demonstrate that LATS1 phosphorylates the Thr7 (T7) residue of the APC/C component CDC26 directly SIGNOR-275472 0.474 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA7 protein Q9Y5G6 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265687 0.2 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR VEPH1 protein Q14D04 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 22055343 f In the neuronal differentiation lperfetto Melted represses warts transcription to disrupt hippo pathway activity and specify rh5 fate wts and melt repress each other s transcription in a double negative, bistable feedback loop that directs robust expression of either rh5 or rh6 in r9 SIGNOR-269959 0.2 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser268 VALPPGAsPQRSRSP 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248519 0.395 tRNA(Trp) smallmolecule CHEBI:29181 ChEBI Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity precursor of 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270515 0.8 CDK2 protein P24941 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180767 0.248 APC-c complex SIGNOR-C150 SIGNOR KIF18A protein Q8NI77 UNIPROT down-regulates quantity by destabilization ubiquitination -1 24510915 t miannu Biochemical studies on the kinesins confirmed KIFC1, KIF18A, KIF2C, and KIF4A as APC/C substrates. Furthermore, we showed that the APC/CCDH1-dependent degradation of KIFC1 regulates the bipolar spindle formation and proper cell division. Our in vitro degradation assays showed a time-dependent degradation for four of the five potential substrates tested: KIF18A, KIF2C, KIFC1 and KIF4A were readily degraded in vitro, however remained stable in the presence of either APC/C inhibitor (Fig​(Fig4A4A and Supplementary Fig S3A). SIGNOR-266110 0.299 SRC protein P12931 UNIPROT ARHGEF4 protein Q9NR80 UNIPROT up-regulates phosphorylation Tyr165 VGSEEDLyDDLHSSS 9606 BTO:0000017 18653540 t llicata This observation strongly argues for the positive role of tyr94 phosphorylation in egf-induced asef activation following the activation of rac1. SIGNOR-179601 0.316 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9009272 t miannu For each mutant GlyR we examined the agonist efficacies of taurine and β-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where β-alanine and taurine exhibited partial or no agonist efficacy, the concentration required for half-maximal inhibition of glycine-gated currents (IC50).experiments described in this report were performed on human α1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and β-alanine act as full agonists of human α1 GlyRs when expressed in this system. SIGNOR-258580 0.8 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr141 EDEAKFPtMNRRGAI 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. a t141d substitution markedly increases basal lipid-independent pkcdelta activity; SIGNOR-185279 0.2 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258722 0.8 TRPC6 protein Q9Y210 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 12032305 t Members of the transient receptor potential channel (TRPC) family have been characterized as molecular substrates mediating receptor-activated cation influx SIGNOR-253339 0.8 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270891 0.472 PCNA protein P12004 UNIPROT DNA polymerase epsilon complex SIGNOR-C377 SIGNOR up-regulates activity binding 9534 BTO:0004055 12930972 t lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). SIGNOR-265512 0.564 GATA1 protein P15976 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0004911 12032775 f The zinc finger transcription factor GATA-1, a central mediator of erythroid gene expression, interacts with multiple proteins including FOG-1, EKLF, SP1, CBP/p300 and PU.1. SIGNOR-259962 0.7 DAGLA protein Q9Y4D2 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI down-regulates quantity chemical modification 9606 26787883 t miannu Diacylglycerol lipases (DAGL√鬱 and DAGL√é¬≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. SIGNOR-264262 0.8 FYN protein P06241 UNIPROT PTPRF protein P10586 UNIPROT up-regulates activity phosphorylation 9534 12496362 t LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site. SIGNOR-251180 0.401 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270414 0.8 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser7 sDSEEEVC -1 8972483 t llicata In vivo phosphorylation of PS-2 was mapped to serine residues 7, 9, and 19 within an acidic stretch at the N terminus, which is absent in PS-1. casein kinase (CK)-1 and CK-2 were shown to phosphorylate the N terminus of PS-2 in vitro.  SIGNOR-250803 0.368 NARS1 protein O43776 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270457 0.8 PRKCB protein P05771 UNIPROT TYR protein P14679 UNIPROT up-regulates phosphorylation Ser523 MEKEDYHsLYQSHL 9606 10347209 t llicata We conclude that pkc-beta activates tyrosinase directly by phosphorylating serine residues at positions 505 and 509 in the cytoplasmic domain of this melanosome-associated protein. our results strongly suggest that direct phosphorylation of tyrosinase by pkc-_ leads to its activation. SIGNOR-67866 0.429 PPARG protein P37231 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 32991581 t brain lperfetto NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog, SIGNOR-263984 0.901 RPL27 protein P61353 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262474 0.846 FOS protein P01100 UNIPROT STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19022561 t miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254878 0.261 PDZD8 protein Q8NEN9 UNIPROT MSN/PDZD8 complex SIGNOR-C61 SIGNOR form complex binding 9606 21549406 t miannu These results demonstrated that both human moesin and its newly identified binding partner, pdzd8 had similar effects on host mt networks, suggesting that they are likely to function as part of a stable mt regulatory complex. SIGNOR-173650 0.322 p38 proteinfamily SIGNOR-PF16 SIGNOR KRT8 protein P05787 UNIPROT up-regulates phosphorylation 9606 11788583 t inferred from 70% family members lperfetto Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis. SIGNOR-270125 0.2 7-(dipropylamino)-5,6,7,8-tetrahydronaphthalen-2-ol chemical CHEBI:111176 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258724 0.8 SALL4 protein Q9UJQ4 UNIPROT SALL1 protein Q9NSC2 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19440552 f miannu Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. SIGNOR-255127 0.441 IFNG protein P01579 UNIPROT LPL protein P06858 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000801 2114181 f Regulation miannu Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. The data indicate that IFN-gamma is inhibiting macrophage LPL at least in part via a reduction of LPL synthesis SIGNOR-251848 0.361 PGK1 protein P00558 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Phosphoglycerate kinase generates one molecule of ATP by catalyzing the reversible conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate. Two isozymes of PGK exist: PGK-1, ubiquitously expressed in all somatic cells, and PGK-2, expressed only in spermatozoa. SIGNOR-266502 0.8 MAPK1 protein P28482 UNIPROT DYNC1LI1 protein Q9Y6G9 UNIPROT unknown phosphorylation Ser516 VSPTTPTsPTEGEAS 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262773 0.255 FOXA1 protein P55317 UNIPROT SFTPB protein P07988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 18003659 f miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. Repression is mediated by SMAD3 through interactions with NKX2.1 and FOXA1, two key transcription factors that are positive regulators of SpB transcription. SIGNOR-254171 0.286 GUCY1A2-B2 complex SIGNOR-C137 SIGNOR IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization ubiquitination phosphorylation:Thr197 GTFKMVFtPKDGSGV 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267624 0.2 ROCK1 protein Q13464 UNIPROT RDX protein P35241 UNIPROT up-regulates activity phosphorylation Thr564 AGRDKYKtLRQIRQG 10090 BTO:0005065 9456324 t lperfetto  A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kc€“phosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active. SIGNOR-248994 0.672 WWTR1 protein Q9GZV5 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 22153608 t Runx family members play key roles in regulating mesenchymal stem cell differentiation during bone formation, and therefore the regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation. gcesareni Taz binding to the transcription factor runx2 promotes osteoblast lineage specification, whereas taz binding to the transcription factor ppargamma inhibits adipogenesis. SIGNOR-195218 0.516 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264166 0.822 M1_polarization phenotype SIGNOR-PH54 SIGNOR TNF protein P01375 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263826 0.7 PLK1 protein P53350 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity phosphorylation Ser1618 LTKAADIsLDNLVEG -1 24703952 t lperfetto Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |Addition of the inhibitors for PLK1 and the p38 MAPK leads to a complete loss of pT1609/pS1618 signal within 3 hr in mitotic cells SIGNOR-264413 0.608 PPP1CB protein P62140 UNIPROT CASP2 protein P42575 UNIPROT up-regulates activity dephosphorylation Ser164 STDTVEHsLDNKDGP -1 19531356 t llicata Nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2. SIGNOR-248576 0.2 RORA protein P35398 UNIPROT SLC1A6 protein P48664 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001011 19381306 t miannu RORα regulates the expression of several genes in Purkinje cells. RORα becomes highly expressed in postmitotic Purkinje cells. It regulates their maturation, particularly dendritic differentiation. Dendritogenesis and the expression of several genes, including Shh, Itpr1, Pcp4, Calb1, Pcp2, and Slc1a6, normally expressed in mature Purkinje cells, are inhibited in RORα-deficient mice. SIGNOR-266850 0.253 MRPS15 protein P82914 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261455 0.735 PLK1 protein P53350 UNIPROT WDCP protein Q9H6R7 UNIPROT up-regulates activity phosphorylation Ser695 SHSPGAVsSLKVFTG 9606 BTO:0000007 30297404 t miannu PLK1 Phosphorylates MMAP to Promote Its Interaction with KIF2A and MRE11. we performed in vitro kinase assays followed by mass spectrometry and found that two sites (S686 and S695) in this cluster were phosphorylated. Thus, all of these results are in agreement that this cluster is phosphorylated by PLK1. SIGNOR-273731 0.2 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser520 RLQTICMsGTGMRSV 9606 20448038 t lperfetto Overexpression of pp2a catalytic subunit (pp2ac) beta-isoform results in dephosphorylation of mekk3 at thr-516 and ser-520 and termination of mekk3-mediated nf-kappab activation. SIGNOR-165229 0.376 AKT proteinfamily SIGNOR-PF24 SIGNOR TP53RK protein Q96S44 UNIPROT up-regulates phosphorylation Ser250 RLRGRKRsMVG 9606 17712528 t gcesareni Here we show that such an activation of prpk is mediated by another kinase, akt/pkb, which phosphorylates prpk at ser250. SIGNOR-157467 0.2 crizotinib chemical CHEBI:64310 ChEBI MET protein P08581 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258102 0.8 CENPS protein Q8N2Z9 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265205 0.2 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000938 17591690 t llicata We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active SIGNOR-156426 0.726 GSK3B protein P49841 UNIPROT OGT protein O15294 UNIPROT up-regulates activity phosphorylation Ser3 sSVGNVAD 10090 BTO:0000142 23395175 t miannu We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. SIGNOR-276482 0.507 XBP1 protein P17861 UNIPROT NPPB protein P16860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20170659 f miannu The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. SIGNOR-255609 0.2 BAG4 protein O95429 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity binding 10090 BTO:0000801 12748303 t gcesareni It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation SIGNOR-245022 0.638 IRF9 protein Q00978 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR form complex binding -1 8943351 t 2 miannu The first STAT-containing transcription factor to be studied, the alpha-interferon-induced ISGF3, is composed of a Stat1:2 heterodimer and a weak DNA-binding protein, p48. The p48 and Stat1:2 heterodimer do not associate stably in the absence of DNA, but we show that amino acids approximately 150 to 250 of Stat1 and a COOH-terminal portion of p48 exhibit physical interaction, implying contact that stabilizes ISGF3 SIGNOR-240600 0.866 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1004 SEHDSDEsSDDDSDS 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251029 0.441 SEMA3A protein Q14563 UNIPROT PLXNA1 protein Q9UIW2 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.  SIGNOR-261813 0.766 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201294 0.812 BKM120 chemical CHEBI:71954 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190383 0.8 USF1 protein P22415 UNIPROT FOSL1 protein P15407 UNIPROT down-regulates activity binding 10090 9160889 t 2 miannu USF specifically interacts with Fra1. USF was repressing this modest Fra1 transactivation SIGNOR-240975 0.474 DHCR24 protein Q15392 UNIPROT DHCR7 protein Q9UBM7 UNIPROT up-regulates activity binding 10029 BTO:0000246 25637936 t miannu DHCR7 coimmunoprecipitates DHCR24. Overexpression of functional DHCR24 increases DHCR7 activity. Because knockdown of DHCR24 has no effect on DHCR7 mRNA (Fig. 3A), this implies that this phenomenon is occurring posttranscriptionally. Thus, the interaction between the two terminal steps of cholesterol synthesis appears to have functional consequences. SIGNOR-267249 0.645 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258774 0.8 JUN protein P05412 UNIPROT CYP19A1 protein P11511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254876 0.348 SRC protein P12931 UNIPROT PIP5K1C protein O60331 UNIPROT up-regulates phosphorylation Tyr649 TDERSWVySPLHYSA 9606 15738269 t lperfetto Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation. SIGNOR-134459 0.288 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 18936167 t gcesareni The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2. SIGNOR-181672 0.692 PHA-680632 chemical CID:11249084 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206100 0.8 ATM protein Q13315 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 9606 16874298 t lperfetto The artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced dna double-strand breaks (dsbs) in an atm and dna-pk dependent process. Here, we show that artemis phosphorylation by atm and dna-pk in vitro is primarily attributable to s503, s516 and s645 and demonstrate atm dependent phosphorylation at serine 645 in vivo SIGNOR-148319 0.61 SQSTM1 protein Q13501 UNIPROT WDFY3 protein Q8IZQ1 UNIPROT up-regulates quantity binding 9606 BTO:0000452 20168092 t miannu  We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions.  SIGNOR-266792 0.574 Cyclopamine chemical CHEBI:4021 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191227 0.8 MARK1 protein Q9P0L2 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 21215781 t The effect has been demonstrated using P10636-8 lperfetto Mark and pka phosphorylate several sites within the repeats (notably the kxgs motifs including ser262, ser324, and ser356, plus ser320)tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process SIGNOR-171050 0.436 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization binding 9606 24239470 t miannu Mutations in SPOP represent the most common point mutations in primary prostate cancer,with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts. Wild-type SPOP will bind and promote the degradation of SRC-3,whereas prostate cancer–derived SPOP mutants lose this ability,leading to increased androgen signaling in certain model systems. SIGNOR-251529 0.488 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 23450633 f gcesareni Ga12/13 recruitment of rho-gefs causes rhoa activation and f-actin assembly, which promotes lats1/lat2 inactivation by an unknown, but myosin-independent mechanism. SIGNOR-192783 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser213 DNMIRRLsPAERAQG 10090 BTO:0000944 15060146 t miannu Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). SIGNOR-260084 0.2 CDC42 protein P60953 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248243 0.941 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT down-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 452646 11551945 t miannu MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription SIGNOR-250146 0.602 SMARCD3 protein Q6STE5 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270705 0.754 PRKCA protein P17252 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser187 DLGERKPsSAAYQKA -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248973 0.375 CDK5 protein Q00535 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Thr135 TVQQHPStPKRHTVL 9606 BTO:0000007 21209322 t lperfetto High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155. SIGNOR-170886 0.2 CDKAL1 protein Q5VV42 UNIPROT tRNA(Lys) smallmolecule CHEBI:29185 ChEBI up-regulates quantity chemical modification 9606 21841312 t We show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in tRNA(Lys)(UUU) and that it is required for the accurate translation of AAA and AAG codons SIGNOR-272474 0.8 MAPK1 protein P28482 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 t gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. SIGNOR-172877 0.43 TRHR protein P34981 UNIPROT GNA11 protein P29992 UNIPROT up-regulates activity binding 9606 BTO:0001379 27515033 t scontino Binding of TRH to TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. SIGNOR-267201 0.471 MAPK1 protein P28482 UNIPROT UBTF protein P17480 UNIPROT down-regulates phosphorylation Thr201 DIPEKPKtPQQLWYT 9606 11741541 t lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-112809 0.399 mTORC1 complex SIGNOR-C3 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates 9606 20670887 f gcesareni Hif1alfa is the transcription factor downstream of mtorc1 in the control of glycolytic genes. SIGNOR-167187 0.366 PPARA protein Q07869 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 16556735 t miannu We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression. SIGNOR-268024 0.586 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI up-regulates quantity precursor of 9606 25406093 t lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. SIGNOR-268565 0.8 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 BTO:0001271 7637391 t gcesareni Op18 is multisite phosphorylated on four ser residues during mitosis;two of these ser residues, ser-25 and ser-38, are targets for cyclin-dependent protein kinases. our findings suggest that stathmin phosphorylation in reh6 cells could be in part mediated by pkc activation. SIGNOR-30357 0.2 solifenacin chemical CHEBI:135530 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition -1 21524581 t Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference SIGNOR-258311 0.8 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser421 IACEEEFsDSEEEGE 9606 11602581 t gcesareni Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1. SIGNOR-111011 0.614 DYNLL1 protein P63167 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 t gcesareni The beclin 1vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1interacting protein ambra1 and dynein light chains 1/2. SIGNOR-168255 0.538 DDB1 protein Q16531 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 BTO:0000567 9418871 t miannu We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription SIGNOR-54096 0.356 LAMTOR5 protein O43504 UNIPROT S100A4 protein P26447 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 22740693 f miannu It suggests that HBXIP is able to activate S100A4 promoter via interacting with STAT4 in breast cancer cells, leading to the up-regulation of S100A4. SIGNOR-255248 0.368 SLBP protein Q14493 UNIPROT H4C1 protein P62805 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265376 0.2 CDK5 protein Q00535 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates phosphorylation Ser13 ARKNAQPsPARAPAE 9606 BTO:0001271 21145489 t llicata We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase SIGNOR-170357 0.362 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204847 0.754 SOX9 protein P48436 UNIPROT COL9A2 protein Q14055 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. SIGNOR-251757 0.36 ETS1 protein P14921 UNIPROT VWF protein P04275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9444957 f miannu Cotransfection of Ets-1 and Erg expression plasmids is sufficient to induce the -60/+19 vWF promoter activity in HeLa cells. SIGNOR-253915 0.297 EIF2AK3 protein Q9NZJ5 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 31226023 t miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation. SIGNOR-260165 0.761 sorafenib tosylate chemical CHEBI:50928 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259221 0.8 MUL1 protein Q969V5 UNIPROT AKT1 protein P31749 UNIPROT down-regulates quantity by destabilization ubiquitination Lys284 LENLMLDkDGHIKIT 9606 BTO:0000007 22410793 t gcesareni The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability. SIGNOR-252437 0.483 BRAP protein Q7Z569 UNIPROT BRAP protein Q7Z569 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 23105109 t miannu Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. SIGNOR-272027 0.2 FLT3 protein P36888 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity 10090 14981546 f These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261521 0.295 LSM8 protein O95777 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270626 0.826 PHF2 protein O75151 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. SIGNOR-264518 0.2 PTPN11 protein Q06124 UNIPROT CDC73 protein Q6P1J9 UNIPROT up-regulates activity dephosphorylation 9606 21726809 t miannu We found in this work that SHP2 dephosphorylates parafibromin and Cdc73, a component of the nuclear RNA polymerase II associated factor (PAF) complex, which can function as a tumor suppressor or oncoprotein in a context dependent manner. SIGNOR-277036 0.503 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257957 0.8 HASPIN protein Q8TF76 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Thr3 T-->R 9606 20705812 t miannu Here we show that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is necessary for CPC accumulation at centromeres and that the CPC subunit Survivin binds directly to H3T3ph. SIGNOR-275418 0.2 DDX3X protein O00571 UNIPROT EIF4E protein P06730 UNIPROT down-regulates activity binding 9606 BTO:0001950 17667941 t miannu DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G. SIGNOR-269200 0.641 HOXA9 protein P31269 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25252870 f miannu Hoxa9bound directly to the putative promoter and a dnase-hypersensitive region in the first intron of the igf1 gene. Transcription rates of the igf1 gene paralleledhoxa9activity SIGNOR-205308 0.2 CDH6 protein P55285 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265868 0.567 PIGS protein Q96S52 UNIPROT PIGK protein Q92643 UNIPROT up-regulates activity binding 10090 BTO:0000095 11483512 t miannu To determine roles for PIG-S and PIG-T, we disrupted these genes in mouse F9 cells by homologous recombination. PIG-S and PIG-T knockout cells were defective in transfer of GPI to proteins, particularly in formation of the carbonyl intermediates. We also demonstrate that PIG-S and PIG-T form a protein complex with GAA1 and GPI8, and that PIG-T maintains the complex by stabilizing the expression of GAA1 and GPI8. SIGNOR-261362 0.942 MDN1 protein Q9NU22 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 27814492 t miannu MDN1 Is Physically and Functionally Associated with the Mammalian PELP1 Complex. To more specifically determine a function of mammalian MDN1 in the subnuclear distribution of PELP1-containing pre-60S-particles, we examined PELP1 localization in control cells or cells depleted from MDN1. Importantly, in the absence of MDN1, PELP1 became sequestered in enlarged nucleoli, indicating that MDN1 is involved in the nucleolar release of PELP1-containing pre-60S ribosomes SIGNOR-261357 0.382 1038915-60-4 chemical CID:24958200 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194399 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR ADRB2 protein P07550 UNIPROT down-regulates phosphorylation Ser345 ELLCLRRsSLKAYGN 9606 11809767 t lperfetto Akt mediates sequestration of the beta(2)-adrenergic receptor in response to insulin. Phosphorylation studies of the c-terminal cytoplasmic domain of the beta(2)-adrenergic receptor by akt in vitro identified ser(345) and ser(346) within a consensus motif for akt phosphorylation. SIGNOR-114466 0.2 PRKACA protein P17612 UNIPROT NFATC1 protein O95644 UNIPROT down-regulates phosphorylation Ser294 PHGSPRVsVTDDSWL 9606 12351631 t lperfetto Here we show that overexpression of pka causes phosphorylation and cytoplasmic accumulation of nf-atc1 in direct opposition to calcineurin by phosphorylating ser-245, ser-269, and ser-294 in the conserved serine-proline repeat domainwe further show that a complete block of nf-atc1 nuclear localization by pka requires a second kinase activity that can be supplied by glycogen synthase kinase-3 (gsk-3) SIGNOR-93539 0.368 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk SIGNOR-64172 0.625 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 9606 12493777 t lperfetto We found that ndr1 autophosphorylates in vitro predominantly on ser-281 and to a lesser extent on thr-74 and thr-444. All of these residues proved to be crucial also for ndr1 activity in vivo SIGNOR-96683 0.2 STAT3 protein P40763 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 11426647 f Constitutive activation of Stat3 signaling is accompanied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms. SIGNOR-252090 0.7 SMARCC1 protein Q92922 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270736 0.816 FOXP3 protein Q9BZS1 UNIPROT CCL5 protein P13501 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 38339310 t miannu Given its role as a potent chemoattractant for T cells, CCL5 can be utilized to attract Tregs to malignant epithelial cells. Wang et al. demonstrated that Forkheadbox protein 3 (FOXP3), a key transcription factor for Tregs, was highly ex- pressed in pancreatic cancer cell lines, which, in turn, upregulated CCL5 expression SIGNOR-277727 0.443 PRKD1 protein Q15139 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 19329994 t lperfetto PKD1 regulates cofilin S3-phosphorylation|Both, oxidative stress as well as RhoA activation enhanced cofilin phosphorylation at S3, implicating an increased inhibition due to PKD1-mediated signalling events SIGNOR-275944 0.339 Caspase 1 complex complex SIGNOR-C220 SIGNOR GSDMD protein P57764 UNIPROT up-regulates activity cleavage Asp275 CLHNFLTdGVPAEGA 9606 BTO:0000007 26375003 t lperfetto Co-expression of GSDMD with caspase-1, 4, 5 or 11 but not apoptotic caspases (caspase-2, 8 and 9) in 293T cells induced the same cleavage of GSDMD|inflammatory caspases specifically cleave GSDMD after the 272FLTD275 (or 273LLSD276) sequence | SIGNOR-256415 0.638 STAT1 protein P42224 UNIPROT TAP1 protein Q03518 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15778351 f miannu We also show that this cytokine-dependent expression of TAP1 transcripts depends on STAT1 and IFN regulatory factor-2 (IRF-2), but not on IRF-1, and provide evidence that IRF-2 constitutively binds to the TAP1 gene promoter and enhances TAP1 promoter activity. We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. SIGNOR-254531 0.276 PTPN12 protein Q05209 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 10090 18482983 t we identify SHP-2 and PTP-PEST as negative regulators of c-Src kinase | Inactivation of catalytically active c-Src kinase by the phosphatases SHP-2 or PTP-PEST by dephosphorylation of the tyrosine residue Tyr-416 within the c-Src kinase domain prevents the phosphorylation of villin SIGNOR-248659 0.544 CYCS protein P99999 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cytochrome c and datp, an event that leads to caspase-9 activation. SIGNOR-53585 0.878 HTR2C protein P28335 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257129 0.254 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates activity transcriptional regulation 9606 12244043 f areggio Taken together, these results suggest that myostatin inhibits MyoD activity and expression via Smad 3 resulting in the failure of the myoblasts to differentiate into myotubes SIGNOR-254987 0.63 CSNK2A1 protein P68400 UNIPROT PTGES3 protein Q15185 UNIPROT up-regulates phosphorylation Ser118 DDSDEDMsNFDRFSE 9606 15040786 t gcesareni Cpges-activating protein kinase is ck-ii (casein kinase ii). Mutations of either of two predicted ck-ii phosphorylation sites on cpges (ser113 and ser118) abrogated its phosphorylation and activation both in vitro and in vivo. Hypoxia induced the mitogen-activated protein kinase-mediated phosphorylation of a single serine residue, ser(122), in the protein, and site-directed mutagenesis demonstrated that ser(122) phosphorylation was necessary for hypoxic acceleration of tal1 turnover. SIGNOR-123598 0.358 UGP2 protein Q16851 UNIPROT UTP(4-) smallmolecule CHEBI:46398 ChEBI down-regulates quantity chemical modification 9606 8631325 t miannu UDP-Glc pyrophosphorylase (EC 2.7.7.9) catalyses the interconversion of MgUTP plus Glc1P and UDP-Glc plus MgPPi. SIGNOR-267927 0.8 MAPK1 protein P28482 UNIPROT TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000567 21617040 t gcesareni Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation ( SIGNOR-248279 0.421 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr732 CSSAQAQyDTPKAGK -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273947 0.354 CASP3 protein P42574 UNIPROT Caspase 3 complex complex SIGNOR-C221 SIGNOR form complex binding cleavage:Asp28 IHGSESMdSGISLDN 15115390 t lperfetto Caspases are expressed as inactive proenzymes of 30−50 kDa that include an amino-terminal domain of variable length and sequence that is followed by two domains of conserved sequences:  a large subunit (approximately 20 kDa, designated p17 in caspase-3) and a small carboxy-terminal subunit (approximately 10 kDa, designated p12 in caspase-3). Activation is accomplished by proteolytic cleavage between these domains and subsequent assembly of heterotetramers that contain two copies each of the large and small subunits but lack the amino-terminal domains. SIGNOR-256387 0.2 SOD1 protein P00441 UNIPROT DERL1 protein Q9BUN8 UNIPROT down-regulates activity binding 9606 BTO:0000007 18519638 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) Various proteins involved in ERAD have been identified recently (Meusser et al. 2005). Among them, components of the retro-translocation machinery including ATPase p97, its cofactors Ufd1 and Npl4, and the ER membrane proteins Derlin-1 and VIMP are of key importance to ERAD function |Here we show that SOD1(mut) specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD. SIGNOR-262785 0.446 paracetamol chemical CHEBI:46195 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000876 17884974 t Luana Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man SIGNOR-257757 0.8 LZTR1 protein Q8N653 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity ubiquitination Lys170 IRQYRLKkISKEEKT 9606 BTO:0000007 30442762 t Gianni By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. SIGNOR-269068 0.252 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-137955 0.2 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu59 HLERECMeETCSYEE -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263668 0.605 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000142 20654717 f gcesareni This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1. SIGNOR-167073 0.744 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 16508002 t gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. SIGNOR-144827 0.635 PSMD11 protein O00231 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263351 0.901 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity binding 9606 20663871 t lperfetto The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-_ (TGF-_) family signaling. I-Smads inhibit TGF-_ family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. SIGNOR-167163 0.784 26S Proteasome complex SIGNOR-C307 SIGNOR Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 9606 29636472 f lperfetto The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all known eukaryotic cells.  SIGNOR-263375 0.7 NTRK2 protein Q16620 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 12074588 t gcesareni We identified the nck2 adaptor protein as a novel interaction partner of the active form of trkb. Additionally, we identified three tyrosines in icd-trkb (y694, y695, and y771) that are crucial for this interaction. SIGNOR-89764 0.339 CDK2 protein P24941 UNIPROT CDK7 protein P50613 UNIPROT unknown phosphorylation Ser164 GLAKSFGsPNRAYTH 9606 11113184 t amattioni Cdk2 phosphorylates serine-164 in the cdk7 t loop. SIGNOR-84832 0.559 DNM2 protein P50570 UNIPROT GJB2 protein P29033 UNIPROT down-regulates binding 9606 25263585 t miannu This study identifies dynamin 2 (dyn2) as a cx26 interactor in yeast and mammalian cells / we demonstrate that dyn2 regulates cx26 endocytosis and ubiquitination SIGNOR-205372 0.333 SRC protein P12931 UNIPROT CEACAM1 protein P13688 UNIPROT up-regulates activity phosphorylation Tyr520 LTATEIIySEVKKQ 9606 BTO:0000007 9867848 t lperfetto Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515 SIGNOR-246475 0.432 RTKs proteinfamily SIGNOR-PF38 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 17306385 t miannu Another phospholipid modifying signaling pathway activated by RTKs is the PI3K pathway. This heterodimeric enzyme comprises two subunits, the p85 regulatory subunit harboring two SH2 domains, and the p110 catalytic subunit. PI3K activation may be achieved by binding of its p85 regulatory subunit to an activated receptor. Alternatively, RTK signaling may activate the small G protein Ras, which in turn recruits PI3K to the plasma membrane and induces a stimulatory conformational change in the lipid kinase SIGNOR-256166 0.2 ITCH protein Q96J02 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 12226085 t miannu In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.  SIGNOR-272604 0.474 LATS1 protein O95835 UNIPROT AMOT protein Q4VCS5 UNIPROT up-regulates quantity by stabilization phosphorylation Ser175 QGHVRSLsERLMQMS 24101513 t lperfetto Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130 SIGNOR-275843 0.533 IRAK4 protein Q9NWZ3 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276126 0.649 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Ser477 NSMNKLPsVSQLINP 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180747 0.409 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 16115609 t The microsomal heme oxygenase system consists of heme oxygenase (HO) and NADPH-cytochrome P450 reductase, and plays a key role in the physiological catabolism of heme which yields biliverdin, carbon monoxide, and iron as the final products. Heme degradation proceeds essentially as a series of autocatalytic oxidation reactions involving heme bound to HO SIGNOR-259333 0.8 CENPL protein Q8N0S6 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265199 0.658 MTOR protein P42345 UNIPROT ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 SIGNOR-C3 23508953 t llicata Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein. SIGNOR-201595 0.2 trichostatin A chemical CHEBI:46024 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258015 0.8 PAK6 protein Q9NQU5 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263021 0.2 Galanin smallmolecule CHEBI:80161 ChEBI GALR2 protein O43603 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257495 0.8 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t Epiregulin may be a mediator of localized cell proliferation gcesareni Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling. SIGNOR-165782 0.89 NEK1 protein Q96PY6 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation Ser168 RCLQVVRsLVKPENY 9606 BTO:0000007 23255108 t miannu Nek1 phosphorylates Von Hippel-Lindau tumor suppressor to promote its proteasomal degradation and ciliary destabilization. Mutation of pVHL at S-168 increases protein stability. SIGNOR-276434 0.259 ATP smallmolecule CHEBI:15422 ChEBI P2RX7 protein Q99572 UNIPROT up-regulates chemical activation 9606 18827222 t mrosina Pericellular ATP activates P2XRs on the T cell in an autocrine fashion (step 4) and perhaps also P2X7 receptors on the APC in a paracrine fashion resulting in IL-1beta processing and release (step 5). SIGNOR-254965 0.8 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Thr501 QMDSGYNtQNCGSNI 9606 18521620 t gcesareni Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp). SIGNOR-178807 0.784 CILK1 protein Q9UPZ9 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 22356909 t lperfetto Our findings demonstrate an important role for ick in modulating the activity of mtorc1 through phosphorylation of raptor thr-908 and thus implicate a potential signaling mechanism by which ick regulates cell proliferation and division. SIGNOR-217562 0.2 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation 9606 22094256 t tpavlidou We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1, thereby maintain expression of g1/s phase genes, suppress the levels of reactive oxygen species (ros), and protect cancer cells from senescence. SIGNOR-177266 0.615 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192461 0.8 PPP2CA protein P67775 UNIPROT ELF1 protein P32519 UNIPROT down-regulates activity dephosphorylation Thr231 CPKYIKWtQREKGIF 9606 18714041 t Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response SIGNOR-248634 0.2 AURKB protein Q96GD4 UNIPROT DSN1 protein Q9H410 UNIPROT down-regulates phosphorylation Ser100 RQSWRRAsMKETNRR 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165546 0.645 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-176748 0.8 PRKACA protein P17612 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity phosphorylation Ser1700 VNSDRRDsLQQTNTT -1 19074150 t miannu We recently demonstrated that PKA activation led to increased alpha(1D) Ca(2+) channel activity in tsA201 cells by phosphorylation of the channel protein. Western blotting showed that the N terminus and C terminus were phosphorylated. Serines 1743 and 1816, two PKA consensus sites, were phosphorylated by PKA and identified by mass spectrometry. SIGNOR-263108 0.382 MEN1 protein O00255 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates binding 9606 12874027 t miannu Menin interacts with fancd2 / loss of menin expression in mouse embryonic fibroblasts leads to increased sensitivity to dna damage. Furthermore, menin is localized to chromatin and nuclear matrix, and the association with nuclear matrix is enhanced by gamma-irradiation. Together, these results suggest that menin plays a critical role in repair of dna damage in concert with fancd2. SIGNOR-103947 0.448 PAMPs stimulus SIGNOR-ST11 SIGNOR COLEC11 protein Q9BWP8 UNIPROT up-regulates activity binding -1 20956340 t lperfetto We finally show that CL-11 binds to intact bacteria, fungi, and viruses and that CL-11 decreases influenza A virus infectivity and forms complexes with DNA|it is conceivable that CL-11 plays a role in activation of the complement system and in the defense against invading microorganisms. SIGNOR-263408 0.7 GARS1 protein P41250 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270804 0.8 tiagabine chemical CHEBI:9586 ChEBI SLC6A1 protein P30531 UNIPROT down-regulates activity chemical inhibition -1 7851497 t miannu Recently, a number of lipophilic GABA transport inhibitors have been designed and synthesized, which are capable of crossing the blood brain barrier, and which display anticonvulsive activity. We have now determined the potency of four of these compounds, SK&F 89976-A (N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid), tiagabine ((R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidencarboxylic acid), CI-966 ([1-[2-[bis 4-(trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid), and NNC-711 (1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride), at each of the four cloned GABA transporters, and find them to be highly selective for GAT-1. SIGNOR-258477 0.8 DGC complex SIGNOR-C217 SIGNOR GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR up-regulates quantity binding 9606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265441 0.2 PAX7/MLL2 complex complex SIGNOR-C91 SIGNOR MYF5 protein P13349 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 f miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198641 0.502 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr576 NSCRSSTtTCPEQDF 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249300 0.44 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI -1 7782287 t gcesareni Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase. SIGNOR-33141 0.672 DDX23 protein Q9BUQ8 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270646 0.721 PLEKHG4B protein Q96PX9 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260565 0.287 PLK1 protein P53350 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 24413556 t miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. SIGNOR-275421 0.2 MRPS9 protein P82933 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261438 0.773 CHEK2 protein O96017 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser988 PPLFPIKsFVKTKCK 9606 BTO:0000150 14701743 t gcesareni In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites. SIGNOR-120575 0.783 HIF1A protein Q16665 UNIPROT FAM162A protein Q96A26 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15082785 t Giulio In this work, we report the identification of an HIF-1 alpha-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1 alpha through a hypoxia-responsive element on the HGTD-P promoter region. SIGNOR-260292 0.285 SNX9 protein Q9Y5X1 UNIPROT EGFR protein P00533 UNIPROT down-regulates 9606 11799118 f gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor.The cdc42 target ack2 interacts with sorting nexin 9 (sh3px1) to regulate epidermal growth factor receptor degradation. SIGNOR-114167 0.563 TUBGCP4 protein Q9UGJ1 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR form complex binding -1 31862189 t lperfetto Here, we present a cryo-EM reconstruction of the native human gamma-TuRC at 3.8A resolution, revealing an asymmetric, cone-shaped structure. Pseudo-atomic models indicate that GCP4, GCP5, and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes distal to the gamma-TuRC “seam.” SIGNOR-262328 0.816 F2R protein P25116 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257219 0.571 CACNA1A protein O00555 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264323 0.8 SP1 protein P08047 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 f miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. SIGNOR-254812 0.2 MAPK8 protein P45983 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates phosphorylation Ser226 IDENCLLsPLAGEDD 9606 12351702 t gcesareni Taken together, these findings suggest that jnk-mediated phosphorylation of the gr-ser226 enhances gr nuclear export and may contribute to termination of gr-mediated transcription. SIGNOR-93558 0.629 TSC2 protein P49815 UNIPROT TSC complex SIGNOR-C101 SIGNOR form complex binding 9606 12172553 t lperfetto TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). SIGNOR-217913 0.934 AMPK complex SIGNOR-C15 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSSN 10116 11069105 t AMPK phosphorylates and activates heart PFK-2 in vitro and in intact cells. AMPK-mediated PFK-2 activation is likely to be involved in the stimulation of heart glycolysis during ischaemia. SIGNOR-260011 0.397 SRC protein P12931 UNIPROT CAV1 protein Q03135 UNIPROT down-regulates activity phosphorylation Tyr14 VDSEGHLyTVPIREQ 9606 12921535 t lperfetto Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn SIGNOR-118007 0.76 Neuropeptide W-30 smallmolecule CHEBI:80256 ChEBI NPBWR1 protein P48145 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257548 0.8 progesterone smallmolecule CHEBI:17026 ChEBI CACNA2D3 protein Q8IZS8 UNIPROT up-regulates quantity 9606 31746409 f miannu In vivo and in vitro, the addition of P4 upregulated the expression of CACNA2D3 and silencing of CACNA2D3 impaired the function of P4 on cell apoptosis and proliferation. SIGNOR-266856 0.8 sertindole chemical CHEBI:9122 ChEBI HTR1B protein P28222 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258545 0.8 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser759 KTPDGNKsPAPKPSD 9606 BTO:0001260 10514499 t lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-71041 0.467 SRP54 protein P61011 UNIPROT SRPRB protein Q9Y5M8 UNIPROT up-regulates activity binding -1 30649417 t miannu The multi-domain SRP GTPase SRP54 recognizes the signal with its M domain and establishes the targeting complex consisting of its NG domain bound to the homologous NG domain of the SRP receptor SRα at a proximal ribosome binding site. SIGNOR-261165 0.815 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276133 0.761 IL6ST protein P40189 UNIPROT IL6ST protein P40189 UNIPROT up-regulates activity phosphorylation Ser661 NVPDPSKsHIAQWSP -1 8511589 t lperfetto The biological functions of interleukin-6 (IL-6) are mediated through a signal-transducing component of the IL-6 receptor, gp130, which is associated with the ligand-occupied IL-6 receptor (IL-6R) protein. Binding of IL-6 to IL-6R induced disulfide-linked homodimerization of gp130. Tyrosine kinase activity was associated with dimerized but not monomeric gp130 protein. Substitution of serine for proline residues 656 and 658 in the cytoplasmic motif abolished tyrosine kinase activation and cellular responses but not homodimerization of gp130. SIGNOR-238625 0.2 Raltegravir chemical CID:54671008 PUBCHEM UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258162 0.8 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 t lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5 SIGNOR-167564 0.2 NOS1 protein P29475 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255996 0.366 CDH10 protein Q9Y6N8 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265850 0.575 GATA3 protein P23771 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 11021798 f fspada Constitutive gata-2 and gata-3 expression suppressed adipocyte differentiation and trapped cells at the preadipocyte stage. SIGNOR-78830 0.7 AHCYL1 protein O43865 UNIPROT PAPOLB protein Q9NRJ5 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268331 0.2 MC3R protein P41968 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257026 0.251 UBQLN2 protein Q9UHD9 UNIPROT Unfolded_Proteins stimulus SIGNOR-ST22 SIGNOR down-regulates 10090 27477512 f lperfetto UBQLN2 recognizes client-bound HSP70 and links it to the proteasome to allow for the degradation of aggregated and misfolded proteins. SIGNOR-262267 0.7 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TNF protein P01375 UNIPROT down-regulates quantity BTO:0000801 22933625 f apalma Furthermore, phagocytosis of apoptotic neutrophils by M1 macrophages increased production of the Th2 cytokine TGFβ by the macrophages, while reducing expression of the Th1 cytokines IL-1β and TNF-α, reflecting a shift toward an M2 phenotype SIGNOR-255446 0.7 SOD1 protein P00441 UNIPROT ER stress stimulus SIGNOR-ST9 SIGNOR up-regulates 10090 18519638 f P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK SIGNOR-262788 0.7 p38 proteinfamily SIGNOR-PF16 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation 9606 10085140 t inferred from 70% family members gcesareni Our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf-beta signaling via tak1 and p38. The two pathways, smad and tak1, synergistically enhance the activity of atf-2 which acts as their common nuclear target SIGNOR-270124 0.2 SKP2 protein Q13309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates ubiquitination 9606 17409098 t gcesareni Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3). SIGNOR-154194 0.761 SERPINC1 protein P01008 UNIPROT F9 protein P00740 UNIPROT down-regulates activity cleavage 31030036 t lperfetto Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1 SIGNOR-264140 0.894 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser25 KRRSARLsAKPPAKV 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76286 0.309 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT down-regulates activity phosphorylation Ser385 RYSDTTDsDPENEPF -1 12297295 t llicata We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).  SIGNOR-251027 0.697 FYN protein P06241 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr731 QQIDSCTyEAMYNIQ 9606 9890970 t lperfetto Fyn associates with cbl and phosphorylates tyrosine 731 in cbl, a binding site for phosphatidylinositol 3-kinasecbl represents a substrate for src-like kinases that are activated in response to the engagement of cell surface receptors, and that src-like kinases are responsible for the phosphorylation of a tyrosine residue in cbl that may regulate activation of phosphatidylinositol 3-kinase SIGNOR-63968 0.807 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser227 FGSFPVHsPITQGTP 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276103 0.289 mTORC2 complex SIGNOR-C2 SIGNOR SLC7A11 protein Q9UPY5 UNIPROT down-regulates activity phosphorylation Ser26 NVNGRLPsLGNKEPP 9606 BTO:0002036 28648777 t miannu MTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity.  SIGNOR-273682 0.278 GTF2H5 protein Q6ZYL4 UNIPROT TFIIH complex SIGNOR-C457 SIGNOR form complex binding 9606 30860024 t lperfetto Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair.|The TFIIH core complex is composed of the seven subunits XPB, XPD, p62, p52, p44, p34, and p8, and is the form of TFIIH active in DNA repair|and additionally the CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269310 0.873 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser245 NQSMDTGsPAELSPT 9606 BTO:0000763 12193595 t gcesareni We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity. SIGNOR-91714 0.716 sirolimus chemical CHEBI:9168 ChEBI CD86 protein P42081 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255479 0.8 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr230 QPYDPNFyDETYDYG 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88903 0.607 SP1 protein P08047 UNIPROT CACNA1G protein O43497 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23868804 t miannu Consistent with this, Sp1 over-expression enhanced promoter activity while siRNA-mediated Sp1 silencing significantly decreased the level of CaV 3.1 protein and reduced the amplitude of whole-cell T-type Ca(2+) currents expressed in the N1E-115 cells. These results provide new insights into the molecular mechanisms that control CaV 3.1 channel expression. SIGNOR-264034 0.263 CDT1 protein Q9H211 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity binding 9606 BTO:0000007 14672932 t Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1. SIGNOR-261681 0.809 PPP1R9B protein Q96SB3 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 10090 BTO:0001976 15996550 f miannu Neurabin and spinophilin are preferentially expressed in neurons, where they are highly localized to dendritic spines via an interaction with F-actin. The results obtained in the present study suggest a mechanism by which neurabin or spinophilin contributes to the organization of the F-actin cytoskeleton in dendritic spines, and in turn to the regulation of spine morphology, via the activity-dependent recruitment of the Rho-specific GEF Lfc SIGNOR-269179 0.7 MAPK3 protein P27361 UNIPROT SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation Ser455 SIDSEPGsPLLDDAK 9606 14988395 t lperfetto Insulin-activated erk-mitogen-activated protein kinases phosphorylate sterol regulatory element-binding protein-2 at serine residues 432 and 455 in vivo.Further characterization by electrophoretic mobility shift assay and promoter reporter gene analyses revealed that phosphorylation does not influence protein/dna interaction, but enhances trans-activity. SIGNOR-123053 0.397 ATF4 protein P18848 UNIPROT FGF21 protein Q9NSA1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22233381 f miannu These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation. SIGNOR-253748 0.436 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser588 QTLSDSLsGSSLYST 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252978 0.513 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258376 0.8 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258717 0.8 RCOR1 protein Q9UKL0 UNIPROT REST-CoREST complex SIGNOR-C111 SIGNOR form complex binding 9606 20080105 t 1 miannu Transcriptional repression of neural-specific genes in nonneuronal cells is dependent on the REST (RE1-silencing transcription factor)–CoREST complex. SIGNOR-239220 0.764 KIF19 protein Q2TAC6 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272532 0.7 POU2F1 protein P14859 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238760 0.2 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-248559 0.432 KIF2A protein O00139 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272533 0.7 9-(1-anilinoethyl)-7-methyl-2-(4-morpholinyl)-4-pyrido[1,2-a]pyrimidinone chemical CHEBI:91428 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207278 0.8 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr479 FSYSASGtA 9606 BTO:0000093 24670654 t gcesareni Phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation SIGNOR-252444 0.638 N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide chemical CHEBI:63082 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Thus, overall, salmeterol is a highly selective β2-adrenoceptor agonist because of its higher β2-affinity and not because of higher β2-intrinsic efficacy. A similar reasoning can be applied to formoterol, although this agonist has higher intrinsic efficacy at all three receptors (rank 6, 8 and 5 at β1, β2 and β3). SIGNOR-257855 0.8 PTPN1 protein P18031 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates activity dephosphorylation 9606 23521888 t lperfetto Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C). SIGNOR-276965 0.386 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGB6 protein Q9Y5F9 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265684 0.2 POLR2M protein Q6EEV4 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266175 0.459 PRKCD protein Q05655 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity phosphorylation Ser346 LLCLRRSsLKAYGNG -1 1848190 t lperfetto We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling. SIGNOR-248856 0.355 PRKCB protein P05771 UNIPROT SLC6A9 protein P48067-2 UNIPROT down-regulates activity phosphorylation Thr590 PALLEHRtGRYAPTI 9823 21864610 t miannu We demonstrated that the isoforms GlyT1a, GlyT1b, and GlyT1c were constitutively phosphorylated, and that phosphorylation was dramatically enhanced, in a time dependent fashion, after PKC activation by phorbol ester. The phosphorylation was PKC-dependent, since pre-incubation of the cells with bisindolylmaleimide I, a selective PKC inhibitor, abolished the phorbol ester-induced phosphorylation. Blotting with specific anti-phospho-tyrosine antibodies did not yield any signal that could correspond to GlyT1 tyrosine phosphorylation, suggesting that the phosphorylation occurs at serine and/or threonine residues. These results together suggest that conventional PKCα and/or β are responsible for the downregulation of glycine transport. We further analyzed the effect of more specific inhibitors to PKCα and PKCβ on the GlyT1 activity. As shown in Fig. 4, panels C-F, incubation of the cells with varying concentrations of the PKCβ inhibitors (referred as PKCβ inhibitor and LY333531) or the PKCα/γ (HDBBE) inhibitors did not prevent the reduction of glycine uptake triggered by PMA, suggesting that PKCα and PKCβ together regulate GlyT1 activity. SIGNOR-262927 0.2 RBBP7 protein Q16576 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263848 0.834 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser309 SLGEGNGsPNHQPEP 9606 19237534 t lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-184180 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YBX1 protein P67809 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16797541 t miannu Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions.  FBX33 recruits Skp-1/Cul1 to YB-1 SIGNOR-271606 0.325 ABL1 protein P00519 UNIPROT CASP9 protein P55211 UNIPROT up-regulates phosphorylation Tyr153 RGNADLAyILSMEPC 9606 15657060 t gcesareni C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9. SIGNOR-133260 0.522 SHMT1 protein P34896 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI up-regulates quantity chemical modification 9606 32439610 t lperfetto Serine catabolism initiated by serine hydroxymethyltransferase (SHMT) transfers thegamma-carbon amino acid side chain to THF, forming glycine and 5,10-methylene-THF (me-THF) (Fig. 1). The cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms perform the same reactions. SIGNOR-268223 0.8 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates 9606 23723069 f miannu Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation. SIGNOR-202146 0.598 HIP1 protein O00291 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001130 16027218 f miannu Hip1 as a transcriptional regulator of the ar / silencing hip1 expression reduces the transcriptional activity and protein levels of the ar SIGNOR-138820 0.2 MDFI protein Q99750 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000944 8797820 t 2 miannu We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals. SIGNOR-240436 0.506 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-150492 0.639 RAF1 protein P04049 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates activity phosphorylation Ser218 VSGQLIDsMANSFVG 9606 10359597 t lperfetto Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf. SIGNOR-235987 0.742 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser151 VARSNPKsPQKPIVR 9606 BTO:0000848 21478863 t We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction SIGNOR-259921 0.635 YWHAH protein Q04917 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 12042314 t miannu 14-3-3_, 14-3-3_, and 14-3-3_ (but not 14-3-3_ and 14-3-3_) could form a complex with p27kip1 / we discovered that akt-mediated p27kip1phosphorylation directly induces p27kip1binding to 14-3-3 and cytoplasmic localization through phosphorylating the newly identified thr198residue. SIGNOR-109771 0.488 LDHB protein P07195 UNIPROT (S)-lactate smallmolecule CHEBI:16651 ChEBI up-regulates quantity chemical modification 9606 24929216 t lperfetto Glucose and alanine produce pyruvate which is reduced to lactate by lactate dehydrogenase in the cytoplasm without oxygen consumption. Lactate removal takes place via its oxidation to pyruvate by lactate dehydrogenase. SIGNOR-267657 0.8 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI VKORC1L1 protein Q8N0U8 UNIPROT up-regulates activity chemical activation 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265914 0.8 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates binding 9534 7629118 t Tyrosine phosphorylation of insulin receptor substrate-1 in vivo depends upon the presence of its pleckstrin homology region. SIGNOR-253604 0.752 WNT1 protein P04628 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 10090 BTO:0000887 16936075 t lperfetto Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6) SIGNOR-253126 0.761 KPNA6 protein O60684 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling. SIGNOR-254332 0.2 AKAP8 protein O43823 UNIPROT PRKACA protein P17612 UNIPROT up-regulates activity binding 9606 BTO:0000007 19531803 t Giulio To determine whether AKAP95 and p105 were present in a complex in mammalian cells, FLAG-tagged AKAP95 wascoexpressed with Myc-tagged p105 in human embryonic kidney (HEK) 293 cells. Immunoprecipitation of either protein pulled down a complex containing AKAP95, p105, and PKA-Ca (Fig. 6D).|The identification of a PKA phosphorylation site in the C-terminal region of p105 suggests that p105 is a candidate substrate for AKAP95-targeted PKA. SIGNOR-260302 0.298 TOPBP1 protein Q92547 UNIPROT BRCA1-B complex complex SIGNOR-C298 SIGNOR form complex binding 25400280 t lperfetto Another BRCA1 complex, the BRCA1–B complex containing BRCA1/TopBP1 and BACH1 (also known and BRIP1/FANCJ) has been reported to play a role in HR and S‐phase cell cycle arrest. The exact role of this complex in HR remains unclear, although it is assumed that BACH1, a DNA helicase, contributes to end resection (possibly through its helicase activity) and RPA loading, whereas TopBP1 is required for ATR activation and subsequent S‐phase checkpoint activation SIGNOR-263218 0.667 RPS6KB1 protein P23443 UNIPROT MRE11 protein P49959 UNIPROT down-regulates quantity by destabilization phosphorylation Thr597 SQRGRADtGLETSTR -1 28967905 t miannu MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. SIGNOR-265944 0.2 KIT protein P10721 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS -1 21135090 t KIT is responsible for the permanent phosphorylation of all three STAT proteins. STAT1, -3, and -5 were phosphorylated on their activation-specific Tyr701, Tyr704, and Tyr694, respectively, following KIT stimulation. SIGNOR-251365 0.718 IL22RA1 protein Q8N6P7 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15120645 t gcesareni Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain. SIGNOR-124489 0.512 SMURF2 protein Q9HAU4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 9606 BTO:0000007 11016919 t lperfetto The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway. SIGNOR-236133 0.773 GSK3B protein P49841 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by repression phosphorylation Ser76 SNLQRMGsSESTDSG 9606 BTO:0000567 20348946 t lperfetto Here, we report that casein kinase 1 alpha (ck1alpha) phosphorylates cdc25a on both s79 and s82 in a hierarchical manner requiring prior phosphorylation of s76 by chk1 or gsk-3beta. This facilitates beta-trcp binding and ubiquitin-mediated proteolysis of cdc25a SIGNOR-164742 0.317 CDX2 protein Q99626 UNIPROT VIL1 protein P09327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19371634 f miannu We concluded that cdx2 regulates intestinal villin expression through recruiting brm-type swi/snf complex to the villin promoter. SIGNOR-185486 0.345 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Ser185 KKREKRRsTSRQFVD 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250587 0.775 PSPH protein P78330 UNIPROT O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI down-regulates quantity chemical modification 9606 BTO:0000142 12213811 t lperfetto Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and d-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. |Phosphoserine phosphatase (PSP)1 is an important enzyme in the phosphorylated pathway of serine biosynthesis, which contributes a major portion of the endogenous l-serine|he enzymatic reaction of PSP is Mg2+-dependent and results in the dephosphorylation of phospho-l-serine with the formation of a phosphoenzyme intermediate, which is subsequently autodephosphorylated. The resulting product, l-serine, is not only a precursor for the biosynthesis of glycine but also an uncompetitive inhibitor for the enzymatic reaction of PSP SIGNOR-268570 0.8 SMAD2 protein Q15796 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity binding 9606 11389444 t lperfetto We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation. SIGNOR-108490 0.773 PPARGC1A protein Q9UBK2 UNIPROT APOA5 protein Q6Q788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255058 0.284 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-26251 0.742 ACTB protein P60709 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269826 0.496 PTK2B protein Q14289 UNIPROT ASAP2 protein O43150 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 10022920 t miannu Tyrosine phosphorylation of Pap by Pyk2 or Src kinases. We have identified a new Pyk2 binding protein designated Pap. Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. We demonstrate that Pap forms a stable complex with Pyk2 and that activation of Pyk2 leads to tyrosine phosphorylation of Pap in living cells. SIGNOR-269704 0.535 SLBP protein Q14493 UNIPROT H2BC12 protein O60814 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265383 0.2 HRH2 protein P25021 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257375 0.251 DKK1 protein O94907 UNIPROT KREMEN2 protein Q8NCW0 UNIPROT up-regulates binding 9606 12050670 t gcesareni Dkk1 has been shown to inhibitwnt by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to blockwnt/beta-catenin . Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of thewntreceptor lrp6 from the plasma membranekremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane SIGNOR-88882 0.597 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates activity phosphorylation 9606 24714526 t miannu HRI is an intracellular heme sensor that coordinates heme and globin synthesis in erythropoiesis by inhibiting protein synthesis of globins and heme biosynthetic enzymes during heme deficiency. HRI is a heme-regulated kinase that phosphorylates the α-subunit of eIF2 in heme deficiency, impairing another round of translational initiation and thereby inhibiting translation. SIGNOR-251817 0.888 DUSP5 protein Q16690 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 10224087 t gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-67355 0.777 UMPS protein P11172 UNIPROT 5-phospho-α-D-ribose 1-diphosphate smallmolecule CHEBI:58017 ChEBI down-regulates quantity chemical modification 9606 2912371 t miannu Uridine 5'-phosphate (UMP) synthase contains two sequential catalytic activities for the synthesis of orotidine 5'-phosphate (OMP) from orotate (EC 2.4.2.10, orotate phosphoribosyltransferase) and the decarboxylation of OMP to form UMP (EC 4.1.1.23, OMP decarboxylase). SIGNOR-267437 0.8 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000007 16239230 t gcesareni ... the PP2A holoenzymes ABC and ABC act downstream of Ras and upstream of MEK1 to promote activation of this MAPK signaling cascade. Furthermore both PP2A holoenzymes were found to associate with Raf1 and catalyze dephosphorylation of inhibitory phospho-Ser-259. SIGNOR-243534 0.509 RAP1GDS1 protein P52306 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171421 0.508 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 10090 BTO:0002572 10988287 t amattioni The temporal pattern of caspase-8 cleavage is consistent with the possibility that it may function upstream of caspase-3 during p53-dependent apoptosis. SIGNOR-256451 0.718 Frizzled proteinfamily SIGNOR-PF11 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates activity 18697834 f Simone Vumbaca […] we suggest that Wnt1, Wnt3a and Wnt5a result in the accumulation of Act-β-Cat SIGNOR-255652 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001103 20219869 f apalma ERK1/2 activation is a component of the pathway through which many mitogenic growth factors can stimulate cell proliferation SIGNOR-256216 0.7 Hypoxia stimulus SIGNOR-ST25 SIGNOR NPTX1 protein Q15818 UNIPROT up-regulates 10090 BTO:0000938 15115814 f lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. SIGNOR-261431 0.7 CHKB protein Q9Y259 UNIPROT choline smallmolecule CHEBI:15354 ChEBI down-regulates quantity chemical modification 27149373 t lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes SIGNOR-275635 0.8 GAPDHS protein O14556 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266498 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser721 PVVSGDTsPRHLSNV 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249346 0.733 Gbeta proteinfamily SIGNOR-PF4 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 t inferred from 70% family members lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-270039 0.2 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT up-regulates activity phosphorylation Ser537 DNSMSVPsPTSATKT 10090 BTO:0000964 34048556 t lperfetto Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity. SIGNOR-268338 0.26 DAPK3 protein O43293 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188793 0.496 RAC2 protein P15153 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 9705280 t gcesareni This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2. SIGNOR-59546 0.775 PRKCG protein P05129 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Ser840 VRSAFTTsTVVRMHV -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249282 0.421 CIITA protein P33076 UNIPROT HLA-E protein P13747 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11137213 f HLA-E is inducible by CIITA through the SXY regulatory module. HLA-F is inducible by NF-kappaB through the kappaB1 site of enhancer A, is responsive to IFN-gamma through the ISRE, and is inducible by CIITA SIGNOR-254019 0.483 CD79A protein P11912 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268192 0.647 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Ser382 KRASFAKsVIGTPEF 9606 BTO:0000007 BTO:0000671 18270262 t gcesareni We demonstrate that wnk1 is rapidly activated and phosphorylated at multiple residues after exposure of cells to hyperosmotic conditions and that activation is mediated by the phosphorylation of its t-loop ser382 residue, possibly triggered by a transautophosphorylation reaction. SIGNOR-160850 0.2 PCDHA10 protein Q9Y5I2 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265664 0.2 SIK1 protein P57059 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates activity phosphorylation Ser348 PSLQSSLsNPNLQAS 9606 BTO:0000567 16306228 t lperfetto We found that QSK and SIK phosphorylated TORC2 at Ser171 as well as at least two additional residues, namely Ser70 and Ser348|QIK also phosphorylates the CREB co-activator TORC2, in unstimulated cells, to sequester it in the cell cytoplasm, thereby inhibiting CREB-dependent gene-expression SIGNOR-249168 0.636 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT down-regulates quantity by repression translation regulation 9606 BTO:0000801 16917108 f Regulation miannu CRP significantly decreased IL-10 mRNA stability SIGNOR-251824 0.475 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT down-regulates quantity by destabilization phosphorylation 10090 11865049 t miannu We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. SIGNOR-267996 0.737 TOX2 protein Q96NM4 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 25352127 t Luana We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). SIGNOR-266097 0.297 AKT2 protein P31751 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 BTO:0000150 20231902 t gcesareni Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation. SIGNOR-164302 0.262 PRKCA protein P17252 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates activity phosphorylation Ser153 SMTDFYHsKRRLIFS 9606 16055744 t lperfetto Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers. SIGNOR-139302 0.382 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269602 0.2 PTPRA protein P18433 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 BTO:0000944 10698938 t Protein tyrosine phosphatase alpha (PTPalpha) is believed to dephosphorylate physiologically the Src proto-oncogene at phosphotyrosine (pTyr)527, a critical negative-regulatory residue. It thereby activates Src, and PTPalpha overexpression neoplastically transforms NIH 3T3 cells. SIGNOR-248438 0.737 INCENP protein Q9NQS7 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 t miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). SIGNOR-275425 0.875 OTUB1 protein Q96FW1 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization deubiquitination 34785775 t lperfetto Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec SIGNOR-276528 0.554 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Thr594 LHGKKNStVDCNGVV 9606 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275781 0.293 UNC5A protein Q6ZN44 UNIPROT DCC protein P43146 UNIPROT down-regulates activity binding 9606 BTO:0001484 25881791 t miannu In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. SIGNOR-268164 0.653 RB1 protein P06400 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 21524151 f miannu Consistent with this, the magnitude of the response (i.e. the fraction of cells undergoing arrest) appears to diminish the closer the cells are to the time of S-phase entry. The existence of a time gap between full pRb phosphorylation and S-phase entry is also consistent with the notion that E2F, once released from pRb, transcriptionally activates factors needed for S-phase entry, a process which likely requires a significant amount of time. SIGNOR-262533 0.7 CSNK2A1 protein P68400 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser228 PGVTPSKsTSASAIM 9606 BTO:0000938 26917740 t lperfetto Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. SIGNOR-275738 0.271 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-267934 0.8 CDK1 protein P06493 UNIPROT ERCC6L protein Q2NKX8 UNIPROT up-regulates phosphorylation Thr1063 VKQFDAStPKNDISP 9606 17218258 t lperfetto Following phosphorylation of pich on the cdk1 site t1063, plk1 is recruited to pich and controls its localization. Starting in prometaphase, pich accumulates at kinetochores and inner centromeres. SIGNOR-152133 0.568 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR MASTL protein Q96GX5 UNIPROT down-regulates activity dephosphorylation Thr194 NMMDILTtPSMAKPR 9606 BTO:0002181 24391510 t miannu We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies SIGNOR-276615 0.485 TRIP13 protein Q15645 UNIPROT MCC complex SIGNOR-C382 SIGNOR down-regulates quantity by destabilization binding 9606 BTO:0000567 25092294 t miannu We have indeed showed that TRIP13 action to disassemble the Cdc20–Mad2 complex requires the presence of p31comet (Fig. 3A). We furthermore found that the joint action of TRIP13 and p31comet is also required for the release of Mad2 from MCC, for the complete disassembly of MCC and for relieving APC/C from checkpoint inhibition (Figs. 3 and ​and4).4). SIGNOR-265972 0.525 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser502 FSTDNSGsQPKQKSD 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177793 0.382 TNKS protein O95271 UNIPROT PSMF1 protein Q92530 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 23622245 t lperfetto We identify the ADP-ribosyltransferase tankyrase (TNKS) and the 19S assembly chaperones dp27 and dS5b as direct binding partners of the proteasome regulator PI31. TNKS-mediated ADP-ribosylation of PI31 drastically reduces its affinity for 20S proteasome alpha subunits to relieve 20S repression by PI31. SIGNOR-263387 0.488 NDUFA6 protein P56556 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)The N-module, which is the tip of the hydrophilic arm and the last one to be incorporated [30,35], results from the assembly of NDUFV1, NDUFV2, NDUFS1 and NDUFA2 [34], to which NDUFA6, NDUFA7, NDUFA12, NDUFS4, NDUFS6 and NDUFV3 must be further associated with to complete the module [24]. SIGNOR-262157 0.831 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity relocalization 9606 19352540 t lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. SIGNOR-185131 0.879 SKP2 protein Q13309 UNIPROT MYBL2 protein P10244 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 10871850 t miannu P19Skp1 and Cul-1 bind to the F-box protein p45Skp2 to form a complex (SCF) that functions as E3 ubiquitin ligase.We show that B-Myb physically and functionally interacts with components of the Cdc34-SCFp45Skp2 ubiquitin pathway and propose that B-Myb degradation may be required for controlling the correct alternation of events during progression through the cell division cycle. SIGNOR-272572 0.383 PTEN protein P60484 UNIPROT CREB1 protein P16220 UNIPROT down-regulates activity dephosphorylation Ser119 EILSRRPsYRKILND 10090 BTO:0002572 21385900 t Our study demonstrates that PTEN can dephosphorylate CREB at Ser133 and that PTEN protein phosphatase activity is required for CREB dephosphoryation.|Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. SIGNOR-248543 0.444 ULK1 protein O75385 UNIPROT FBP1 protein P09467 UNIPROT down-regulates activity phosphorylation Ser63 HLYGIAGsTNVTGDQ 9606 BTO:0000007 27153534 t done miannu Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown). SIGNOR-274032 0.2 AKT3 protein Q9Y243 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t gcesareni We show that phosphorylation of b-raf by akt occurs at multiple residues within its aminoterminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity. SIGNOR-78693 0.292 Gbeta proteinfamily SIGNOR-PF4 SIGNOR WWC1 protein Q8IX03 UNIPROT unknown phosphorylation 9606 BTO:0000149 24269383 t inferred from 70% family members llicata We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro. SIGNOR-270121 0.2 SMARCD3 protein Q6STE5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding -1 22068056 t lperfetto We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes. SIGNOR-238289 0.549 ABL2 protein P42684 UNIPROT CAT protein P04040 UNIPROT up-regulates activity phosphorylation Tyr386 YRARVANyQRDGPMC 9606 12777400 t Manara These findings indicate that (i) ABL1 and Arg activate catalase by phosphorylation at both Tyr231 and Tyr386 SIGNOR-260772 0.343 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA10 protein Q9Y5H3 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265682 0.2 SCNN1B protein P51168 UNIPROT CACNA1H protein O95180 UNIPROT up-regulates activity binding 9606 BTO:0000142 30736831 t miannu This study describes the functional interaction between Cav3.2 calcium channels and the Epithelial Sodium Channel (ENaC). β- and γ-ENaC subunits could be co-immunoprecipitated with Cav3.2 calcium channels from brain lysates, dorsal horn and lumbar dorsal root ganglia. Αβγ-ENaC channels enhanced Cav3.2 calcium channel trafficking to the plasma membrane in tsA-201 cells. This effect was reciprocal such that Cav3.2 channel expression also enhanced β-ENaC trafficking to the cell surface. these findings reveal ENaC as an interactor and potential regulator of Cav3.2 calcium channels expressed in neuronal tissues. SIGNOR-269273 0.2 BAG5 protein Q9UL15 UNIPROT HSPA1A protein P0DMV8 UNIPROT down-regulates activity binding 9606 BTO:0000142 15603737 t Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction. SIGNOR-261196 0.746 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000150 10550055 t lperfetto The brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to dna damage. phosphorylation of brca1 by the checkpoint kinase atm may be critical for proper responses to dna double-strand breaks. Phosphorylation of brca1 on ser1423 and ser1524 by atm SIGNOR-72068 0.816 CYP1B1 protein Q16678 UNIPROT 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI up-regulates quantity chemical modification 9606 BTO:0000093 8790407 t Luana These studies demonstrate that human P450 1B1 is a catalytically efficient E2 4-hydroxylase that is likely to participate in endocrine regulation and the toxicity of estrogens. SIGNOR-269754 0.8 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1001 SKESEHDsDESSDDD 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251032 0.441 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1323 ALAPRSVsLKDKGRF -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249087 0.368 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT down-regulates activity phosphorylation Ser626 DQTNVLSsTFLSPQC 9606 BTO:0000007 16141410 t In vitro and in vivo (HEK 293 cells) kinase assays with synthetic peptides and full-length myocardin demonstrated that myocardin was a primed GSK3beta substrate, with serines 455 to 467 and 624 to 636 being the major GSK3beta phosphorylation sites.  GSK3β phosphorylation at the sites identified inhibits myocardin intrinsic transcriptional activity SIGNOR-251247 0.403 NAA25 protein Q14CX7 UNIPROT NatB complex SIGNOR-C416 SIGNOR form complex binding 9606 18570629 t miannu In the present study we present the components of hNatB (human NatB complex). It consists of the Nat3p homologue hNAT3 (human N-acetyltransferase 3) and the Mdm20p homologue hMDM20 (human mitochondrial distribution and morphology 20). They form a stable complex and in vitro display sequence-specific N(alpha)-acetyltransferase activity on a peptide with the N-terminus Met-Asp-. SIGNOR-267231 0.896 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 19874086 f Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass SIGNOR-188964 0.574 CTNNB1 protein P35222 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 10775268 t gcesareni Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding SIGNOR-76987 0.698 MPG protein P29372 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 25207814 t miannu Here we report that MID1 catalyzes the in vitro ubiquitination of the catalytic subunit of PP2A (PP2Ac) in the absence of alpha4. In the presence of alpha4, the level of PP2Ac ubiquitination is reduced.The high molecular weight smear pattern was not as obvious, suggesting that domains within the C-terminal half of MID1 may contribute to the polyubiquitination of PP2Ac. SIGNOR-271930 0.2 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg759 KNNAIEPrSFSQNSR -1 10350471 t lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. SIGNOR-263641 0.75 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 30519351 t miannu One of the most well studied activators of CCND1 transcription is β-catenin, which could be actived by AKT signalling to inducing G1/S transition. When β-catenin is translocated from the cytoplasm to the nucleus, it forms a complex with the ternary complex factor (TCF) and/or lymphoid enhancer-binding factor (LEF) and stimulates cyclin D1 gene transcription (Fig. 4C).In agreement with the data described above, a chromatin immunoprecipitation (ChIP) assay confirmed that TNC regulates the binding of β-catenin to the TCF/LEF-binding site in the CCND1 promoter (Fig. 4C). Additionally, the β-cateninbinding activity with respect to the CCND1 promoter was much higher in TNC-overexpression PANC-1 cells than in the vector controls. SIGNOR-277738 0.797 RIMBP3 protein Q9UFD9 UNIPROT RIMS1 protein Q86UR5 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264360 0.345 SEC23IP protein Q9Y6Y8 UNIPROT 1-acyl-sn-glycerol 3-phosphate smallmolecule CHEBI:16975 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269657 0.8 BAZ2B protein Q9UIF8 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity binding 9606 31999386 t inferred from 70% of family members miannu The BAZ2B bromodomain has been shown to bind to acetylated H3K14 (H3K14ac), whose presence at promoter regions is generally associated with gene activation. This suggests a potential role for BAZ2B in transcriptional activation. SIGNOR-269843 0.2 HSPA9 protein P38646 UNIPROT iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI up-regulates activity relocalization 27714045 t lperfetto Cluster transfer from ISCU to recipient apoproteins is assisted by a dedicated chaperone/cochaperone (HSPA9/HSC20) system that facilitates cluster release from the primary scaffold ISCU and transfer to recipient apoproteins or to intermediate carriers SIGNOR-262131 0.8 propionic acid chemical CHEBI:30768 ChEBI FFAR3 protein O14843 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257490 0.8 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA6 protein Q9Y5G7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265694 0.2 AXIN2 protein Q9Y2T1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 BTO:0000142;BTO:0000671;BTO:0000763 10911903 t gcesareni It has been found that a multiprotein complex assembled by the cytoplasmic component conductin induces degradation of cytoplasmic beta-catenin. The complex includes apc, the serine/threonine kinase gsk3 beta, and beta-catenin, which bind to conductin at distinct domains. SIGNOR-79947 0.845 CASP3 protein P42574 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 BTO:0000142 10200555 f amattioni Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation SIGNOR-66866 0.7 NRXN1 protein P58400 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626543 t miannu The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites SIGNOR-265453 0.822 HTR7 protein P34969 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257430 0.251 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Ser964 MMDAPPLsPFPHIKQ 9606 12006580 t llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  SIGNOR-250764 0.803 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192467 0.8 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MCM10 protein Q7L590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 22570418 t miannu By screening the known DDB1 interacting proteins, we discovered that VprBP is the substrate recognition subunit that targets Mcm10 for degradation. Hence, these results establish that Cul4-DDB1-VprBP ubiquitin ligase mediates the stress-induced proteolysis of replication factor, Mcm10. SIGNOR-272045 0.389 heparan sulfate octasaccharide smallmolecule CHEBI:142519 ChEBI ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 27241222 f miannu Many observations in animal models deficient for HSPGs and recent observations of human genetic mutations for biosynthesis of HSPGs have identified the importance of HSPGs for normal embryonic development and ECM organization. SIGNOR-264017 0.7 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr792 PRNSAELtVIKVSSQ 9606 17376779 t gcesareni Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1 SIGNOR-153867 0.837 GPR17 protein Q13304 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256692 0.395 FUBP1 protein Q96AE4 UNIPROT PMAIP1 protein Q13794 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In particular, elevated expression of the Bcl-2 family members Bik and Noxa was detected. SIGNOR-259128 0.2 CDX2/PAX6/P300 complex SIGNOR-C33 SIGNOR GCG protein P01275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10506141 f miannu Pax-6 and cdx-2 also directly interacted with one another at the protein level. pax-6, bound to its dna recognition site in the glucagon g1 promoter element, tethered cdx-2 to the molecular complex of pax-6 and p300. Further, we found that the presence of cdx-2 enhanced the interaction of pax-6 with p300, thus establishing a molecular complex of transcription factors implicated in tissue-specific glucagon gene expression with the basal transcriptional machinery. SIGNOR-70957 0.457 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-259422 0.2 LCK protein P06239 UNIPROT CCDC50 protein Q8IVM0 UNIPROT down-regulates activity phosphorylation Tyr279 TDGEDADyTHFTNQQ 9606 BTO:0000567 19059208 t miannu We found that Ymer was considerably phosphorylated on tyrosine residues also via Src family kinases such as Lck. A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling. SIGNOR-262854 0.2 4-[4-(6-methoxy-2-naphthalenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine chemical CHEBI:91442 ChEBI TEK protein Q02763 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207287 0.8 MRGPRX1 protein Q96LB2 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257259 0.2 MRAP protein Q8TCY5 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members. SIGNOR-252362 0.498 TAF6 protein P49848 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263922 0.91 CCKAR protein P32238 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257148 0.253 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1190 DIYETDYyRKGGKGL 10090 BTO:0000944 11579209 t lperfetto Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor. SIGNOR-235503 0.782 Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR down-regulates 9606 15623580 f lperfetto All these studies indicate the possibility that disruption of nucleosomes can take place independently of replication and can be coupled with transcription.The exchange of core histones on mitotic chromatin at anaphase and telophase observed by FRAP may reflect the replacement of a subset of nucleosomes in genome regions that are transcriptionally reactivated in the earliest parts of the new cell cycle. This interpretation is consistent with evidence of chromatin remodeling and chromatin association with RNA pol II at the anaphase–telophase transition (Fig. 9; Prasanth et al., 2003). In situ incorporation of Br-U for 5 min at the same stage showed little labeling outside of NORs (Fig. 9), suggesting that the majority of transcription is yet to commence at this point. The replacement of core histones conceivably precedes transcription to allow the clearance of promoter regions for factors to engage. SIGNOR-273458 0.7 PIK3R1 protein P27986 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242643 0.824 EIF2S1 protein P05198 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 31226023 f miannu Activated PERK phosphorylates the α subunit of eukaryotic initiation factor 2 (eIF2α), which inhibits the conversion of inactive GDP-bound eIF2α back to the active GTP-bound form, thereby suppressing translation initiation.The resulting global attenuation of protein synthesis reduces the ER protein influx and allows the ER to reprogram for preferential expression of UPR genes. SIGNOR-260166 0.7 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264165 0.763 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr536 QKGQESEyGNITYPP 9606 8692915 t Manara The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites. SIGNOR-260820 0.419 INS protein P01308 UNIPROT INSR protein P06213 UNIPROT up-regulates activity binding 10029 16956584 t lperfetto Insulin binds to the alpha subunit of the insulin receptor (IR) on the cell surface. SIGNOR-236748 0.933 AKT1 protein P31749 UNIPROT TARBP2 protein Q15633 UNIPROT up-regulates activity phosphorylation Ser283 ILSLRSCsLGSLGAL -1 27407113 t miannu We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. In vitro kinase assays demonstrated that TRBP-D3 can be phosphorylated by S6K1, S6K2, but also AKT1 (Figure ​(Figure1C),1C), SIGNOR-274064 0.2 WNT5A protein P41221 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates 9606 SIGNOR-C110 21078818 f gcesareni We demonstrate here that prototype canonical wnt3a and noncanonical wnt5a ligands specifically trigger completely unrelated endogenous coreceptors-lrp5/6 and ror1/2, respectively-through a common mechanism that involves their wnt-dependent coupling to the frizzled (fzd) coreceptor and recruitment of shared components, including dishevelled (dvl), axin, and glycogen synthase kinase 3 (gsk3). SIGNOR-169663 0.483 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TP73 protein O15350 UNIPROT down-regulates phosphorylation Thr86 AASASPYtPEHAASV 9606 12676926 t lperfetto Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-216702 0.523 HDAC1 protein Q13547 UNIPROT GLI1 protein P08151 UNIPROT up-regulates activity deacetylation 20081843 t Here, we identify a mechanism whereby Hh signalling is regulated, in which acetylation of Gli1 at Lys 518 represents a transcriptional inhibitory switch, while its HDAC1-mediated deacetylation is responsible for transcriptional activation. SIGNOR-253544 0.584 HNRNPU protein Q00839 UNIPROT HEXIM1 protein O94992 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262283 0.248 IFNB1 protein P01574 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR up-regulates activity binding 9606 11278538 t miannu Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2. SIGNOR-260335 0.766 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 10347229 t miannu  Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha. SIGNOR-272549 0.619 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252751 0.755 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation 9606 18394876 t gcesareni The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1 SIGNOR-253002 0.676 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251596 0.699 MAPK3 protein P27361 UNIPROT IRX2 protein Q9BZI1 UNIPROT up-regulates activity phosphorylation Ser317 TPQGSRTsPGAPPPA -1 15133517 t miannu To identify the phosphorylated residue, we introduced a serine-to-alanine substitution at residues 294 and 326 and a threonine-to-alanine substitution at residue 331 in Irx2(291–356). Erk1 phosphorylated S294A and T331A, but not S326A (Fig. 4b), indicating that Ser326 is the bona fide MAP kinase target. SIGNOR-263060 0.2 PLK2 protein Q9NYY3 UNIPROT NPM1 protein P06748 UNIPROT up-regulates phosphorylation Ser4 sMDMDMSP 9606 BTO:0000567 15190079 t gcesareni Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis. SIGNOR-125720 0.525 PCDH19 protein Q8TAB3 UNIPROT GABRA2 protein P47869 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C331 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267218 0.2 SPEN protein Q96T58 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 12374742 t gcesareni We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen. SIGNOR-94201 0.696 GNB5 protein O14775 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates activity binding 9606 BTO:0004032 21303898 t miannu The D2-class dopamine receptors (D2, D3, and D4) couple to the Gi/o family of G proteins and thus induce inhibition of AC SIGNOR-267850 0.466 CPC complex SIGNOR-C554 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 37292983 f miannu Here, we focus on the chromosome passenger complex (CPC), that forms a chromatin body that regulates chromosome segregation in mitosis. SIGNOR-275427 0.7 SB 203580 chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 10512765 t gcesareni Pretreatment of hela cells with sb 203580, a pyridinyl imidazole compound that specifically inhibits p38 mitogen-activated protein kinase (mapk). It has previously been established that sb 203580 acts primarily to block the catalytic activity of p38 mapk. However, it has been suggested that in cells, the compounds could also inhibit p38 mapk activation by virtue of their ability to bind to the inactive enzyme. SIGNOR-71024 0.8 CSNK2A1 protein P68400 UNIPROT STARD10 protein Q9Y365 UNIPROT down-regulates phosphorylation Ser284 GGAGGEGsDDDTSLT 9606 BTO:0002181 17561512 t gcesareni Interestingly, hypotonic extracts prepared from hek293t cells expressing the serine to alanine mutant exhibited increased lipid transfer activity compared with those from wild-type stard10-expressing cells, suggesting that, in a cellular context, phosphorylation on serine 284 negatively regulates stard10 activity SIGNOR-155740 0.394 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189129 0.388 ERN1 protein O75460 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity binding 10090 18519638 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) Activated IRE1 has been demonstrated to recruit TRAF2 and ASK1 on the ER membrane and thus to activate ASK1|ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut (Fig. 4B), suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation. SIGNOR-262790 0.671 STK11 protein Q15831 UNIPROT MARK3 protein P27448 UNIPROT up-regulates activity phosphorylation Thr211 TVGGKLDtFCGSPPY 9606 BTO:0000568 12879020 t lperfetto Regulation of the wnt signalling component par1a by the peutz-jeghers syndrome kinase lkb1. Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1. Mark3 is activated by phosphorylation on thr-211. SIGNOR-104063 0.318 PRKCG protein P05129 UNIPROT NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251633 0.2 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT down-regulates phosphorylation Ser511 ENIIFGVsYDEYRYR 9606 21930781 t lperfetto Serine 511 has been previously implicated in the regulation of cftr by ck2, as the mutant s511d was found to be insensitive to tbb in xenopus oocytes but to have no major impact on the single-channel behavior of cftr SIGNOR-176623 0.28 TP53 protein P04637 UNIPROT FGF2 protein P09038 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255431 0.448 CASP8 protein Q14790 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity -1 10988287 f lperfetto One indirect means through which caspase-8 might regulate caspase-9 activation is through a bcl-2-regulated pathway. SIGNOR-81811 0.583 GDAP1 protein Q8TB36 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 33610749 f lperfetto However, it remains elusive if additional proteins are involved in the regulation of mitochondrial fission, such as proposed fission factor GDAP1 SIGNOR-272977 0.7 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. CD44 is also upregulated by NUP98‐HOXA9. SIGNOR-261502 0.2 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR4 protein P31391 UNIPROT up-regulates activity chemical activation 9606 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257584 0.8 FFAR4 protein Q5NUL3 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257313 0.251 RNF139 protein Q8WU17 UNIPROT INSIG1 protein O15503 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 20068067 t miannu TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Thus, we conclude that INSIG-1 and 2 physically interact with TRC8, and that TRC8 enhances ubiquitylation of INSIG-1 in a RING-dependent manner SIGNOR-271955 0.485 CXCL1 protein P09341 UNIPROT Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000130 35022267 f miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. SIGNOR-277721 0.7 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258989 0.751 Gbeta proteinfamily SIGNOR-PF4 SIGNOR EWSR1 protein Q01844 UNIPROT unknown phosphorylation 9606 19076070 t inferred from 70% family members lperfetto Here we report that ews and ews-fli1 become phosphorylated at thr79 in the n-terminal domain in response to mitogens or dna damage. Mitogen-induced phosphorylation of ews and ews-fli1 was weak and catalysed by erk1 (extracellular signal-regulated kinase 1) and erk2. SIGNOR-270062 0.2 ATM protein Q13315 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser239 DPMTQDGsQPMDTNM 9606 22588298 t llicata On genotoxic stress, atm phosphorylates bmps-activated smad1 in the nucleus on s239, which disrupts smad1 interaction with protein phosphatase ppm1a, leading to enhanced activation and upregulation of smad1. SIGNOR-197533 0.2 DUSP1 protein P28562 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t fstefani We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively. SIGNOR-40879 0.675 CAMK2B protein Q13554 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser571 PWPLRRTsAQGQPSP 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275774 0.399 MUC1 protein P15941 UNIPROT KLF4 protein O43474 UNIPROT up-regulates activity binding 17308127 t lperfetto Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element. Our results show that MUC1-C binds constitutively to KLF4, occupies PE21 with KLF4, and enhances the KLF4 occupancy of PE21.  SIGNOR-270543 0.284 IKBKB protein O14920 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR unknown phosphorylation 9606 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-217376 0.867 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from 70% of family members gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-269880 0.645 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-251053 0.288 atropine chemical CHEBI:16684 ChEBI CHRM2 protein P08172 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258392 0.8 RWDD3 protein Q9Y3V2 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates sumoylation 9606 17956732 t lperfetto Rsume,_a small_rwd-containing protein, enhances sumo conjugation and stabilizes hif-1alpha during hypoxia SIGNOR-158590 0.465 PSMB3 protein P49720 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263359 0.862 PPP1CA protein P62136 UNIPROT CDC25C protein P30307 UNIPROT up-regulates binding 9606 14592972 t gcesareni Pp1 recognizes cdc25 directly by interacting with a pp1-binding motif in the cdc25 n-terminus. SIGNOR-118917 0.49 DRD4 protein P21917 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257098 0.28 Isoetharine chemical CHEBI:6005 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu The affinities of D2 receptors for agonists and antagonists were compared for receptors labeled with [1251]-7-OHPIPAT and with [*251]-NCQ-298 under conditions that promote, respectively, coupling or uncoupling of receptors to G proteins. Table 1. SIGNOR-258433 0.8 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 9030586 t lperfetto Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. SIGNOR-248960 0.325 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB4 protein P13762 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-254002 0.2 GART protein P22102 UNIPROT N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267305 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD -1 19661060 t miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276231 0.2 PRKAR1A protein P10644 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258755 0.86 IFNAR complex SIGNOR-C243 SIGNOR CCL2 protein P13500 UNIPROT up-regulates quantity by expression 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260851 0.319 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser868 ITRGEWQsEAQDTMK 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277853 0.2 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192826 0.8 NCAPD3 protein P42695 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263912 0.884 ADORA1 protein P30542 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256976 0.395 EAF2 protein Q96CJ1 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 t miannu The eaf1-related eaf2 protein is also a positive regulator of ell elongation activity SIGNOR-138540 0.74 EZR protein P15311 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001802 16488997 f Ezrin is indispensable for Six1-induced metastasis and highly expressed in a panel of representative pediatric cancers. SIGNOR-259375 0.7 GNG3 protein P63215 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199141 0.2 TTL protein Q8NG68 UNIPROT TUBA1B protein P68363 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176915 0.445 PRLHR protein P49683 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256973 0.309 IL1B protein P01584 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267486 0.2 PITX1 protein P78337 UNIPROT LHB protein P01229 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 19106114 f miannu GNRH1 induces expression of early growth response 1 (EGR1), which interacts with steroidogenic factor 1 (SF1) and paired-like homeodomain transcription factor 1 (PITX1) to regulate Lhb promoter activity. SIGNOR-254920 0.354 TGFB1 protein P01137 UNIPROT OMD protein Q99983 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16970923 f miannu We found tgf-beta1 to down regulate osad SIGNOR-149565 0.271 Core mediator complex complex SIGNOR-C405 SIGNOR RNA Polymerase II complex SIGNOR-C391 SIGNOR up-regulates activity binding 9606 25693131 t miannu The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator — a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). Because of its direct and extensive interactions with Pol II, Mediator regulates multiple stages of Pol II transcription (for example, initiation and re-initiation). Mediator interactions with the super elongation complex (SEC) also seem to be important for its regulation of Pol II elongation. SIGNOR-266682 0.338 CD19 protein P15391 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 10090 BTO:0000776 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-252670 0.51 SRGAP2 protein O75044 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260517 0.594 TLK2 protein Q86UE8 UNIPROT ASF1A protein Q9Y294 UNIPROT up-regulates quantity by stabilization phosphorylation Ser192 GWSTSENsLNVMLES 9606 20016786 t Manara We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | Consistent SIGNOR-260787 0.681 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr334 DSTQTSDtATNSTLP -1 7836371 t Phosphorylation of the FPR carboxyl terminus by GRK2 is the result of a high affinity interaction and proceeds in a hierarchical manner. sequential mechanism of phosphorylation beginning with residues 328 and/or 329, followed by residues 331 and/or 332, and finally residues 334 through 339. Attenuation of receptor-mediated signal amplification in response to external stimuli, an essential step in the balance of cellular activation, may be mediated by receptor phosphorylation. SIGNOR-251451 0.2 PRKACA protein P17612 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 9660950 t lperfetto The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka). SIGNOR-217364 0.499 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA2 protein Q9Y5H1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265691 0.2 PHLPP1 protein O60346 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248331 0.755 MAPK3 protein P27361 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 9606 BTO:0000664 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262914 0.326 DDHD1 protein Q8NEL9 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 22922100 t miannu Members of the intracellular phospholipase A1 family of proteins have been implicated in organelle biogenesis and membrane trafficking. The mammalian family comprises three members: phosphatidic acid-preferring phospholipase A1 (PA-PIA1)/DDHD1, p125/Sec23ip and KIAA0725p/DDHD2, all of which have a DDHD domain. SIGNOR-269653 0.8 REST protein Q13127 UNIPROT HCN1 protein O60741 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000938 21905079 t lperfetto Levels of NRSF and its physical binding to the Hcn1 gene were augmented after SE, resulting in repression of HCN1 expression and HCN1-mediated currents (I(h) ), and reduced I(h) -dependent resonance in hippocampal CA1 pyramidal cell dendrites. SIGNOR-268970 0.2 vorinostat chemical CHEBI:45716 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257949 0.8 SRC protein P12931 UNIPROT KLF16 protein Q9BXK1 UNIPROT up-regulates activity phosphorylation Tyr10 AAVACVDyFAADVLM 9606 BTO:0003041 22203677 t miannu We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f).  SIGNOR-276398 0.246 TNF protein P01375 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005760 16877633 f Regulation of expression miannu TNF, a proinflammatory cytokine present in several lung pathologies, decreases the expression and activity of the epithelial Na(+) channel (ENaC) by approximately 70% in alveolar epithelial cells. SIGNOR-251954 0.309 bepotastine chemical CHEBI:71204 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002126 18446005 t Luana We therefore tested how receptor internalization influenced the binding properties of a variety of H1-receptor antagonists. In this report, we present our findings that there were clear differences between the effect of histamineinduced H1-receptor internalization on the inhibition of [ 3 H]mepyramine binding by sedative and non-sedative H1-receptor antagonists in intact cells SIGNOR-257781 0.8 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189133 0.388 TFIID complex SIGNOR-C343 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity binding 9606 27096372 t miannu Our structures suggest that a primary function of TFIID during PIC assembly is the proper positioning of TBP on the upstream promoter, which ultimately determines the placement of Pol II relative to the TSS. The structures presented here offer a structural framework for understanding the complex mechanism underlying TFIID function, shedding new light into the overlapping roles of TFIID as both a coactivator and a general platform for PIC assembly in the coordination of transcription initiation. SIGNOR-263934 0.532 MET protein P08581 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0001033 22035268 f miannu C-Met expression and activation appears to be one of the common mechanisms of resistance to other targeted therapies. Given these multiple roles of c-Met in prostate cancer, several c-Met inhibitors have been developed. Evidence to date suggests that aberrant activation of the HGF/c-Met axis in prostate cancer epithelial cells appears to be a relatively late event in tumor progression. C-Met expression increases in advanced stages of the disease, with the highest expression observed in bone metastases. SIGNOR-263658 0.7 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC3 protein Q9UN70 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265674 0.2 DOT1L protein Q8TEK3 UNIPROT H3-4 protein Q16695 UNIPROT unknown methylation Lys80 REIAQDFkTDLRFQS 9606 12123582 t miannu HDOT1L Is a Nucleosomal H3-K79-Specific HMTase. We identified a human DOT1-like (DOT1L) protein and demonstrated that this protein possesses intrinsic H3-K79-specific histone methyltransferase (HMTase) activity in vitro and in vivo. Furthermore, we found that K79 methylation level is regulated throughout the cell cycle. By using two different methods, we demonstrate that the K79 methylation level decreases during S phase, reaches its lowest level in G2, increases during M phase, and maintains at a high level during G1 phase. SIGNOR-267142 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser14 LYSFFSPsPARKRHA 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276085 0.281 JAK2 protein O60674 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity phosphorylation Tyr304 PNEPVSDyINANIIM 9534 BTO:0004055 8995399 t lperfetto Tyrosine residues 304 and 327 in shp-2 are phosphorylated by jaks, and phosphorylated shp-2 can associate with the downstream adapter protein grb2 SIGNOR-236266 0.789 CDK2AP1 protein O14519 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity binding 22427660 t lperfetto The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G1-to-S phase transition. SIGNOR-264781 0.448 ATF3 protein P18847 UNIPROT GDF15 protein Q99988 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15670751 t lperfetto In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells. SIGNOR-253725 0.434 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A9/b1 integrin complex SIGNOR-C166 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259020 0.405 NR3C1 protein P04150 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin SIGNOR-235346 0.463 UBE2J1 protein Q9Y385 UNIPROT DIO2 protein Q92813 UNIPROT down-regulates quantity by destabilization ubiquitination Lys237 VCIVQRQkIAYLGGK 9606 BTO:0001379 29892818 t scontino ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244. SIGNOR-267481 0.384 MAPK14 protein Q16539 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation 9606 7479834 t gcesareni Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression. SIGNOR-26511 0.617 PTBP2 protein Q9UKA9 UNIPROT HNRNPH1 protein P31943 UNIPROT up-regulates activity binding 9606 BTO:0000567 11003644 t lperfetto Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA. SIGNOR-261269 0.395 NMBR protein P28336 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257248 0.27 CSNK2A1 protein P68400 UNIPROT KIF1C protein O43896 UNIPROT unknown phosphorylation Ser1092 PRMRRQRsAPDLKES -1 10559254 t llicata Serine 1092 was a substrate for the protein kinase casein kinase II in vitro, and inhibition of casein kinase II in cells diminished the association of KIF1C with 14-3-3gamma. Our data thus suggest that KIF1C can form dimers and is associated with proteins of the 14-3-3 family. SIGNOR-250912 0.312 PKA proteinfamily SIGNOR-PF17 SIGNOR PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275951 0.2 SLC18A2 protein Q05940 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 t miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. SIGNOR-269197 0.8 CTDSP1 protein Q9GZU7 UNIPROT TWIST1 protein Q15672 UNIPROT down-regulates activity dephosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000007 26975371 t gcesareni These results indicate that SCP1 is the phosphatase that counter-regulates the MAPK-mediated phosphorylation of S68-Twist1. SIGNOR-245962 0.2 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 22343533 t gcesareni Ror1 and ror2 bind wnt5a. SIGNOR-196133 0.741 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF ARID1B variant complex SIGNOR-C482 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270708 0.832 GZMA protein P12544 UNIPROT SET protein Q01105 UNIPROT down-regulates cleavage 9606 11555662 t miannu Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity. SIGNOR-110462 0.704 CHEK1 protein O14757 UNIPROT CDC7 protein O00311 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni Chk1 directly phosphorylates essential s-phase kinases cdc7. SIGNOR-163161 0.728 MMP14 protein P50281 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 28709001 f MMP14 Promotes Adipogenesis Downstream of or in Parallel to TIMP3 SIGNOR-255909 0.7 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser64 EPGTPPSsPLSAEQL 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276090 0.291 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Ser539 GLITINSsQEHLTVQ 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177797 0.382 CDK6 protein Q00534 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 BTO:0000776;BTO:0000785 16160006 t gcesareni Phosphorylation on thr-187, by cdk2 leads to protein ubiquitination and proteasomal degradationp27(kip1) was phosphorylated by v-cyclin-cdk6 predominantly on ser10, which enhances its cytoplasmic localization. Interestingly, upon reactivation of kshv lytic cycle, v-cyclin-cdk6 phosphorylated p27(kip1) on thr187, which resulted in down-regulation of p27(kip1) protein levels. SIGNOR-140405 0.852 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Thr179 PQSNIPEtPPPGYLS 9606 10197981 t llicata Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain. SIGNOR-66746 0.74 SB 505124 chemical CHEBI:100922 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206742 0.8 BIRC5 protein O15392 UNIPROT CPC complex SIGNOR-C554 SIGNOR form complex binding 9606 23175282 t miannu It is now known that the chromosomal passenger complex (CPC) is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin (also known as Dasra)5–7 (Figure 1A). SIGNOR-275424 0.796 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248375 0.604 SP7 protein Q8TDD2 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004058; BTO:0000165 11792318 f Giulio Giuliani To test whether Osx could activate typical osteoblast genes, we transfected an Osx expressing vector into both C2C12 and C3H10T1/2 cells. Our results showed that Osx produced an induction of osteocalcin RNA in both cell types. SIGNOR-255409 0.501 FAM162A protein Q96A26 UNIPROT VDAC1 protein P21796 UNIPROT up-regulates activity binding 9606 BTO:0001061 15082785 t Giulio HGTD-P was coprecipitated with VDAC but not with ANT or cyclophilin D (Fig. 7A, left upper panel).|However, it is not clear at present whether HGTD-P participates directly in channel formation in association with VDAC or modulates its channel-forming activity. SIGNOR-260293 0.2 CAPN2 protein P17655 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 BTO:0000590 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251608 0.559 PTEN protein P60484 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation Tyr419 RLIEDNEyTARQGAK 9606 22482061 t lperfetto Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells . SIGNOR-277009 0.547 PPM1F protein P49593 UNIPROT MAP3K7 protein O43318 UNIPROT down-regulates activity dephosphorylation 9606 28906490 t miannu However, our current work shows that POPX2 can downregulate TAK1 and affect the anti-apoptotic activities of TAK1, implying that silencing POPX2 could facilitate TAK1 activation and will lead to increased cell survival.|We have also demonstrated that POPX2 can directly dephosphorylate TAK1 (XREF_FIG). SIGNOR-277047 0.402 IL23R protein Q5VWK5 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. SIGNOR-87841 0.572 CTNNBIP1 protein Q9NSA3 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10898789 t gcesareni We identify a novel beta-catenin-interacting protein, icat, that was found to inhibit the interaction of beta-catenin with tcf-4 and represses beta-catenin-tcf-4-mediated transactivation. SIGNOR-79399 0.811 GSK3B protein P49841 UNIPROT CABYR protein O75952 UNIPROT unknown phosphorylation Thr151 PATPKTTtPPSSPPP -1 15752768 t GSK3β interacts with and phosphorylates CABYR in vitro. GSK3β interacts with and phosphorylates CABYR in vitro. the functional extent of the CABYR phosphorylation sites to participate in cellular processes through GSK3β remains to be investigated. SIGNOR-251224 0.406 MELK protein Q14680 UNIPROT PDPK1 protein O15530 UNIPROT down-regulates activity phosphorylation Thr354 WENLHQQtPPKLTAY 9606 BTO:0000007 22544756 t miannu The results showed that MPK38 interacted with and inhibited PDK1 activity via Thr(354) phosphorylation.  SIGNOR-276414 0.269 SLC4A10 protein Q6U841 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI down-regulates quantity relocalization 9606 23056253 t miannu The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pH(i)) and chloride concentration ([Cl(-)](i)) in neurons.  SIGNOR-264686 0.8 SLC9A3 protein P48764 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265602 0.8 PTGS2 protein P35354 UNIPROT prostaglandin G2(1-) smallmolecule CHEBI:82629 ChEBI up-regulates quantity chemical modification -1 7592599 t Luana [14C]Arachidonate metabolism by oPGHS-1 and hPGHS-2 was examined in reactions with a series of GSP/Cox ratios (Fig. 3). The principal metabolite for both isoforms was the endoperoxide PGH2, with lesser amounts of PGF2a, PGE2, PGD2, SIGNOR-269770 0.8 S100G protein P29377 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 31731478 t miannu Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. SIGNOR-268517 0.8 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT down-regulates activity polyubiquitination Lys634 KVYQMLQkWVMREGI 9606 BTO:0000815 29642005 t miannu Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2) regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation.  We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. MIB2 Ubiquitylates RIPK1 at Lysines K377 and K634 SIGNOR-272663 0.297 KARS1 protein Q15046 UNIPROT Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR form complex binding 9606 32644155 t miannu In mammalian cells, eight cytoplasmic aminoacyl-tRNA synthetases (AARS), and three non-synthetase proteins, reside in a large multi-tRNA synthetase complex (MSC). the MSC is suggested to be a super-complex of two identical, symmetrically arranged sub-units, each containing a single copy of the constituents, with the exception of LysRS which is present as a dimer in each sub-unit (Figure ​(Figure1B,1B, adapted from (27,28)). The sub-units are proposed to be joined by dimers of AspRS and the ProRS domain of GluProRS, and possibly by LysRS tetramers (20). Four AARSs containing GST-like domains important in protein-protein interactions form a MetRS-AIMP3–GluProRS–AIMP2 core of the complex (27,29). These proteins, together with AspRS, and possibly LeuRS and IleRS (30), form a distinct sub-complex denoted as sub-complex I (27). Sub-complex II consists of AIMP1, GlnRS, ArgRS, a dimer of LysRS, and AIMP2 (which is shared by both sub-complexes). SIGNOR-270353 0.2 GSK3B protein P49841 UNIPROT NEFH protein P12036 UNIPROT down-regulates phosphorylation Ser503 GGEEETKsPPAEEAA 9606 12130654 t lperfetto Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment SIGNOR-90668 0.306 TNFSF10 protein P50591 UNIPROT TNFRSF10A protein O00220 UNIPROT up-regulates binding 9606 14585074 t amattioni Trail interacts with tril-r1 and trail-r2 and activetes them SIGNOR-101082 0.933 E2F1 protein Q01094 UNIPROT MCPH1 protein Q8NEM0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22136275 f miannu Overexpression of E2F1 led to the upregulation of MCPH1 transcription, and knocking down the endogenous E2F1 resulted in the inhibition of the MCPH1 promoter activity. SIGNOR-253848 0.351 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation Ser463 SPHNPISsVS 9606 BTO:0000416 9136927 t lperfetto Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro SIGNOR-217985 0.657 LEPR protein P48357 UNIPROT PTPN11 protein Q06124 UNIPROT up-regulates activity binding 9606 11085989 t miannu Because the long leptin receptor lacking tyrosine 985 exhibits a significantly reduced ability to activate ERK phosphorylation, this residue is at least in part mediating stimulation of the ERK pathway by ObRb. This residue binds SHP-2 and is required for tyrosine phosphorylation of SHP-2 SIGNOR-263506 0.478 PRKAA1 protein Q13131 UNIPROT INSIG1 protein O15503 UNIPROT up-regulates quantity by stabilization phosphorylation Thr222 ITIAFLAtLITQFLV 9606 BTO:0000007 30733434 t miannu Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner. SIGNOR-277430 0.258 PRKACA protein P17612 UNIPROT PJA2 protein O43164 UNIPROT up-regulates activity phosphorylation Thr389 RVITQREtENNQMTS -1 21423175 t miannu In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h). SIGNOR-276323 0.2 PRKCA protein P17252 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY -1 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚  SIGNOR-249223 0.32 APC protein P25054 UNIPROT ODC1 protein P11926 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12112318 t APC-dependent regulation of ornithine decarboxylase in human colon tumor cells|Upon induction of APC expression, ODC promoter activity and RNA levels were suppressed SIGNOR-253670 0.27 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR WWTR1 protein Q9GZV5 UNIPROT down-regulates activity phosphorylation Ser105 TGAGAAGsPAQQHAH 26375055 t lperfetto We found that TAZ is phosphorylated in vitro and in vivo by the mitotic kinase CDK1 at S90, S105, T326, and T346 during the G2/M phase of the cell cycle. Interestingly, mitotic phosphorylation inactivates TAZ oncogenic activity SIGNOR-276524 0.264 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 BTO:0000007 18156174 t llicata Together, our findings suggest that src-dependent phosphorylation at tyr-529 facilitates inactive erk binding to rsk2, which might be a general requirement for rsk2 activation by egf through the mek/erk pathway. SIGNOR-160052 0.36 MRPL43 protein Q8N983 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262353 0.69 COL4A3 protein Q01955 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254667 0.7 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269486 0.8 CDK7 protein P50613 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity phosphorylation Thr439 FTPSGILtPHALGSR 9606 26728557 t Luana CDKs and Xrn2 phosphorylation promote transcription termination. | Cdk7 phosphorylated Xrn2-Thr439 but was less efficient than Cdk9. | SIGNOR-259851 0.249 ADRA2C protein P18825 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256978 0.4 YAP1 protein P46937 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23075495 f gcesareni Yap and taz are two main downstream effectors of the hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-256669 0.7 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 19250911 t gcesareni Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation. SIGNOR-184198 0.787 nintedanib chemical CHEBI:85164 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257799 0.8 AMOT protein Q4VCS5 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates relocalization 9606 23431053 t AMOT proteins, a family of proteins including AMOT, AMOTL1, and AMOTL2, interact extensively with multiple TJ components and are important for maintaining TJ integrity and epithelial cell polarity. gcesareni Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms. SIGNOR-201132 0.672 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7780739 t Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts. SIGNOR-248625 0.611 pyruvate smallmolecule CHEBI:15361 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 24363178 t miannu As an alternative to decarboxylation by PDH, the second major fate of mitochondrial pyruvate is the irreversible, ATP-dependent carboxylation of pyruvate to oxaloacetate by pyruvate carboxylase (PC). Oxaloacetate is a critical intermediate in metabolism, linking carbohydrate, lipid, amino acid, and nucleotide metabolism (Fig. 2) SIGNOR-266553 0.8 MAP2K7 protein O14733 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Tyr182 ADAEMTGyVVTRWYR 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273953 0.421 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 12801888 t inferred from 70% family members llicata Our results suggest that map kinase can phosphorylate thr276 of smad4 and that phosphorylation can lead to enhanced tgf-beta-induced nuclear accumulation and, as a consequence, enhanced transcriptional activity of smad4. SIGNOR-270107 0.2 NR2F6 protein P10588 UNIPROT LHCGR protein P22888 UNIPROT down-regulates quantity by repression transcriptional regulation 9534 BTO:0000318 10644740 t Luana Functional analysis showed that EAR2 and EAR3/COUP-TFI repressed the hLHR promoter activity, whereas TR4 activated hLHR gene transcription. SIGNOR-266216 0.306 IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation Ser36 RHDSGLDsMKDEEYE 11815618 t lperfetto Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. |TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha. SIGNOR-249367 0.492 CSNK2A1 protein P68400 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Ser231 KSNIVLLsAEEKKEQ 9606 7678037 t llicata These data suggest taht CKII can phosphorylate more than one site on CD20 molecule. | Taken together, this data shown that insulin can increase serine/ threonine phosphorylation and may stimulate CKII activity in B cells. SIGNOR-250915 0.309 CDK5 protein Q00535 UNIPROT GRIN2A protein Q12879 UNIPROT up-regulates activity phosphorylation Ser1232 SGHFTMRsPFKCDAC 10116 BTO:0000938 11675505 t llicata Here, we demonstrate that cyclin dependent kinase-5 (Cdk5) associates with and phosphorylates NR2A subunits at Ser-1232 in vitro and in intact cells. Moreover, we show that roscovitine, a selective Cdk5 inhibitor, blocks both long-term potentiation induction and NMDA-evoked currents in rat CA1 hippocampal neurons. These results suggest that Cdk5 plays a key role in synaptic transmission and plasticity through its up-regulation of NMDARs. SIGNOR-250666 0.535 SMARCA4 protein P51532 UNIPROT ABCG2 protein Q9UNQ0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18234970 f miannu An increased association of the chromatin remodeling factor, Brg-1, to the ABCG2 promoter was observed consistently in S1 and H460 cells where ABCG2 expression was activated by romidepsin treatment SIGNOR-255150 0.307 CDK1 protein P06493 UNIPROT ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr846 RAFSFSKtPKRALRR 9606 SIGNOR-C17 16247472 t lperfetto Thr-814 to ala greatly diminished the ability of p34cdk1/cyclin b to phosphorylate recombinant ect2-c protein (figure 1b, left panel). These data suggest that thr-814 is a major cdk1 phosphorylation site in ect2-c in vitrothe sequence thr-pro-lys-arg (tpkr) starting at amino acid 814we found that the t814a mutation slightly reduces the exchange activity of ect2 on rac1 SIGNOR-141179 0.587 PRKCA protein P17252 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Ser262 SPAKDCGsQKYAYFN 9606 14702389 t gcesareni Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes. SIGNOR-120907 0.545 CREB5 protein Q02930 UNIPROT STAT1 protein P42224 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002817 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253810 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255579 0.7 STK11 protein Q15831 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity phosphorylation Ser615 GEKNERTsVAGTVRK 9606 BTO:0002181 34216621 t miannu  Resveratrol promotes the binding between LKB1 and Sirt1, which we first reported, and this binding leads to LKB1-mediated phosphorylation of Sirt1 at three different serine residues in the C terminus of Sirt1. Mechanistically, LKB1-mediated phosphorylation increases intramolecular interactions in Sirt1, such as the binding of the C terminus to the deacetylase core domain, thereby eliminating DBC1 (Deleted in Breast Cancer 1, Sirt1 endogenous inhibitor) inhibition and promoting Sirt1-substrate interaction.  SIGNOR-277322 0.584 DDX20 protein Q9UHI6 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253117 0.855 SLC6A3 protein Q01959 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 30465801 t miannu Key regulators of transmitter release and the signaling dynamics of dopamine are the plasma membrane reuptake transporter (DAT) and the vesicular monoamine transporter (VMAT2). These proteins serve to remove dopamine molecules from the extracellular and cytosolic space, respectively and both determine the amount of transmitter released from synaptic vesicles. SIGNOR-269189 0.8 SARS1 protein P49591 UNIPROT alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI up-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. SIGNOR-270800 0.8 PLXNB3 protein Q9ULL4 UNIPROT ARHGDIA protein P52565 UNIPROT up-regulates activity binding 10116 BTO:0000526 20696765 t miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays. SIGNOR-268435 0.252 DZIP3 protein Q86Y13 UNIPROT H2AC21 protein Q8IUE6 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHKP 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271758 0.2 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 16481469 t gcesareni Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed SIGNOR-144551 0.337 H4C1 protein P62805 UNIPROT Nucleosome_H3.1 variant complex SIGNOR-C324 SIGNOR form complex binding -1 21812398 t miannu The elemental repeating unit of chromatin is the nucleosome core particle (NCP), which consists of 146 base pairs of DNA wrapped in 1.65 left-handed superhelical turns around the histone octamer. The histone octamer comprises two each of the core histones, H2A, H2B, H3 and H4, which form two H2A/H2B dimers and an H3/H4 tetramer, respectively, in the NCP. SIGNOR-263722 0.2 MRPS18A protein Q9NVS2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262334 0.712 PKC proteinfamily SIGNOR-PF53 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL -1 19661060 t miannu Activation of the TRPV4 ion channel is enhanced by phosphorylation. TRPV4 is phosphorylated in response to activation of PKC. We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276229 0.2 PTPN2 protein P17706 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 BTO:0000782 22080863 t lperfetto Previously, we reported that sfks can serve as bona fide substrates for tcptp and that tcptp dephosphorylates the y418 activation loop autophosphorylation site (corresponding to y394 in lck and y417 in fyn) to inactivate sfks SIGNOR-177113 0.328 PRKCA protein P17252 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates phosphorylation 9606 20577053 t gcesareni The action of metformin was shown to be mediated through activation of apkc?/?, Which phosphorylates cbp at ser436, and disrupts the transcriptionally active creb-cbp-crtc2 complex, SIGNOR-166368 0.263 CSNK1A1 protein P48729 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Ser12 FSLHDALsGSGNPNP -1 8253806 t llicata L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I. SIGNOR-250789 0.311 MAPK1 protein P28482 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 10915800 t llicata Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo. SIGNOR-80092 0.412 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Ser355 SALQGFNsPGMLSLG 9606 BTO:0000567 10849446 t lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. SIGNOR-236587 0.704 B4GALT1 protein P15291 UNIPROT UDP(3-) smallmolecule CHEBI:58223 ChEBI up-regulates quantity chemical modification 9606 16157350 t miannu Beta-1,4-Galactosyltransferase-I (beta4Gal-T1) transfers galactose from UDP-galactose to N-acetylglucosamine (GlcNAc) residues of the branched N-linked oligosaccharide chains of glycoproteins. SIGNOR-268470 0.8 PCBD1 protein P61457 UNIPROT HNF1B protein P35680 UNIPROT up-regulates activity binding 9606 BTO:0000482 24204001 t miannu Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. SIGNOR-254910 0.591 PLK4 protein O00444 UNIPROT FBXW5 protein Q969U6 UNIPROT down-regulates activity phosphorylation Ser151 SQFNKDDsLLLASGV 21725316 t lperfetto The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6. SIGNOR-275476 0.554 LAMTOR3 protein Q9UHA4 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates binding 9606 15547943 t gcesareni We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations. SIGNOR-130924 0.605 TLN1 protein Q9Y490 UNIPROT A4/b7 integrin complex SIGNOR-C187 SIGNOR up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257635 0.543 MPHOSPH10 protein O00566 UNIPROT UTP3 protein Q9NQZ2 UNIPROT up-regulates activity binding -1 28813493 t miannu Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. SIGNOR-261176 0.932 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269249 0.2 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser684 IGIPQFHsPVGSPLK 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248334 0.56 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1931 SPTSPTYsPTSPKGS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273099 0.749 MYC protein P01106 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity transcriptional regulation 10116 10823814 t inferred from family member C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-270247 0.419 PRKCA protein P17252 UNIPROT RAB11A protein P62491 UNIPROT unknown phosphorylation Ser177 TEIYRIVsQKQMSDR -1 22188018 t miannu This report shows for the first time that Rab11 is differentially phosphorylated by distinct PKC isoenzymes and that this post-translational modification might be a regulatory mechanism of intracellular trafficking.Our results demonstrate that classical PKC (PKCα and PKCβII but not PKCβI) directly phosphorylate Rab11 in vitro. In addition, novel PKCε and PKCη but not PKCδ isoenzymes also phosphorylate Rab11. Mass spectrometry analysis revealed that Ser 177 is the Rab11 residue to be phosphorylated in vitro by either PKCβII or PKCε. SIGNOR-263168 0.2 CDK5 protein Q00535 UNIPROT CORO1A protein P31146 UNIPROT up-regulates activity phosphorylation Thr424 AAPEASGtPSSDAVS 9606 BTO:0001588 26823173 t lperfetto We here show that phosphorylation of coronin 1 on Thr(418/424) by cyclin-dependent kinase (CDK) 5 activity was responsible for coronin 1-G_s association and the modulation of cAMP production. Together these results show an essential role for CDK5 activity in promoting the coronin 1-dependent cAMP/PKA pathway. SIGNOR-245187 0.291 CDH20 protein Q9HBT6 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265859 0.3 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates activity phosphorylation Ser521 WTNRLYEsFKASDPL -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276329 0.2 POU5F1 protein Q01860 UNIPROT NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254939 0.764 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH2 protein Q04721 UNIPROT up-regulates activity cleavage 9606 25610395 t lperfetto The membrane-bound Notch segment that results from this cleavage, known as Notch Intracellular Truncation domain (NEXT), is a -secretase substrate (Kopan and Ilagan, 2009). -Secretase performs the subsequent cleavage at S3 (De Strooper et al., 1999), releasing Notch intracellular domain (NICD) from the membrane and allowing for signal transduction through binding with the CBL-1, Su(H), Lag-1 (CSL; Schroeter et al., 1998; Struhl and Adachi, 1998) family of DNA binding proteins. SIGNOR-209723 0.579 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MARS1 protein P56192 UNIPROT up-regulates activity phosphorylation Ser209 LQKQPQPsPAEGRAV 9606 BTO:0000567 25097229 t miannu Here, we report that methionyl-tRNA synthetase (MRS) is phosphorylated at Ser209 and Ser825 by extracellular signal-related kinase (ERK1/2) under conditions of stress caused by reactive oxygen species (ROS), and that this phosphorylated MRS shows increased affinity for non-cognate tRNAs with lower affinity for tRNA(Met), leading to an increase in Met residues in cellular proteins. SIGNOR-277834 0.2 NUMB protein P49757 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates BTO:0001103 12361602 t apalma Numb is an inhibitor of Notch signaling that interacts with the intracellular portion of Notch and antagonizes its activity by preventing nuclear translocation SIGNOR-255374 0.794 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser274 ASPQRSRsPSPQPSS 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248689 0.619 EIF2AK2 protein P19525 UNIPROT PPP2R5A protein Q15172 UNIPROT up-regulates phosphorylation Ser28 VDGFTRKsVRKAQRQ 9606 18957415 t llicata Phosphorylation of serine 28 by pkr promotes mitochondrial localization of b56alpha, because wild-type but not mutant s28a b56alpha promoted mitochondrial pp2a activity. SIGNOR-181793 0.331 FZD4 protein Q9ULV1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 27096005 t areggio Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin. SIGNOR-258955 0.595 SYK protein P43405 UNIPROT CGAS protein Q8N884 UNIPROT up-regulates activity phosphorylation Tyr214 GLLNTGSyYEHVKIS 10090 BTO:0003292 36252040 t miannu Mechanistically, viral infection or foreign DNA transfection triggers recruitment of the spleen tyrosine kinase (SYK) and cGAS to the endosomal vacuolar H+ pump (V-ATPase), where SYK is activated and then phosphorylates human cGASY214/215 (mouse cGasY200/201) to prime its activation. SIGNOR-277844 0.2 CSNK1D protein P48730 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization phosphorylation Ser35 LGPSPGPsPGSAHSM 9606 BTO:0001225 30177679 t miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  SIGNOR-277407 0.2 PRKCB protein P05771 UNIPROT EIF6 protein P56537 UNIPROT down-regulates activity phosphorylation Ser235 QPSTIATsMRDSLID 9606 14654845 t lperfetto Our results show that release of eIF6 from 60S subunits may operate, in mammalian cells, through a RACK1–PKC betaII pathway. |Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which were reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation led to eIF6 phosphorylation, and mutation of a serine residue in the carboxy terminus of eIF6 impaired RACK1/PKC-mediated translational rescue. |S235A eIF6 inhibits ribosomal joining in the presence of RACK1–PKCbetaII SIGNOR-249245 0.309 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 15994200 t gcesareni These observations suggest that RET/PTC is able to phosphorylate the Y315 residue of PKB, an event that results in maximal activation of PKB for RET/PTC-induced thyroid tumorigenesis. SIGNOR-138437 0.463 IRX1 protein P78414 UNIPROT ERMAP protein Q96PL5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261667 0.2 FGFR4 protein P22455 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Tyr701 DGPKGTGyIKTELIS 9606 BTO:0000007 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251141 0.352 CHEK1 protein O14757 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Thr521 MALGKDVtPPPETEV 9606 36991467 t miannu MAP4 is a novel target of FBXW7 via the phosphorylated threonine T521 modified by CHEK1 in ESCC. The threonine T521 of MAP4, which was phosphorylated by CHEK1, played a key role in the FBXW7-related degradation system. SIGNOR-277846 0.2 CDK1 protein P06493 UNIPROT VHL protein P40337 UNIPROT down-regulates quantity by destabilization phosphorylation Ser80 QVIFCNRsPRVVLPV 9606 BTO:0000815 36813923 t miannu  Mechanistically, CDK1 directly phosphorylates pVHL at Ser80, which primes the recognition of pVHL by PIN1. PIN1 then binds to phosphorylated pVHL and facilitates the recruitment of the E3 ligase WSB1, therefore targeting pVHL for ubiquitination and degradation.  SIGNOR-277836 0.2 GALR1 protein P47211 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256966 0.251 SP1 protein P08047 UNIPROT FMR1 protein Q06787 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15479157 f miannu we show that Sp1 (specificity protein 1) and Sp3 are also strong positive regulators of FMR1 promoter activity. SIGNOR-255204 0.2 CD40LG protein P29965 UNIPROT IGSF6 protein O95976 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9809579 f miannu CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily SIGNOR-261727 0.329 DOT1L protein Q8TEK3 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27856324 f irozzo Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1 […]. Of all the BCL-2 family members, only BCL-2 and MCL-1 are directly activated by MLL-AF4. SIGNOR-255881 0.2 NAALAD2 protein Q9Y3Q0 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267542 0.8 PTPRA protein P18433 UNIPROT KCNB1 protein Q14721 UNIPROT down-regulates dephosphorylation 9606 16870705 t gcesareni Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha. SIGNOR-148301 0.2 CRK protein P46108 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 BTO:0000007 11314030 t llicata Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II. SIGNOR-250777 0.726 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267881 0.8 BAZ1B protein Q9UIG0 UNIPROT MDC1 protein Q14676 UNIPROT down-regulates 9606 20965415 f gcesareni H2ax tyr142 is constitutively phosphorylated by the kinase wstf, a member of the baz/wal family of chromatin remodelling enzymes, and blocks mdc1 recruitment SIGNOR-168831 0.368 RAP1GDS1 protein P52306 UNIPROT RHOC protein P08134 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc SIGNOR-171399 0.301 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser287 WEPPGRAsPSQGSSP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120475 0.27 ADSS1 protein Q8N142 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI down-regulates quantity chemical modification 9606 10496970 t miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267344 0.8 A6/b1 integrin complex SIGNOR-C164 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257706 0.567 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser715 MQLEEQAsRQISSKK 9606 BTO:0002181 26206521 t miannu Active PLK1, in turn, phosphorylates MCAK at Ser715 which promotes its microtubule depolymerase activity essential for faithful chromosome segregation. SIGNOR-276931 0.807 CRTC2 protein Q53ET0 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity transcriptional regulation 9606 26652733 t Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB SIGNOR-256103 0.2 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser732 RRVRKLPsTTL 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219320 0.752 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270468 0.8 CAMK2B protein Q13554 UNIPROT GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 t miannu ERK1/2 and CaMKIIβ mediated phosphorylation of GABAB1 at serine 867 (S867) and threonine 872 (T872). We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277850 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GABBR1 protein Q9UBS5 UNIPROT down-regulates quantity by destabilization phosphorylation Thr873 WQSEAQDtMKTGSST 9606 BTO:0000007 37686242 t miannu We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1. SIGNOR-277852 0.2 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 17419683 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt SIGNOR-154261 0.417 SUZ12 protein Q15022 UNIPROT SUZ12/EED complex SIGNOR-C76 SIGNOR form complex binding 9606 16712789 t miannu Suz12 is a polycomb group protein that forms polycomb repressive complexes (prc2/3) together with eed and histone methyltransferase ezh2. SIGNOR-146761 0.943 TNKS protein O95271 UNIPROT TERF1 protein P54274 UNIPROT down-regulates activity ADP-ribosylation -1 11739745 t lperfetto Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA. SIGNOR-263377 0.799 NUMA1 protein Q14980 UNIPROT TUBA1C protein Q9BQE3 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116677 0.26 LEF1 protein Q9UJU2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229764 0.7 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates activity binding 9606 BTO:0000130 35022267 t miannu Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis. neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth.Taken together, these results show that the neutrophil attracting cytokines Cxcl1 and 2 are highly expressed in metastatic livers in response to gemcitabine withdrawal and this favours CXCR2-dependent recruitment of neutrophils at the hepatic metastatic site. SIGNOR-277720 0.906 GSK3B protein P49841 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 NNTSTDGsLPSTPPP 10090 BTO:0003328 16543145 t MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1. SIGNOR-251242 0.509 PAX7 protein P23759 UNIPROT PAX7/MLL1 complex complex SIGNOR-C90 SIGNOR form complex binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198632 0.2 GPI protein P06744 UNIPROT β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Glucose 6-phosphate isomerase (GPI) catalyzes the interconversion of G6P into fructose-6-phosphate (F6P) in the second step of the Embden-Meyerhof pathway (Figure 1). As a result of this reversible reaction, products of the hexose-monophosphate shunt can be recycled to G6P. SIGNOR-266462 0.8 RNF41 protein Q9H4P4 UNIPROT ERBB3 protein P21860 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 12411582 t miannu Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3 SIGNOR-272599 0.684 CCNB1 protein P14635 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR form complex binding 9606 25603287 t lperfetto The central mitotic kinase, cyclin-dependent kinase-1 (human cdk1 is present through all stages of the cell cycle, but its activity is cell-cycle regulated by phosphorylation/dephosphorylation and cyclin binding.Cdk1-cyclin b phosphorylates ser/thr residues directly preceding pro; thus, it is classified as a proline-directed kinase. SIGNOR-205590 1 CHEK2 protein O96017 UNIPROT TRIM32 protein Q13049 UNIPROT up-regulates activity phosphorylation Ser55 LEKLLASsINGVRCP 9606 BTO:0000007 37943659 t miannu We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.  SIGNOR-277790 0.2 WNK1 protein Q9H4A3 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates activity phosphorylation Thr1023 QKKQGKNtIDVWWLF 9606 BTO:0000007 36318922 t miannu Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS. SIGNOR-277859 0.5 IKBKB protein O14920 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization phosphorylation Ser92 MDETDASsAVKVKRA 9606 BTO:0002181 38197897 t miannu IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. SIGNOR-277860 0.2 RPS6KB1 protein P23443 UNIPROT SRPK2 protein P78362 UNIPROT up-regulates activity phosphorylation Ser494 HDRSRTVsASSTGDL 9606 BTO:0000007 29153836 t no miannu  Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. SIGNOR-275459 0.361 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCNN1G protein P51170 UNIPROT down-regulates quantity by destabilization phosphorylation -1 11805112 t inferred from 70% family members lperfetto Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4. SIGNOR-270171 0.2 DHFR2 protein Q86XF0 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI down-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. |We demonstrate that the DHFRP4, or dihydrofolate reductase-like 1 (DHFRL1), gene is expressed and shares some commonalities with DHFR. SIGNOR-268260 0.8 IKBKB protein O14920 UNIPROT TARDBP protein Q13148 UNIPROT down-regulates quantity by destabilization phosphorylation Thr8 MSEYIRVtEDENDEP 9606 BTO:0002181 38197897 t miannu IκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation. Furthermore, we identified IKKβ-induced phosphorylation sites of TDP-43 and found that phosphorylation at Thr8 and Ser92 is important for the reduction of TDP-43 by IKK. SIGNOR-277861 0.2 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr68 DPPLESKyECPICLM 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277862 0.575 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr326 KMETQSMyVSELKRT 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277863 0.575 SRC protein P12931 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT up-regulates activity phosphorylation Tyr353 AQQCNGIyIWKIGNF 9606 BTO:0002181 37977223 t miannu  To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. SIGNOR-277864 0.575 EGFR protein P00533 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Tyr228 YPGGSDNyGSLSRVT 9606 BTO:0000017 14996911 t llicata In A431 cells, epidermal growth factor induced striking p120 phosphorylation at Y228. Y228-phosphorylated p120 localized to adherens junctions and lamellipodia, and was significantly enhanced in cells around the colony periphery. SIGNOR-251092 0.631 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137639 0.2 SRC protein P12931 UNIPROT TRIM25 protein Q14258 UNIPROT up-regulates activity phosphorylation Tyr278 NSKFDTIyQILLKKK 9606 BTO:0002181 30100205 t miannu Here, we demonstrated that TRIM25 interacted with c-Src and underwent tyrosine phosphorylation by c-Src kinase upon viral infection and the phosphorylation is required for the complete activation of RIG-I signaling. Analysis using a c-Src inhibitor and TRIM25 mutant, in which tyrosine 278 is substituted by phenylalanine (Y278F), suggested that the phosphorylation positively regulates K63-linked polyubiquitination of RIG-I and subsequent antiviral signaling.  SIGNOR-277405 0.273 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 9155018 t inferred from 70% family members lperfetto Mnk1 was phosphorylated and activated in vitro by erk1 and p38 map kinasespreliminary results showed that thr344 at least was one of the major sites phosphorylated by erk1 SIGNOR-270022 0.2 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser418 TTENRFHsLPFSLTK 9606 BTO:0000938 24614225 t lperfetto Thus, serine 418 is phosphorylated in vivo. Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204688 0.532 DAPK1 protein P53355 UNIPROT MYL12A protein P19105 UNIPROT up-regulates activity phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 BTO:0000567 11485996 t miannu DAPK Phosphorylates Myosin II RLC in Vitro and in Vivo. Together these results show that similar to the conventional MLCKs, Ser-19 is the primary RLC residue phosphorylated by DAPK and that phosphorylation of Thr-18 is also possible. SIGNOR-262843 0.276 WT1 protein P19544 UNIPROT PAX2 protein Q02962 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000671 7720589 t A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis SIGNOR-252298 0.611 EGFR protein P00533 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates phosphorylation Tyr1276 GGGPGGDyAAMGACP 9606 BTO:0000150 7929151 t lperfetto The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism. SIGNOR-34748 0.66 PLK1 protein P53350 UNIPROT IKBKB protein O14920 UNIPROT down-regulates phosphorylation Ser740 SFTALDWsWLQTEEE 9606 18957422 t lperfetto Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma SIGNOR-181802 0.346 MYC protein P01106 UNIPROT HLA-A protein P04439 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254603 0.271 Caspase 3 complex complex SIGNOR-C221 SIGNOR KDM4C protein Q9H3R0 UNIPROT down-regulates activity cleavage 9606 29207681 t miannu JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels. SIGNOR-263871 0.2 CEP76 protein Q8TAP6 UNIPROT PLK1 protein P53350 UNIPROT down-regulates activity binding 9606 BTO:0001938 27065329 t miannu Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. SIGNOR-262731 0.418 PPM1A protein P35813 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 18930133 t PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation. SIGNOR-248487 0.311 FGG protein P02679 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253373 0.7 POLR2C protein P19387 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266163 0.877 CSNK1G2 protein P78368 UNIPROT PER1 protein O15534 UNIPROT down-regulates phosphorylation 9606 15917222 t miannu Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1. SIGNOR-137751 0.399 HSBP1 protein O75506 UNIPROT WASH complex complex SIGNOR-C258 SIGNOR up-regulates quantity relocalization 9606 BTO:0000007 29844016 t lperfetto The Trimeric Coiled-Coil HSBP1 Protein Promotes WASH Complex Assembly at Centrosomes SIGNOR-261007 0.2 LYN protein P07948 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr359 AKPDSSFyKGLDLNG -1 10942405 t Lyn phosphorylates Y904 and Y359 of band 3. The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton movements, and anion transport. SIGNOR-251412 0.341 lenalidomide chemical CHEBI:63791 ChEBI CRBN protein Q96SW2 UNIPROT up-regulates activity chemical activation 9606 26131937 t gcesareni Lenalidomide, like thalidomide and pomalidomide, binds CRBN and induces degradation of specific substrates SIGNOR-236891 0.8 PDK1 protein Q15118 UNIPROT PKN2 protein Q16513 UNIPROT up-regulates activity phosphorylation Thr816 GYGDRTStFCGTPEF 9606 BTO:0000007 10753910 t miannu PDK1 phosphorylates the PRKs at their conserved activation loop threonines (Thr-774 and Thr-816 for PRK1 and PRK2, respectively) both in vitro and in vivo. SIGNOR-250265 0.342 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265112 0.8 GOT2 protein P00505 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267518 0.8 MMP9 protein P14780 UNIPROT ECM stimulus SIGNOR-ST20 SIGNOR down-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272399 0.7 GSK3B protein P49841 UNIPROT APP protein P05067 UNIPROT unknown phosphorylation Thr743 VEVDAAVtPEERHLS -1 8764598 t The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). SIGNOR-251220 0.552 oxotremorine M chemical CHEBI:38322 ChEBI CHRM4 protein P08173 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258657 0.8 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser122 PKPPPAAsPGVRAGH -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277878 0.2 PPP2CA protein P67775 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser211 LVGVTSSsCPADLTQ -1 29945972 t miannu MS analysis revealed that PP2A dephosphorylates TFEB at several residues, including Ser-109, Ser-114, Ser-122, and Ser-211, thus facilitating TFEB activation. SIGNOR-277879 0.2 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI Mitochondrial respiratory chain complex II complex SIGNOR-C278 SIGNOR up-regulates activity chemical activation 26083061 t lperfetto Respiratory chain complexes I–III depend on Fe-S clusters for function SIGNOR-262136 0.8 FBXW7 protein Q969H0 UNIPROT CCDC6 protein Q16204 UNIPROT down-regulates binding 9606 BTO:0000551 23108047 t miannu Fbxw7 interacts with and targets ccdc6 for ubiquitin-mediated proteasomal degradation SIGNOR-199279 0.371 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser109 KSHSRQAsTDAGTAG 9606 25601544 t Luana We performed mass spectrometry to determine additional sites on YAP1 targeted by NDR, identifying three additional serines, namely S61, S109, and S164, to also be phosphorylated by NDR in vitro  SIGNOR-259856 0.389 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 BTO:0000567 8621729 t lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling|The immunoprecipitates were assayed for GST-MEK1 activation. D, activation of MEK1 by A-Raf requires the presence of serine residue 218 and 222. SIGNOR-235944 0.733 PTK6 protein Q13882 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation Tyr699 TAKAVDGyVKPQIKQ 9606 BTO:0000150 17997837 t llicata Phosphospecific antibodies, mutational analysis, and in vitro kinase assays demonstrated that brk specifically mediated stat5b phosphorylation at the activating tyrosine, y699. SIGNOR-159066 0.437 tacedinaline chemical CHEBI:90195 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258007 0.8 PEA15 protein Q15121 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates 9606 11702783 f inferred from 70% of family members gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. SIGNOR-269904 0.2 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr2035 GIKTSEGtPGFRAPE 9606 BTO:0000938 20595391 t lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. SIGNOR-166474 0.2 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT down-regulates activity phosphorylation Ser109 KERRRTEsINSAFAE 10116 BTO:0001556 14636580 t miannu In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. We determined that modification of HAND1 at residues 107 and 109 affects dimerization affinities with E-proteins, thus changing the bHLH dimer equilibrium within the cell. These modifications also affect HAND1 function. SIGNOR-249989 0.298 PLCG1 protein P19174 UNIPROT 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176606 0.8 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 BTO:0000093 17535811 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-155246 0.768 NMDA receptor_2D complex SIGNOR-C350 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264225 0.735 MC2R protein Q01718 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268694 0.504 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257518 0.8 TGFB2 protein P61812 UNIPROT TGFB2 protein P61812 UNIPROT up-regulates binding 9606 16885528 t gcesareni The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge SIGNOR-148608 0.2 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr454 VRGFPTIyFSPANKK -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262895 0.2 CLOCK/BMAL2 complex SIGNOR-C196 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 t lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 SIGNOR-253713 0.506 FUBP1 protein Q96AE4 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased. SIGNOR-259129 0.2 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser731 DPLPPVFsGTPKGSG 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259821 0.2 MAPK3 protein P27361 UNIPROT STMN2 protein Q93045 UNIPROT down-regulates activity phosphorylation Ser62 ELILKPPsPISEAPR 10116 BTO:0000142 9525956 t lperfetto SCG10, a growth cone-enriched MT-destabilizing protein, has been recently characterized as an in vitro substrate for various serine/threonine kinases including PKA, MAP kinase, and CDK (19). We have found that SCG10 is phosphorylated in vivo in developing rat brain.| The sites for MAP kinase phosphorylation were identified as Ser-62 and Ser-73 of SCG10|By expressing a series of phosphorylation site mutants, we showed that the MT-destabilizing effect of SCG10 could be modulated. While the nonphosphorylatable mutant showed higher activity than the wild-type protein, the activity of the mutant in which phosphorylation on all four sites was mimicked by an aspartate residue was greatly reduced. These data suggest that the nonphosphorylated state of SCG10 represents the most active form of the protein. SIGNOR-249115 0.356 APC-c complex SIGNOR-C150 SIGNOR CCNA2 protein P20248 UNIPROT down-regulates quantity by destabilization ubiquitination 21596315 t lperfetto Complexed with the activator proteins CDC20 or CDH1 (Fang et al., 1998, Visintin et al., 1997), the APC/C recognizes, ubiquitinates, and targets for proteasomal degradation a multitude of cell cycle regulators containing KEN or D box degrons, including securin, cyclin A, and cyclin B. SIGNOR-265050 0.546 TNF protein P01375 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261034 0.7 PRKCI protein P41743 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000195 18270268 t llicata Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation. SIGNOR-160855 0.347 EIF3M protein Q7L2H7 UNIPROT EIF3_complex complex SIGNOR-C401 SIGNOR form complex binding -1 16920360 t miannu Consistent with its diverse functions, eIF3 is the largest and most complex initiation factor: the mammalian version, for example, contains 13 nonidentical subunits that are designated eIF3a to eIF3m 8, 9, 10, 11, 12, 13 (Table 1). SIGNOR-266388 0.935 CDX2 protein Q99626 UNIPROT MEP1A protein Q16819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22326557 t TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis| SIGNOR-253965 0.479 TFDP1 protein Q14186 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253857 0.56 XBP1 protein P17861 UNIPROT XBP1 protein P17861 UNIPROT up-regulates activity binding -1 12805554 t miannu E4BP4, ATF-6, OASIS, and XBP-1 all formed strong homodimeric associations on the array Transcription factor dimerization can increase the selectivity of protein-DNA interactions and generate a large amount of DNA binding diversity from a relatively small number of proteins SIGNOR-224199 0.2 FUBP1 protein Q96AE4 UNIPROT TNF protein P01375 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19637194 f irozzo FBP1 down-regulates cell cycle inhibitors and proapoptotic genes. Interestingly, we also observed the up-regulation of proapoptotic genes following FBP1 knockdown in Hep3B cells. In addition, mRNA levels of the death ligands tumor necrosis factor (TNF) α and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) were significantly increased. SIGNOR-259130 0.2 GABRD protein O14764 UNIPROT GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263770 0.404 NEDD4L protein Q96PU5 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000938 23778145 t miannu The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2). SIGNOR-253458 0.338 BRAF protein P15056 UNIPROT BRAF protein P15056 UNIPROT down-regulates activity phosphorylation Ser614 SHQFEQLsGSILWMA 9606 BTO:0002181 27345148 t miannu The phosphorylation of S614 is mitogen inducible and the result of autophosphorylation. These data suggest that phosphorylation at this site is inhibitory, and part of the physiological shut-down mechanism of BRAF signalling. SIGNOR-277255 0.2 PLK1 protein P53350 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr1008 LNANDEAtVSVLGEL 9606 17376779 t gcesareni Bubr1 was phosphorylated by plk1 in vitro at two plk1 consensus sites in the kinase domain of bubr1 SIGNOR-153863 0.837 Succinyl-CoA ATP variant complex SIGNOR-C398 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 9606 27487822 t miannu In the citric acid cycle, succinyl-CoA synthetase (SCS) catalyzes the only step that provides substrate-level phosphorylation: succinyl-CoA + NDP + Pi = succinate + CoA + NTP, where N is adenosine or guanosine and the reaction requires magnesium ions. SIGNOR-266267 0.8 GDNF protein P39905 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252176 0.2 MITF protein O75030 UNIPROT SERPINF1 protein P36955 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001177 22115973 f miannu Here we show that the basic-helix-loop-helix-leucine zipper microphthalmia-associated transcription factor (MITF), which plays central roles in the development and function of a variety of cell types including RPE cells, upregulates the expression of a multifunctional factor PEDF in RPE cells. SIGNOR-254587 0.31 Orexin A smallmolecule CHEBI:80319 ChEBI HCRTR1 protein O43613 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257510 0.8 AKT1 protein P31749 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates quantity phosphorylation Ser257 PSRPPRPsRPPPPTP 9606 BTO:0000815 30517763 t miannu AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation SIGNOR-272922 0.322 NFX1 protein Q12986 UNIPROT TERT protein O14746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17267499 f miannu NFX1-123 augments the activation of hTERT expression through interactions with PABPCs SIGNOR-226015 0.511 POU5F1 protein Q01860 UNIPROT BMP4 protein P12644 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254932 0.481 CSN1S1 protein P47710 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser529 GLPNGLLsGDEDFSS 9606 21232017 t gcesareni Phosphorylation of serine 529 of p65 is mediated by casein kinase ii, but is prevented in nonstimulated cells by the interaction with ikba SIGNOR-171222 0.2 PPP1CC protein P36873 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248494 0.271 LEF1 protein Q9UJU2 UNIPROT NCAM1 protein P13591 UNIPROT up-regulates activity transcriptional regulation 10090 BTO:0003952 11696550 f miannu Consistent with our observation that expression of exogenous LEF-1 causes transactivation of the N-CAM promoter, a recent study demonstrated that noggin-dependent induction of LEF-1 coincidentally increased N-CAM expression (50). Ectopic noggin added to skin cultures up-regulates LEF-1 expression and stimulates hair induction. Based on promoter assays and EMSAs, our results further support the notion that N-CAM is a direct target of LEF-1. SIGNOR-254549 0.277 CDC25A protein P30304 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000007 23429262 t lperfetto We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases’ activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. SIGNOR-245456 0.644 TP53 protein P04637 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 24212651 f miannu P53 is a nuclear transcription factor with a pro-apoptotic function SIGNOR-256664 0.7 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg27 PTGGGRGrGMRSRGR 9606 24726729 t miannu Cnbp interacts with protein arginine methyltransferase prmt1 / r25 or r27 appear to be the major methylation sites in cnbp /arginine methylation of cnbp impedes rna binding SIGNOR-204962 0.373 CXCL5 protein P42830 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 BTO:0000584 38339310 t miannu CXCL5 is another ELR+ CXC chemokine and, thus, also potently attracts neutrophils. Just like CXCL1, CXCL5 also signals through CXCR2, explaining why, often, CXCL5 and CXCL1 are seen to function in parallel in PDAC. CXCL5 was increased in human pancreatic tissue compared to the normal pancreas, and the knockdown of CXCL5 in pancreatic cancer cell lines reduced the proliferation and migration ability of cells SIGNOR-277730 0.747 PKA proteinfamily SIGNOR-PF17 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 10230396 t inferred from 70% family members gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-270129 0.2 TFEB protein P19484 UNIPROT CYP17A1 protein P05093 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Among the differentially expressed genes, we detected upregulation of known targets in TFEB-WT and TFEB-nuc cells (Figure 2B; Tables S1 and S2), including genes functioning in lysosomal and autophagy pathways|Using quantitative PCR (qPCR), we validated expression patterns observed by RNA sequencing for selected genes (CTSD, SQSTM1, MCOLN1, IL33, FAP, GPNMB, IFI30, FOLR1, and G0S2) SIGNOR-276786 0.2 RIN1 protein Q13671 UNIPROT ABL2 protein P42684 UNIPROT up-regulates phosphorylation 9606 BTO:0000149 15886098 t CrkL forms a constitutive complex with Abl, thus explaining the strong preference of Bcr-Abl for CrkL. gcesareni Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl SIGNOR-136961 0.608 motesanib chemical CHEBI:51098 ChEBI RET protein P07949 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194572 0.8 MED7 protein O43513 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266657 0.849 WSB1 protein Q9Y6I7 UNIPROT HIPK2 protein Q9H2X6 UNIPROT down-regulates ubiquitination 9606 18093972 t lperfetto Ubiquitination and degradation of homeodomain-interacting protein kinase 2 by wd40 repeat/socs box protein wsb-1 SIGNOR-160032 0.579 ULBP2 protein Q9BZM5 UNIPROT KLRK1 protein P26718 UNIPROT up-regulates binding 9606 BTO:0000782 10894171 t gcesareni Here we describe a family of gpi-anchored cell surface proteins that function as ligands for the mouse activating nkg2d receptor. These molecules are encoded by the retinoic acid early inducible (rae-1) and h60 minor histocompatibility antigen genes on mouse chromosome 10 and show weak homology with mhc class i. SIGNOR-79233 0.598 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser183 GLRTRTGsNIDCEKL 9606 15703181 t lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. SIGNOR-133880 0.2 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Thr291 EDEESYDtESEFTEF 9606 BTO:0000782 8622692 t llicata Casein kinase ii phosphorylates i kappa b alpha at s-283, s-289, s-293, and t-291 and is required for its degradation. SIGNOR-40514 0.572 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-244580 0.2 NR1I2 protein O75469 UNIPROT UGT1A1 protein P22309 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18172616 f miannu This study indicates that hepatocyte nuclear factor 1alpha (HNF1alpha) bound to the proximal promoter motif not only enhances the basal reporter activity of UGT1A1, including the distal (-3570/-3180) and proximal (-165/-1) regions, but also influences the transcriptional regulation of UGT1A1 by CAR, PXR, GR, and AhR to markedly enhance reporter activities. SIGNOR-254440 0.464 clenbuterol chemical CHEBI:174690 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257861 0.8 IQSEC2 protein Q5JU85 UNIPROT GRIA3 protein P42263 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 27009485 t miannu BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors. SIGNOR-264914 0.2 TNF protein P01375 UNIPROT TNFRSF1B protein P20333 UNIPROT up-regulates activity binding 14732063 t [...] two distinct types of TNF-Rs have been identified and molecularly cloned: TNF-R55 (also referred to as TNFR1, p55 or CD120a) and TNF-R75 (also called TNFR2, p75 or CD120b) SIGNOR-253594 0.929 UBQLN2 protein Q9UHD9 UNIPROT HNRNPA3 protein P51991 UNIPROT up-regulates quantity by stabilization binding 25616961 t lperfetto We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations.||Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein SIGNOR-262272 0.455 FZD7 protein O75084 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity 23290138 f Simone Vumbaca We observed that overexpression of Fzd7 or stimulation with FN resulted in increased levels of active Rac1 in primary myoblasts SIGNOR-255647 0.44 YWHAE protein P62258 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-252398 0.279 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG5-LLGL2_variant complex SIGNOR-C506 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270892 0.452 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273059 0.635 MAPKAPK2 protein P49137 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser179 RRFRRSQsDCGELGD -1 15850461 t miannu Human CapZIP was phosphorylated at Ser-179 and Ser-244 by MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) or MAPKAP-K3 in vitro. In the present paper we have identified CapZIP as a protein that is phosphorylated exceptionally rapidly by several SAPKs in vitro (Figure 4), and which is expressed in muscles and immune cells. Both MAPKAP-K2 and MAPKAP-K3 phosphorylated CapZIP at Ser-179 in vitro. An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263079 0.486 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser534 KSQHRSSsSAPHHNH 10441130 t miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation SIGNOR-250341 0.421 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNJ1 protein P48048 UNIPROT up-regulates activity phosphorylation Ser4 sSRNVFDT -1 12221079 t miannu We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface. SIGNOR-275989 0.2 MAPK9 protein P45984 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 BTO:0000782 14517246 t gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin SIGNOR-118223 0.551 Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR BMI1 protein P35226 UNIPROT up-regulates activity phosphorylation Ser316 ANRPRKSsVNGSSAT 22505453 t lperfetto The polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate SIGNOR-249584 0.7 panobinostat chemical CHEBI:85990 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257753 0.8 COL15A1 protein P39059 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. Types XV and XVIII collagen are classified as multiplexins, which are heparan sulfate proteoglycans (HSPGs). The multiplexins can bind growth factors and also aid in linking the basement membrane to other basement membrane glycoproteins and endomysium SIGNOR-254678 0.7 PIM1 protein P11309 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18593906 t gcesareni We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels. SIGNOR-179300 0.387 ribosomal RNA smallmolecule CHEBI:18111 ChEBI B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-269470 0.8 DNA polymerase alpha:primase complex complex SIGNOR-C262 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 24043831 f lperfetto At the replication fork, primase is present in a constitutive complex with DNA polymerase α (Pol α), which extends the RNA primer with deoxynucleotides and makes the resulting RNA–DNA primer available to the leading- and lagging-strand polymerases, Pols ε and δ, for processive elongation  SIGNOR-261344 0.7 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 ChEBI ADRA1D protein P25100 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258467 0.8 TGFB1 protein P01137 UNIPROT SFTPB protein P07988 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004299 18003659 f miannu TGF-beta represses transcription of pulmonary surfactant protein-B gene in lung epithelial cells. SIGNOR-254170 0.284 Caspase 3 complex complex SIGNOR-C221 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni Caspase-3 is responsible for apoptosis execution SIGNOR-256548 0.7 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Thr450 TAQMITItPPDQDDS 9606 11839802 t gcesareni Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2a and dephosphorylation of akt and glycogen synthase kinase 3 beta SIGNOR-114767 0.891 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT up-regulates activity binding 9606 BTO:0000776 15644327 t lperfetto Baff interacts with baff receptor (baffr). SIGNOR-133210 0.781 SMC5/6 complex SIGNOR-C374 SIGNOR Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 27427983 f miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265488 0.7 NDUFB1 protein O75438 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and |The main ND4-module intermediate binds NDUFB1, NDUFB4, NDUFB5, NDUFB6, NDUFB10, NDUFB11 and MT-ND4 SIGNOR-262162 0.77 NEK2 protein P51955 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 24695856 t lperfetto Our data support a model in which centrosome disjunction is triggered by the hyperphosphorylation of c-nap1, a major linker component. This occurs in response to a shift in the balance of activities of the nek2?_Pp1 bi-stable switch. C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro. SIGNOR-204833 0.769 CDK1 protein P06493 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser373 SSRSAPAsPNHAGVL 9606 20810654 t gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. SIGNOR-167822 0.377 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation Thr221 AGTSFMMtPYVVTRY 9606 BTO:0000007 17761173 t lperfetto We next examined whether the phosphorylation of JNK at threonine 183 (Thr183) and tyrosine 185 (Tyr185) was enhanced by GRASP‐1 expression. Phosphorylation of Thr183 and Tyr185 by SEK1/MKK4, which is in turn phosphorylated and activated by several kinases including MEKK1, is known to activate JNK1/2/3 SIGNOR-260614 0.737 NKRF protein O15226 UNIPROT IFNB1 protein P01574 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0005065 10562553 t Luana Constitutive silencing of IFN-beta promoter is mediated by NRF (NF-kappaB-repressing factor), a nuclear inhibitor of NF-kappaB SIGNOR-266227 0.364 sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-268133 0.8 BMP4 protein P12644 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 8006002 t fspada Bmp-4 bound to alk-3 and alk-6 efficiently SIGNOR-35763 0.776 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr120 HKFNVTGtPEQYVPY 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275588 0.2 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates activity phosphorylation Tyr145 PVEDDADyEPPPSND 9606 12817019 t lperfetto Phosphorylation of slp-76 is required for prolonged erk activation in response to sdf-1_ cr signal transduction results in slp-76 tyrosine phosphorylation at the amino-terminal tyrosines 113, 128, and 145 via a mechanism requiring the zap-70 tyrosine kinase. SIGNOR-102515 0.801 DDIT3 protein P35638 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260173 0.463 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 24098653 t fspada Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation SIGNOR-202706 0.695 IFNG protein P01579 UNIPROT SLC11A1 protein P49279 UNIPROT up-regulates 9606 BTO:0000801 11909746 f Functional studies in Nramp1 transfected macrophages have demonstrated that the Nramp1 protein plays a vital role in early macrophage activation [10,29,30]. Nramp1 is constitutively expressed in macrophage cell lines of the myeloid lineage (isolated peritoneal, splenic, and liver resident macrophages), and can be induced by treatment of macrophages with IFN-γ, or IFN-γ plus lipopolysaccharide (LPS) SIGNOR-254038 0.353 MYC protein P01106 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12835716 t gcesareni C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a SIGNOR-102740 0.775 KIF1B protein O60333 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272519 0.7 FGFR2 protein P21802 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates activity phosphorylation 10116 BTO:0002809 9182757 t fspada In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway. SIGNOR-236950 0.772 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000938 9346240 t lperfetto Experiments in this study reveal that akt phosphorylates bad both in vitro and in vivo and that akt-mediated phosphorylation of bad effectively blocks bad induced cell death.[...] In addition, these findings implicate a particular phosphorylation site on bad, serine 136, in the suppression of bad-mediated death by akt.[...]The Phosphorylation of bad may lead to the prevention of cell death via a mechanism that involves the selective association of the phosphorylated forms of bad with 14-3-3 protein isoforms. Akt phosphorylates bad in vitro and in vivo we show that growth factor activation of the pi3'k/akt signaling pathway culminates in the phosphorylation of the bcl-2 family member bad, thereby suppressing apoptosis and promoting cell survival. Akt phosphorylates bad in vitro and in vivo erbb-mediated phosphorylation of bad by akt promotes survival by blocking the interaction of this pro-apoptotic molecule with bcl-2 and bcl-x proteins SIGNOR-52859 0.819 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 10090 BTO:0000664 17475908 t miannu All together, these data indicate that ERK-dependent phosphorylation of hnRNP-E2 at serines 173, 189, and 272, and threonine 213 is responsible for increased hnRNP-E2 protein stability in BCR/ABL-transformed cells. SIGNOR-262668 0.2 FGF4 protein P08620 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. SIGNOR-18567 0.664 GDNF protein P39905 UNIPROT GCH1 protein P30793 UNIPROT up-regulates activity 9606 12358777 f miannu GDNF can support the function of primary dopaminergic neurones by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting that the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription SIGNOR-252221 0.28 GNAQ protein P50148 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates activity binding -1 17606614 t We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q) SIGNOR-256494 0.2 EPHA2 protein P29317 UNIPROT YES1 protein P07947 UNIPROT up-regulates activity phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 BTO:0001007 33941853 t miannu EphA2 interacts with YES1 and phosphorylates YES1 at Tyr426 site. SIGNOR-277556 0.407 Kindlin proteinfamily SIGNOR-PF48 SIGNOR Av/b3 integrin complex SIGNOR-C177 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259001 0.475 STC2 protein O76061 UNIPROT STC2/HMOX1 complex SIGNOR-C244 SIGNOR form complex binding BTO:0000298 22503972 t Giorgia Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is a heat shock protein.|Taken together, our findings point to three novel functions of STC2, and suggest that STC2 interacts with HO1 to form a eukaryotic 'stressosome' involved in the degradation of heme. SIGNOR-260387 0.349 LPAR2 protein Q9HBW0 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257382 0.587 PHF12 protein Q96QT6 UNIPROT TLE3 protein Q04726 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266993 0.2 HSPA1A protein P0DMV8 UNIPROT PACRG protein Q96M98 UNIPROT up-regulates quantity by stabilization binding -1 12150907 t miannu Our in vitro data suggest that CHIP competes with Hsp70 in binding to Parkin, probably via suppression of the ATPase activity of Hsc/Hsp70 (Figure 4E).In fact, it acts as an inhibitory factor that suppresses the ubiquitination of Pael-R mediated by Parkin in vitro, and Hsp70 enhances the efficiency of folding of overexpressed Pael-R in vivo. SIGNOR-272890 0.2 SDHC protein Q99643 UNIPROT SDH complex SIGNOR-C400 SIGNOR form complex binding 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. Four nuclear genes encode the four subunits, SDHA (15 exons), SDHB (8 exons), SDHC (6 exons) and SDHD (4 exons), mapping on to chromosomes 5p15, 1p35-p36.1, 1q21 and 11q23, respectively. SIGNOR-266273 0.954 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT up-regulates activity phosphorylation Tyr713 KKDTETVySEVRKAV 9606 BTO:0000007 12972546 t miannu PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1. SIGNOR-262868 0.279 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT down-regulates 9606 16308421 f gcesareni Foxo1 antagonized ppargamma activity and vice versa indicating that these transcription factors functionally interact in a reciprocal antagonistic manner. SIGNOR-252915 0.2 UFL1 protein O94874 UNIPROT ATM protein Q13315 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000007 30886146 t lperfetto UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation. UFL1 is recruited to double strand breaks by the MRE11/RAD50/NBS1 complex, and monoufmylates histone H4 following DNA damage. SIGNOR-265073 0.2 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16235 0.568 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C29 SIGNOR-C29 18756288 t gcesareni Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-180545 0.621 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser159 KKKKKRFsFKKSFKL -1 1560845 t gcesareni Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin SIGNOR-243192 0.724 ZMYND11 protein Q15326 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding methylation:Lys38 PSTGGVKkPHRYRPG 24675531 t miannu We found that full-length BS69 specifically interacted with H3K36me3 in native nucleosome co-immunoprecipitation (co-IP) experiments. We propose that BS69 specifically associates with H3K36me3-enriched chromatin through the PWWP domain, which facilitates the recruitment of MYND-bound transcription and chromatin remodeling factors including EZH2, HDAC1, Brg1 and E2F6 to target gene loci, thereby repressing target gene transcription. SIGNOR-263897 0.2 PLCG1 protein P19174 UNIPROT ITPRIPL1 protein Q6GPH6 UNIPROT up-regulates 9606 BTO:0000938 21368195 f gcesareni Recruitment of g protein also can activate phospholipase c (plc) that in turn increases inositol triphosphate (ip3) levels and induces ca2+ release from internal stores SIGNOR-172500 0.2 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser709 SEEEEEEsDSSETEK -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276252 0.2 UVB radiation stimulus SIGNOR-ST17 SIGNOR cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI down-regulates quantity chemical modification 9606 BTO:0001253 30080183 t lperfetto Ultraviolet radiation results in the conversion of 7-dehydrocholesterol to pre-vitamin D, which isomerizes to vitamin D in the skin SIGNOR-270563 0.7 RARA protein P10276 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t inferred from family member gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-270293 0.524 calcium(2+) smallmolecule CHEBI:29108 ChEBI Cadherins proteinfamily SIGNOR-PF71 SIGNOR up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265811 0.8 G6PC1 protein P35575 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 12093795 t miannu Glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, is anchored to the endoplasmic reticulum by nine transmembrane helices. The amino acids comprising the catalytic center of G6Pase include Lys(76), Arg(83), His(119), Arg(170), and His(176). During catalysis, a His residue in G6Pase becomes phosphorylated generating an enzyme-phosphate intermediate. Glucose-6-phosphatase (G6Pase,1 EC 3.1.3.9), a key enzyme in glucose homeostasis, catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and phosphate, the terminal steps in gluconeogenesis and glycogenolysis SIGNOR-266582 0.8 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates activity binding 10090 BTO:0000944 19171758 t miannu In this study, we report that Kank disrupts the function of active Rac1 through IRSp53. The binding between IRSp53 and Kank inhibits the association of active Rac1 with IRSp53 rather than the association of active cdc42 with IRSp53. Kank inhibits the formation of lamellipodia and membrane ruffles induced by active Rac1 in NIH3T3 cells. SIGNOR-265554 0.732 MTOR protein P42345 UNIPROT DAP protein P51397 UNIPROT down-regulates activity phosphorylation Ser3 DQEWESPsPPKPTVF 9606 20537536 t miannu A critical step in autophagy induction comprises the inactivation of a key negative regulator of the process, the Ser/Thr kinase mammalian target of rapamycin (mTOR). Here we identify death-associated protein 1 (DAP1) as a novel substrate of mTOR that negatively regulates autophagy. Mapping of the phosphorylation sites and analysis of phosphorylation mutants indicated that DAP1 is functionally silenced in growing cells through mTOR-dependent phosphorylations on Ser3 and Ser51. SIGNOR-259813 0.402 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser834 GSHTSGQsNGRDHQA 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276509 0.374 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BU1 protein Q8N257 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRGRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271990 0.2 GYS1 protein P13807 UNIPROT UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI down-regulates quantity chemical modification 9606 26882899 t miannu Glycogenin initiates the first step of glycogen synthesis by self glycosylation of a short 8–12 glucose oligosaccharide primer. Glycogen synthase (GYS) elongates the glucose oligossacharide primer, which utilises UDP-glucose as the glucosyl donor. SIGNOR-267938 0.8 RPS6KA4 protein O75676 UNIPROT TP53 protein P04637 UNIPROT down-regulates 9606 19797274 f gcesareni Mitogen- and stress-activated kinase 2 (msk2) inhibits the transcription factor p53, and we investigate here the mechanisms underlying this inhibition. In the absence of stress stimuli, msk2 selectively suppressed the expression of a subset of p53 target genes.Msk2 can also control the the transcriptional activity of p53 in a kinase-indipendent mannermsk2 can also control the the transcriptional activity of p53 in a kinase-indipendent manner SIGNOR-188334 0.251 AKT proteinfamily SIGNOR-PF24 SIGNOR ILF3 protein Q12906 UNIPROT up-regulates activity phosphorylation Ser647 RGRGRGGsIRGRGRG 9606 20870937 t llicata Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our previous work showed that CD28 costimulation of T cells activated AKT to phosphorylate NF90 at Ser647 and caused NF90 to undergo nuclear export and stabilize IL-2 mRNA. SIGNOR-168169 0.2 DAB1 protein O75553 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000142 22394407 t lperfetto The induction of disabled-1 (dab-1) tyrosine phosphorylation, and the subsequent activation of src family kinases, were found to be essential steps for the activation of notch-1 signaling by reelin SIGNOR-196438 0.384 DRAM2 protein Q6UX65 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30755245 f irozzo DRAM2 plays an oncogenic role in NSCLC via regulating p53 expression. Knockdown of DRAM2 caused an increase of p53 and p21 expression, and overexpression of p53 caused a decrease of DRAM2 expression. SIGNOR-259147 0.2 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 10734133 t gcesareni These results, combined with secondary dephosphorylation tests, confirm and extend earlier findings that ptp-1b and t-cell ptp are physiological enzymes for the insulin receptor kinase. SIGNOR-76088 0.307 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser429 KEESVESsLPLNAIE 9606 BTO:0000007 19816404 t lperfetto These data indicate that atm is responsible for directly phosphorylating s386 and s429 after dna damagemdm2 phosphorylation inhibits p53 poly ubiquitination SIGNOR-188412 0.751 TGFB1 protein P01137 UNIPROT ANKH protein Q9HCJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20930330 f miannu TGF-β1 was shown to stimulate ANK and PC-1 expression in articular chondrocytes, and subsequent ePPi level, as well as to increase ePi uptake by inducing PiT-1 expression in a chondrogenic cell line. SIGNOR-252201 0.2 Monobutylphthalate chemical CHEBI:88522 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9606 BTO:0000816 16326050 t miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SIGNOR-268752 0.8 PTPN22 protein Q9Y2R2 UNIPROT CBL protein P22681 UNIPROT down-regulates dephosphorylation Ser798 SDISNASsSFGWLSL 9606 BTO:0000782 10068674 t amattioni The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state. SIGNOR-65405 0.392 PRKCD protein Q05655 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Ser29 ATPAARAsKKILLPE 9606 BTO:0000007 11042191 t lperfetto Phosphorylation of GRK2 by protein kinase C abolishes its inhibition by calmodulin. In vitro, GRK2 was preferentially phosphorylated by PKC isoforms alpha, gamma, and delta. Two-dimensional peptide mapping of PKCalpha-phosphorylated GRK2 showed a single site of phosphorylation, which was identified as serine 29 by HPLC-MS. A S29A mutant of GRK2 was not phosphorylated by PKC in vitro and showed no phorbol ester-stimulated phosphorylation when transfected into human embryonic kidney (HEK)293 cells. SIGNOR-249059 0.2 SMO protein Q99835 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 16885213 t gcesareni We found that smo, by virtue of what appears to be constitutive activity, activates all members of the g(i) family but does not activate members of the g(s), g(q), and g(12) families. SIGNOR-148484 0.2 ketanserin chemical CHEBI:6123 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258685 0.8 RPIA protein P49247 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267070 0.8 RNF111 protein Q6ZNA4 UNIPROT PML protein P29590 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530056 t miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. SIGNOR-272883 0.359 NMDA receptor_2B complex SIGNOR-C348 SIGNOR CTTN protein Q14247 UNIPROT up-regulates quantity relocalization 9606 BTO:0000142 14684878 t miannu Here we show that cortactin is concentrated with F-actin in dendritic spines of cultured hippocampal neurons but is redistributed to the dendritic shaft in response to NMDA receptor activation. these findings indicate that the translocation of cortactin is induced by the activation of NMDA receptors. SIGNOR-266600 0.302 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CALD1 protein Q05682 UNIPROT down-regulates phosphorylation 9606 BTO:0001260 10514499 t inferred from 70% family members lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-270162 0.2 WNT10B protein O00744 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131625 0.607 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser637 VDLSKVTsKCGSLGN -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250085 0.512 PBX2 protein P40425 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265778 0.253 ILK protein Q13418 UNIPROT CFL1 protein P23528 UNIPROT down-regulates phosphorylation Ser3 sGVAVSDG 9606 18252715 t gcesareni Actin (de)polymerization is regulated by cofilin, the ser(3) phosphorylation (ps(3)cofilin) of which inhibits its actin-severing activity. To determine how ilk regulates ps(3)cofilin, we examined the effects of ilk on ps(3)cofilin using normal rie1 cells. SIGNOR-160756 0.354 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser164 FGHSAAVsPTFMPRS 9606 12050114 t gcesareni Tob is rapidly phosphorylated at ser 152, ser 154, and ser 164 by erk1 and erk2 upon growth-factor stimulation. SIGNOR-88724 0.358 CBL protein P22681 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. SIGNOR-252668 0.601 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT up-regulates 9606 9362449 f Nck interacts witn ErbB1 through SH2 and SH3 domains gcesareni We found that nck does not directly bind to egf receptor, instead it binds via its sh2 domain to a 62 kda phosphotyrosine protein SIGNOR-52954 0.586 CAMK2A protein Q9UQM7 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Thr66 ATRKALGtVNRATEK 9606 BTO:0000567 24781523 t miannu CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase SIGNOR-276377 0.312 RNF152 protein Q8N8N0 UNIPROT RRAGA protein Q7L523 UNIPROT down-regulates activity polyubiquitination 9606 BTO:0000007 25936802 t miannu  Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases.  SIGNOR-272222 0.734 SHOC2 protein Q9UQ13 UNIPROT PPP1CA protein P62136 UNIPROT up-regulates activity binding 9606 BTO:0000007 16630891 t Using a proteomics approach, we have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site SIGNOR-251647 0.584 PEX1 protein O43933 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding 10029 16314507 t Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. SIGNOR-253618 0.56 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser535 ESEQSMDsEEPDSRG -1 12133000 t The largest (epsilon) subunit of eIF2B is a substrate for glycogen synthase kinase (GSK)-3 in vitro, and phosphorylation by GSK3 inhibits the activity of eIF2B. The site of phosphorylation has previously been identified as Ser(535). SIGNOR-251236 0.568 DOK1 protein Q99704 UNIPROT Av/b8 integrin complex SIGNOR-C185 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257699 0.2 RPL41 protein P62945 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262458 0.2 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity precursor of 9606 24632615 t miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. SIGNOR-266555 0.8 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 15831498 t gcesareni Here we present evidence that smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of smad7 on two lysine residues in its n terminus. Acetylation or mutation of these lysine residues stabilizes smad7 and protects it from tgfbeta-induced degradation. we have recently shown that smad7 is acetylated on lysine residues 64 and 70 by p300 SIGNOR-135469 0.471 KDM4C protein Q9H3R0 UNIPROT AR protein P10275 UNIPROT up-regulates activity binding 9606 BTO:0001033 29207681 t miannu JMJD2C was found to be co-localized with AR and LSD1 in the epithelium of prostate carcinoma and normal prostate cells. For the detailed mechanism, JMJD2C, AR and LSD1 assembled on the chromatin to remove the methyl groups from mono-, di- and trimethylated H3K9. Importantly, JMJD2C specifically removed the demethylation of the trimethyl H3K9 marks and modulated the transcriptional activity of AR. Moreover, JMJD2C cooperated with LSD1 and activated AR-mediated gene expression via decreasing H3K9me3 at the promoter of AR targeting genes KLK2 and PSA. SIGNOR-263879 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 24877152 f Conversely, a reduced amount of IGF-1R diminished the levels of P-AKT, allowing dissociation and nuclear translocation of Smad3 and enhancement of the TGFŒ≤1 signaling pathway and fibrosis SIGNOR-254375 0.7 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1B protein P49286 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257546 0.8 PLK1 protein P53350 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity phosphorylation Thr680 SKMQLLEtEFSHTVG -1 18922800 t miannu These findings indicate mechanistic roles contributed by protein phosphorylation and Plk1 to the SAC activity of Mad1.Here, we have studied the phosphorylation of Mad1 and mapped using liquid chromatography-tandem mass spectrometry several phosphorylated amino acids in this protein. One phosphorylated residue, Thr680, was characterized to be important for the kinetochore localization of Mad1 and its SAC function. SIGNOR-276173 0.45 DYRK1B protein Q9Y463 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser240 KVAERRSsPLLRRKD 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 15546868 t lperfetto Mirk activated mef2 not through direct phosphorylation of mef2 but by phosphorylation of its inhibitors, the class ii histone deacetylases (hdacs). Mef2 is sequestered by class ii hdacs such as hdac5 and mef2-interacting transcriptional repressor (mitr). Mirk antagonized the inhibition of mef2c by mitr, whereas kinase-inactive mirk was ineffective. Mirk phosphorylates class ii hdacs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner SIGNOR-235813 0.2 PPARG protein P37231 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 16150867 f lperfetto Adipocyte differentiation is regulated largely through the actions of the peroxisome proliferator-activated receptor (PPAR) gamma nuclear receptor SIGNOR-228622 0.7 GSK3B protein P49841 UNIPROT CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells SIGNOR-154668 0.442 PLG protein P00747 UNIPROT Fibrinolysis phenotype SIGNOR-PH6 SIGNOR up-regulates 9606 1447176 f lperfetto The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme SIGNOR-263535 0.7 KIT protein P10721 UNIPROT SLA protein Q13239 UNIPROT down-regulates activity phosphorylation Tyr273 SFFSSPPyFED 9534 BTO:0001538 24284075 t miannu Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity SIGNOR-263142 0.2 LMO2 protein P25791 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 f miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. SIGNOR-198249 0.335 CDK2 protein P24941 UNIPROT ID3 protein Q02535 UNIPROT down-regulates phosphorylation Ser5 sPVRGCYE 9606 9372912 t lperfetto We now show that an analogous cell-cycle-regulated phosphorylation of id3 alters the specificity of id3 for abrogating both e-box-dependent bhlh homo- or heterodimer complex formation in vitro and e-box-dependent reporter gene function in vivo._ SIGNOR-53306 0.346 E2F1 protein Q01094 UNIPROT TLR3 protein O15455 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 22310660 f lperfetto Together, these data indicated that E2F1 suppresses TLR3 transcription, but during immune stimulation, Rb is upregulated to block the inhibitory effect of E2F1 on TLR3, highlighting a role of Rb-E2F1 axis in the innate immune response in epithelial cells. SIGNOR-254136 0.2 UFD1 protein Q92890 UNIPROT AMFR protein Q9UKV5 UNIPROT up-regulates activity binding 17681147 t miannu Here we show that Ufd1 directly interacts with gp78 and functions as a cofactor. Ufd1 enhances the E3 activity of gp78, accelerates the ubiquitination and degradation of reductase, and eventually promotes receptor-mediated uptake of low-density lipoprotein. SIGNOR-252425 0.2 CAMK4 protein Q16566 UNIPROT HDAC4 protein P56524 UNIPROT down-regulates activity phosphorylation Ser467 RPLGRTQsAPLPQNA BTO:0001938 11470791 t llicata CaMKIV phosphorylates HDAC4 in vitro and promotes its nuclear-cytoplasmic shuttling in vivo. | Thus, CaMKIV can phosphorylate HDAC4 at Ser-467 and/or Ser-632 in vitro. | Collectively, our results suggest that CaMKIV reverses the transcriptional repression activity of HDAC4 by stimulating the mobilization of HDAC4 out of the nucleus. SIGNOR-250711 0.61 FOXO1 protein Q12778 UNIPROT POMC protein P01189 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000614 28270795 f miannu Foxo1 (when activated) stimulates the transcription of AgRP and NPY, but suppresses the transcription of POMC; thereby antagonizing the transcriptional action of STAT3 in these hypothalamic subpopulations. SIGNOR-263503 0.412 bexarotene chemical CHEBI:50859 ChEBI RXR proteinfamily SIGNOR-PF44 SIGNOR up-regulates activity chemical activation 9606 BTO:0002058 17483357 t miannu Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification. SIGNOR-259233 0.8 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser168 QGGGAFFsPSPGSSS 9606 11997522 t lperfetto Phosphorylation of nfatc4 by p38 mitogen-activated protein kinasesthe p38 map kinase phosphorylates multiple residues, including ser(168) and ser(170), in the nfat homology domain of nfatc4. Replacement of ser(168,170) with ala promotes nuclear localization of nfatc4 and increases nfat-mediated transcription activity. SIGNOR-87393 0.2 CBL protein P22681 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates ubiquitination 9606 BTO:0000782 11526404 t lperfetto Cbl-b, a ring-type e3 ubiquitin protein ligase, is implicated in setting the threshold of t lymphocyte activation. The p85 regulatory subunit of phosphatidylinositol 3 kinase (pi3k) was identified as a substrate for cbl-b. We have shown that cbl-b negatively regulated p85 in a proteolysis-independent manner. SIGNOR-110060 0.685 TGFB1 protein P01137 UNIPROT CDK2 protein P24941 UNIPROT down-regulates 9606 SIGNOR-C16 10611320 f gcesareni Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2. SIGNOR-73537 0.285 MAPK3 protein P27361 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser674 QSPKRPRsPGSNSKV 9606 10648599 t lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-74308 0.379 N-(2,6-difluorophenyl)-5-[3-[2-[5-ethyl-2-methoxy-4-[4-(4-methylsulfonyl-1-piperazinyl)-1-piperidinyl]anilino]-4-pyrimidinyl]-2-imidazo[1,2-a]pyridinyl]-2-methoxybenzamide chemical CHEBI:91401 ChEBI INSR protein P06213 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192883 0.8 SMOC1 protein Q9H4F8 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20359165 f lperfetto The expression of several osteoblast differentiation markers (ALP, COL1, OPN, ON, BSP and OC) was higher in SMOC1-overexpressing cells than in emptyvector-expressing cells SIGNOR-260400 0.2 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR down-regulates 9606 BTO:0000132 23805129 f lperfetto Inhibition of actin polymerization also augments the kinetics and degree of alpha-granule release (Flaumenhaft et al., 2005). These results suggest that F-actin disassembly might actually be required for normal granule secretion and that activation-mediated granule release is related to actin. SIGNOR-266000 0.7 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser66 GVYATRSsAVRLRSS -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248884 0.287 DLG4 protein P78352 UNIPROT LRFN2 protein Q9ULH4 UNIPROT up-regulates activity binding 9606 BTO:0000938 21736948 t miannu SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses. SIGNOR-264094 0.744 GSDMD protein P57764 UNIPROT Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates cleavage:Asp275 CLHNFLTdGVPAEGA 26375003 f lperfetto These results establish that proteolytic cleavage at Asp275 in GSDMDis sufficient to instructmammalian cells to undergo pyroptosis SIGNOR-256416 0.7 MC3R protein P41968 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257358 0.274 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr287 RDPLLEVyDVPPSVE 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246405 0.799 UVB radiation stimulus SIGNOR-ST17 SIGNOR MC1R protein Q01726 UNIPROT up-regulates 9606 9767234 f miannu Melanocyte-stimulating hormone (MSH) receptor binding activity and melanocortin-1 receptor (MC1-R) gene expression on normal human melanocytes have been studied as responses to the effects of ultraviolet B (UVB), interleukin-1 (IL-1), endothelin-1 (ET-1) and tumour necrosis factor-alpha (TNF-alpha), which are known as UV sensitive regulators of melanocytic function. MSH receptor (MSH-R) binding activity was upregulated by UVB, IL-1alpha, -1beta and ET-1, but was downregulated by TNF-alpha.Northern blotanalysis showed that MC1-R mRNA expression was induced 24 h after UVB irradiation in a dose-dependent manner, and that 24-h treatment with ET-1 also induced an expression of MC1-R mRNA,whereas TNF-a downregulated the expression. In addition, IL-1a and -1b have a small but real inductiveeffect on MC1-R mRNA expression. SIGNOR-252388 0.7 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89166 0.544 WNT11 protein O96014 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates 9606 BTO:0000938 BTO:0000887 22309736 f gcesareni We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles. SIGNOR-195963 0.2 CYCS protein P99999 UNIPROT Apoptosome complex SIGNOR-C230 SIGNOR form complex binding -1 10206961 t lperfetto  APAF-1 binds and hydrolyzes ATP or dATP to ADP or dADP, respectively. The hydrolysis of ATP/dATP and the binding of cytochrome c promote APAF-1 oligomerization, forming a large multimeric APAF-1.cytochrome c complex. Such a complex can be isolated using gel filtration chromatography and is by itself sufficient to recruit and activate procaspase-9.  SIGNOR-256430 0.833 GATA6 protein Q92908 UNIPROT CYP17A1 protein P05093 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002850 BTO:0000975 15284005 f miannu The transcription factor GATA6, which regulates the promoter activity of CYP17 and CYP11A, was increased in the PCOS compared to normal theca cells. SIGNOR-254198 0.35 DUSP23 protein Q9BVJ7 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser322 NYPFPLTsWPCSFSP 9606 20855292 t lperfetto DUSP23 prevents GCM1 from ubiquitination and prolongs the half-life of GCM1.|Second, DUSP23 is able to dephosphorylate Ser322 in GCM1 in vitro and in a stable cell line expressing HA-GCM1. SIGNOR-276982 0.472 PRKCZ protein Q05513 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 17183360 t lperfetto Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) SIGNOR-217370 0.485 PAMPs stimulus SIGNOR-ST11 SIGNOR NAIP protein Q13075 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256424 0.7 PPARD protein Q03181 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001951 18048767 f miannu Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. SIGNOR-255053 0.268 HDAC1 protein Q13547 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates activity deacetylation 10090 24463822 t The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a SIGNOR-256486 0.373 PRKCD protein Q05655 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation Ser318 GDKILQVsFKTNKSH 9606 20086103 t lperfetto Tandem phosphorylation of serines 221 and 318 by protein kinase cdelta coordinates mrna binding and nucleocytoplasmic shuttling of hurstabilization of mrna by the ubiquitous rna binding protein human antigen r (hur), a member of the embryonic lethal abnormal vision (elav) protein family, requires canonical binding to au-rich element (are)-bearing target mrna and export of nuclear hur-mrna complexes to the cytoplasm. In human mesangial cells (hmc) both processes are induced by angiotensin ii (angii) via protein kinase cdelta (pkcdelta)-triggered serine phosphorylation of hur. SIGNOR-163528 0.628 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates phosphorylation 9606 18596912 t lbriganti The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-210182 0.465 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 14707117 t gcesareni Furthermore, we demonstrate that pstpip serves as a scaffold protein between ptp-pest and wasp and allows ptp-pest to dephosphorylate wasp. This finding suggests a possible mechanism for ptp-pest to directly modulate actin remodeling through the pstpip-wasp interaction. SIGNOR-121136 0.451 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 21098032 t gcesareni Kinase activity of plk3 was significantly activated by hyperosmotic stimulation. Further downstream, active plk3 phosphorylated atf-2 at the thr-71 site in vivo and in vitro. SIGNOR-170008 0.2 PAMPs stimulus SIGNOR-ST11 SIGNOR MEFV protein O15553 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256426 0.7 TSC complex SIGNOR-C101 SIGNOR RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-235895 0.915 PAX7 protein P23759 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18854138 f lperfetto Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-181624 0.61 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269253 0.836 AURKB protein Q96GD4 UNIPROT NSUN2 protein Q08J23 UNIPROT down-regulates phosphorylation Ser139 SRKILRKsPHLEKFH 9606 17215513 t lperfetto Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2. SIGNOR-152001 0.714 SGK1 protein O00141 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser1130 GARDRVRsMSGGHGL -1 27451907 t miannu SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.  SIGNOR-277266 0.59 PYCARD protein Q9ULZ3 UNIPROT NLRP1 inflammasome complex SIGNOR-C224 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256408 0.678 MRGPRX2 protein Q96LB1 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257385 0.2 LEF1 protein Q9UJU2 UNIPROT CEBPA protein P49715 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19620402 f miannu We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha. SIGNOR-254551 0.353 ER stress stimulus SIGNOR-ST9 SIGNOR QRICH1 protein Q2TAL8 UNIPROT up-regulates 9606 33384352 f miannu QRICH1 promotes cell death under ER stress SIGNOR-269398 0.7 IL4R protein P24394 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 18852293 t lperfetto Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6. SIGNOR-249530 0.614 AIM2 protein O14862 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR form complex binding 30288079 t lperfetto Canonical inflammasomes form activation platforms for caspase-1. Their assembly depends on some dedicated cytosolic PRRs from the nucleotide-binding domain leucin-rich repeat (NLR) family including NLR and pyrin domain containing receptor 1 (NLRP1), NLRP3, and NLR and caspase recruitment domain containing receptor 4 (NLRC4); the AIM2-like receptors (ALR) family including absent in melanoma 2 (AIM2); or the tripartite motif (TRIM) family including pyrin. SIGNOR-256399 0.744 ACTB protein P60709 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR up-regulates 9606 BTO:0000007 19121306 f lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260610 0.309 MTHFD1 protein P11586 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268249 0.8 MT-CO3 protein P00414 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267743 0.677 LCK protein P06239 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr537 CKNVVPLyDLLLEML 9606 BTO:0000150;BTO:0000567 9500442 t gcesareni On the basis of these data and other reports describing the structure and activity of y537 mutations, as well as knowledge of the three-dimensional structure of the her ligand binding domain, we propose an alternate model wherein y537f mutation favors an open pocket conformation, affecting the estrogen binding kinetics and stability of the hormone-bound, transcriptionally active closed pocket conformation. SIGNOR-55853 0.388 RPS6KA1 protein Q15418 UNIPROT Translational_regulation phenotype SIGNOR-PH202 SIGNOR up-regulates 9606 17360704 f gianni Mutation of rpS6 at Ser(235/236) reveals that phosphorylation of these sites promotes its recruitment to the 7-methylguanosine cap complex, suggesting that Ras/ERK signaling regulates assembly of the translation preinitiation complex. These data demonstrate that RSK provides an mTOR-independent pathway linking the Ras/ERK signaling cascade to the translational machinery. SIGNOR-268528 0.7 ATM protein Q13315 UNIPROT RIF1 protein Q5UIP0 UNIPROT up-regulates activity binding 9606 15342490 t miannu Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. After induction of double-strand breaks (DSBs), Rif1 formed foci that colocalized with other DNA-damage-response factors. This response was strictly dependent on ATM (ataxia telangiectasia mutated) and 53BP1, but not affected by diminished function of ATR (ATM- and Rad3-related kinase), BRCA1, Chk2, Nbs1, and Mre11. SIGNOR-259059 0.485 SRC protein P12931 UNIPROT GRK2 protein P25098 UNIPROT up-regulates activity phosphorylation Tyr92 FYEEIKKyEKLETEE 16725308 t miannu Here, we demonstrate that c-Src kinase activity increases the interaction between GRK2 and Galphaq. Tyrosine phosphorylation of GRK2 appears to be critically involved in the modulation of this interaction since the stimulatory effect of c-Src is not observed with a GRK2 mutant with impaired tyrosine phosphorylation (GRK2 Y13,86,92F), whereas a mutant that mimics GRK2 tyrosine phosphorylation in these residues displays an increased interaction with Galphaq.  SIGNOR-266293 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR leucine smallmolecule CHEBI:25017 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270413 0.8 FFAR4 protein Q5NUL3 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256773 0.251 beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI PFKM protein P08237 UNIPROT up-regulates activity binding 9606 19454274 t The PFKFB enzymes synthesize fructose-2,6-bisphosphate (F2,6BP) which allosterically activates 6-phosphofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. PFK-1 is inhibited by ATP when energy stores are abundant and F2,6BP can override this inhibition and enhance glucose uptake and glycolytic flux SIGNOR-267267 0.8 SIRT2 protein Q8IXJ6 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by stabilization 9606 23175188 f miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. SIGNOR-255147 0.381 PRKCZ protein Q05513 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates quantity by destabilization phosphorylation Ser249 ARTFSRMsLLHKHQE 9606 BTO:0001939 30804505 t miannu APKC kinases phosphorylate S249 of SNAI1, which leads to protein degradation. SIGNOR-277437 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR PDCD1 protein Q15116 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys233 LDFQWREkTPEPPVP 9606 BTO:0000007 36104103 t miannu We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. SIGNOR-277606 0.2 PIP5K1A protein Q99755 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 18772438 f gcesareni Wnt3a stimulates the formation of phosphatidylinositol 4,5-bisphosphates [ptdins (4,5)p2] through frizzled and dishevelled, the latter of which directly interacted with and activated pip5ki. In turn, ptdins (4,5)p2 regulated phosphorylation of lrp6 at thr1479 and ser1490 SIGNOR-180800 0.275 NFKB1 protein P19838 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001321 11909978 t NF-kappa B activates prostate-specific antigen expression and is upregulated in androgen-independent prostate cancer. SIGNOR-253668 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252347 0.2 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248356 0.461 ABL1 protein P00519 UNIPROT EGFR protein P00533 UNIPROT up-regulates phosphorylation Tyr1172 ISLDNPDyQQDFFPK 9606 16943190 t gcesareni We show that activated abl phosphorylates the egfr primarily on tyrosine 1173. SIGNOR-149273 0.425 CORT protein O00230 UNIPROT MRGPRX2 protein Q96LB1 UNIPROT up-regulates binding 9606 BTO:0000938 16111673 t gcesareni The mrgx2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin n-terminal peptides (pamp) SIGNOR-139855 0.521 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by stabilization phosphorylation Thr56 FSSQPGHtPHPAASR 9606 10669763 t gcesareni Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation. p44mapk/extracellular signal-regulated kinase 1 (erk1) and p42 mapk/erk2 are activated by il-3, colocalize with mitochondrial bcl2, and can directly phosphorylate bcl2 on ser-70 in a stauro-resistant manner both_ in vitro_ and_ in vivo. SIGNOR-74939 0.548 PGM2 protein Q96G03 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI down-regulates quantity chemical modification 9606 32898648 t miannu Human PGM1 deficiency is an inborn error of metabolism (OMIM: 614921), affecting cellular glucose homeostasis, the storage of glucose as glycogen, and the N-glycosylation of proteins. Like other PGM enzymes, the human protein catalyzes the Mg2+-dependent interconversion of glucose 1-phosphate (G1P) and glucose 6-phosphate (G6P). SIGNOR-268116 0.8 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1899 SPTYSPTsPVYTPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120144 0.314 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 15125841 t Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro SIGNOR-248816 0.851 MIF protein P14174 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by destabilization relocalization 10090 BTO:0004488 29371591 t P00441:p.Gly94Ala (mutation causing interaction) Here, we show that MIF inhibits mutant SOD1 nuclear clearance when overexpressed in motor neuron-like NSC-34 cells|SOD1WT is evenly distributed between the cytoplasm and the nucleus while mutant SOD1G93A shows predominantly cytoplasmic distribution (Fig. 1a, b). Expression of MIF in cells expressing SOD1WT had no effect on the distribution of the SOD1WT–EGFP protein. However, expression of MIF together with the mutant SOD1G93A–EGFP, inhibited the nuclear clearance of misfolded SOD1 resulting in a more wild-type-like distribution of the mutant SOD1 protein SIGNOR-262797 0.31 dactolisib chemical CHEBI:71952 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 BTO:0000848 21803746 t ATP-competitive inhibitor of PI3K and mTOR gcesareni While the pi3k inhibitors, ly294002 or wortmannin, in the presence of plx4032 were individually inactive against pprm cell lines (fig. S4), the dual pi3k and mtorc1/2 inhibitor bez235 was highly specific (vs. parental lines) and potent in growth-inhibiting pprm cell lines SIGNOR-175709 0.8 MAPK1 protein P28482 UNIPROT PTTG1 protein O95997 UNIPROT up-regulates phosphorylation Ser165 LFQLGPPsPVKMPSP 9606 10906323 t gcesareni Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function. SIGNOR-79515 0.357 ZBTB20 protein Q9HC78 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 23776228 t miannu ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription. SIGNOR-266868 0.26 CH5132799 chemical CID:49784945 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190937 0.8 MAPK3 protein P27361 UNIPROT BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr753 YACASPKtPIQAGGY 9606 19933846 t gcesareni Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity. SIGNOR-161819 0.635 BMP10 protein O95393 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000562 16049014 t acerquone We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins. SIGNOR-139052 0.623 SPI1 protein P17947 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 20861919 f apalma In the myeloid compartment, Gfi1 is part of a regulatory network that determines lineage fate decision between granulocyte and monocyte/macrophage development. In this compartment, Gfi1 antagonizes the function of the transcription factor Pu.1. Pu.1 promotes monocytic differentiation, whereas Gfi1 enhances granulocytic differentiation. SIGNOR-256372 0.7 SOHLH1 protein Q5JUK2 UNIPROT ZP3 protein P21754 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16690745 t Luana Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters. SIGNOR-266078 0.384 NR0B1 protein P51843 UNIPROT NCOR2 protein Q9Y618 UNIPROT up-regulates activity binding 9606 BTO:0002588 19237537 t miannu The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes. SIGNOR-271785 0.398 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Ser372 EEIYGANsPIWESGF 24870244 t lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) SIGNOR-275496 0.406 pirenzepine chemical CHEBI:8247 ChEBI CHRM3 protein P20309 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258395 0.8 LAMTOR5 protein O43504 UNIPROT LIN28B protein Q6ZN17 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23494474 f miannu We found that HBXIP was able to upregulate Lin28B in breast cancer MCF-7 cells. SIGNOR-255251 0.252 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885022 t gcesareni We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase SIGNOR-148447 0.768 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Thr507 FGESRAStFCGTPDY 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. studies reported herein show that a t505a substitution reduces pkcdelta-thr(295) autophosphorylation SIGNOR-185287 0.2 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Ser396 GHQGTVPsDNIDSQG -1 8662852 t we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411). SIGNOR-251195 0.687 SEPTIN7 protein Q16181 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 SIGNOR form complex binding 9606 16914550 t miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. SIGNOR-148898 0.2 MAPK1 protein P28482 UNIPROT ALOX5 protein P09917 UNIPROT up-regulates activity phosphorylation Ser272 CSLERQLsLEQEVQQ 9606 BTO:0000567 12670876 t lperfetto Intriguingly, a significant difference in the potency of nonredox-type inhibitors (but not of BWA4C) was determined between wild-type 5-LO and the mutant S271A/S663A-5-LO (lacking phosphorylation sites for ERK1/2 and MAPKAPK-2) in HeLa cells. Collectively, our data suggest that compared with Ca2+-mediated 5-LO product formation, enzyme activation involving 5-LO phosphorylation events specifically and strongly alters the susceptibility of 5-LO toward nonredox-type inhibitors in intact cells. SIGNOR-264439 0.387 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin SIGNOR-182840 0.606 FBXW7 protein Q969H0 UNIPROT JUN protein P05412 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 14739463 t miannu  We report that in neurons the stability of c-Jun is regulated by the E3 ligase SCF(Fbw7), which ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.  SIGNOR-272950 0.504 VAV1 protein P15498 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 9013873 f gcesareni Vav may link gp130 activation to downstream mapk activation in hematopoietic cells. SIGNOR-46064 0.518 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR Core Binding Factor complex complex SIGNOR-C214 SIGNOR down-regulates activity relocalization 9606 BTO:0000661 9632809 f The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, α and β. The gene encoding the β subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, β-SMMHC, which is associated with acute myelogenous leukemia.Thus, the result suggess that β-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the α subunit. SIGNOR-255741 0.2 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR down-regulates activity chemical inhibition 9606 32745890 t miannu Glucose deprivation, activates the glucose level–sensing kinase, AMPK, which in turn influences Rac1-dependent macropinocytosis. In this context macropinosomes take up necrotic cell debris as a rich nutrient source to fuel tumor cell growth SIGNOR-277765 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262522 0.2 SLC36A4 protein Q6YBV0 UNIPROT proline smallmolecule CHEBI:26271 ChEBI up-regulates quantity relocalization 8355 21097500 t lperfetto HPAT4 in Xenopus oocytes mediated sodium-independent, electroneutral uptake of [(3)H]proline, with the highest rate of uptake when the uptake medium pH was 7.4 and an affinity of 3.13 μM. Tryptophan was also an excellently transported substrate with a similarly high affinity (1.72 μM). SIGNOR-264736 0.8 CSNK2A2 protein P19784 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity phosphorylation Thr770 DSILRLQtWDEAVFR 9606 BTO:0000007 21068236 t miannu Phosphorylation of RIG-I by casein kinase II inhibits its antiviral response.Threonine at amino acid (aa) 770 and serine at aa 854 to 855 of RIG-I are phosphorylated by casein kinase II (CK2) in the resting state of the cell and dephosphorylated when cells are infected by RNA virus. SIGNOR-276285 0.2 vorinostat chemical CHEBI:45716 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257951 0.8 MEF2D protein Q14814 UNIPROT ASH2L protein Q9UBL3 UNIPROT up-regulates 9606 BTO:0000887 18026121 f gcesareni Targeting of ash2l to specific genes is mediated by the transcriptional regulator mef2d. Furthermore, this interaction is modulated during differentiation through activation of the p38 mapk signaling pathway via phosphorylation of mef2d. SIGNOR-159334 0.473 SEC61A1 protein P61619 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-265279 0.761 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Ser87 AARARFEsKVPSFYY 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time. SIGNOR-249224 0.316 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MRTFA protein Q969V6 UNIPROT down-regulates phosphorylation 9606 18694962 t Translocation from Nuleus to Cytoplasm gcesareni Serum induces rhoa-dependent translocation of mkl1 from the cytoplasm to the nucleus and also causes a rapid increase in mkl1 phosphorylation. Serum-induced phosphorylation of the serum response factor coactivator mkl1 by the extracellular signal-regulated kinase 1/2 pathway inhibits its nuclear localization. SIGNOR-270131 0.2 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 20138985 t lperfetto Pras40 is an insulin-regulated inhibitor of the mtorc1 protein kinase. Insulin stimulates akt/pkb-mediated phosphorylation of pras40, which prevents its inhibition of mtorc1 in cells and in vitro. Phosphorylation of pras40 on thr246 by pkb/akt facilitates efficient phosphorylation of ser183 by mtorc1. SIGNOR-252539 0.724 P2RY6 protein Q15077 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257076 0.2 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 16537444 t gcesareni Using substrate trapping mutants of ptp1b or tcptp, we have demonstrated that both phosphatases interact with met and that these interactions require phosphorylation of twin tyrosines (tyr-1234/1235) in the activation loop of the met kinase domain. We demonstrate that phosphorylation of tyr-1234/1235 in the activation loop of the met receptor is elevated in the absence of either ptp1b or tcptp and further elevated upon loss of both phosphatases. This enhanced phosphorylation of met corresponds to enhanced biological activity and cellular invasion. SIGNOR-145145 0.627 NFATC4 protein Q14934 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21871017 t miannu NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration SIGNOR-264027 0.285 PTPRF protein P10586 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 12018405 t lperfetto Some 10 years ago, Hashimoto et al. (87) had shown that the LAR catalytic domain can dephosphorylate the EGFR receptor in vitro, and more recently, Kulas and colleagues (88) have demonstrated that the antisense mediated suppression of LAR can enhance the growth factor induced activation of EGFR in rat hepatoma cells.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types. SIGNOR-277029 0.34 PRKG1 protein Q13976 UNIPROT RGS2 protein P41220 UNIPROT up-regulates activity phosphorylation Ser46 KDWKTRLsYFLQNSS -1 14608379 t lperfetto Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.  SIGNOR-249240 0.675 ATP6V1H protein Q9UI12 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 10090 BTO:0004122 29782852 t miannu ATP6V1H interacts with TGF-β receptor I and AP-2 complex to regulate the proliferation and differentiation of BMSCs. SIGNOR-266886 0.2 MLST8 protein Q9BVC4 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205612 0.83 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269617 0.2 CHEK1 protein O14757 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates phosphorylation Thr309 LRKGRGEtRICKIYD 9606 15665856 t gcesareni We demonstrate that chk1 interacts with rad51, and that rad51 is phosphorylated on thr 309 in a chk1-dependent manner SIGNOR-133375 0.839 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR HJURP protein Q8NCD3 UNIPROT up-regulates activity binding -1 17256767 t miannu These data define a new protein complex in mammalian cells where 14‐3‐3 associates with FAKTS through phosphorylated S479. Our research identifies a widely expressed eukaryotic protein FAKTS, as a new Akt/PKB substrate localized in the nucleus. Akt/PKB promotes FAKTS association with 14‐3‐3, placing FAKTS under the control of 14‐3‐3 proteins. FAKTS may play an important role in transmitting Akt/PKB‐mediated signals in the complex network of intracellular signal transduction. SIGNOR-262624 0.2 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr896 EPKSPGEyVNIEFGS 9606 7515062 t gcesareni The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling. SIGNOR-27028 0.895 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni In vertebrates,pka-mediated phosphorylation of gli2 and gli3 initiates a phosphorylation cascade that leads to processing into repressors of transcription or frank degradation SIGNOR-154276 0.454 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr194 NMMDILTtPSMAKPR 9606 BTO:0002181 24391510 t miannu We demonstrate that PP2A/B55 is required for Gwl dephosphorylation at the essential Cdk site Thr194.Gwl phosphorylation by CycA/Cdk2 in vitro. Flag WT and Thr194A Gwl was transiently expressed and purified from asynchronous HEK 293T cells and incubated with recombinant CycA/Cdk2, following treatment with alkaline phosphatase (aPh) in the indicated samples. The proteins were analysed by immuno-blotting with anti-Gwl and Gwl pThr194 antibodies SIGNOR-276614 0.277 ATM protein Q13315 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates activity phosphorylation Ser43 RNPEAALsPTFRSDS 32615088 t miannu Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. SIGNOR-265969 0.2 CASC3 protein O15234 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265241 0.923 NR0B2 protein Q15466 UNIPROT AR protein P10275 UNIPROT down-regulates binding 9606 11735420 t gcesareni We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation SIGNOR-112589 0.421 PRKACA protein P17612 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates activity phosphorylation Ser1444 NIKARASsSPVILVG -1 24351927 t gcesareni Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site€.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro. SIGNOR-237444 0.411 SRC protein P12931 UNIPROT DLG4 protein P78352 UNIPROT up-regulates phosphorylation Tyr523 REDSVLSyETVTQME 9606 24981431 t llicata These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission. SIGNOR-205120 0.576 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDK7 protein P50613 UNIPROT up-regulates activity phosphorylation Ser164 GLAKSFGsPNRAYTH -1 11113184 t lperfetto Activating phosphorylation of CDK7 by CDC2 and CDK2. The ability of pure CDK2-cyclin A to activate CDK7 in T170-dependent fashion (Fig. ​(Fig.3C,3C, lane 2) strongly suggested a direct phosphorylation mechanism. Tryptic phosphopeptide mapping confirmed that both CDK2-cyclin A (Fig. ​(Fig.4A)4A) and CDC2-cyclin B (Fig. ​(Fig.4D)4D) phosphorylated CDK7 on both S164 and T170. SIGNOR-270807 0.635 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216773 0.842 ALDOC protein P09972 UNIPROT beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266489 0.8 erlotinib hydrochloride chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 17178722 t JAK2(V617F), a mutant of tyrosine kinase JAK2. Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. gcesareni This study shows that the anti-cancer drug erlotinib (tarceva) is a potent inhibitor of jak2(v617f) activity. SIGNOR-151271 0.8 3-[(4-Bromophenyl)methyl]-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one chemical CID:10248127 PUBCHEM ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition 9606 17888667 t Luana AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE. SIGNOR-257761 0.8 AURKA protein O14965 UNIPROT SKI protein P12755 UNIPROT down-regulates quantity by destabilization phosphorylation Ser326 RRVPRVSsEPPASIR -1 26138431 t miannu Here we show that AURKA phosphorylates in vitro the transcripcional co-repressor Ski on aminoacids Ser326 and Ser383. Phosphorylations on these aminoacids decreased Ski protein half-life SIGNOR-276918 0.2 TFDP1 protein Q14186 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity binding 9606 14618416 t miannu DP-1 is a heterodimerization partner for members of the E2F family of transcription factors; E2F/DP-1 regulates the expression of various cellular promoters, particularly gene products that are involved in the cell cycle. SIGNOR-253865 0.809 RNF144B protein Q7Z419 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001109 12853982 t miannu P53RFP, a p53-inducible RING-finger protein, regulates the stability of p21WAF1. Here we report the isolation of a novel transcriptional target of p53, designated p53RFP (p53-inducible RING-finger protein), whose product has E3 ubiquitin ligase activity. Its expression was negatively correlated to that of p21(WAF1) protein; p53RFP is likely to play a role in the regulation of this protein, probably through interaction with, and ubiquitination of, p21(WAF1). SIGNOR-271478 0.363 WNK3 protein Q9BYP7 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264624 0.463 GTP smallmolecule CHEBI:15996 ChEBI GNAI1 protein P63096 UNIPROT up-regulates chemical activation 9606 12040175 t gcesareni Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of gdp from the alfa subunit followed by gtp-binding to galfa and the dissociation of galfa from gbetagamma subunits1. The alfa subunits of g proteins are divided into four subfamilies: galfas, galfai, galfaq and galfa12, and a single gpcr can couple to either one or more families of galfa proteins. SIGNOR-88238 0.8 CAMK2D protein Q13557 UNIPROT ITPR2 protein Q14571 UNIPROT down-regulates activity phosphorylation Ser150 EKNAMRVsLDAAGNE 9534 BTO:0001538 23019322 t miannu Phopho-specific antibodies demonstrate that InsP(3)R2 Ser-150 is phosphorylated in vivo by CaMKIIδ. The results of this study show that serine 150 of the InsP(3)R2 is phosphorylated by CaMKII and results in a decrease in the channel open probability. SIGNOR-262692 0.311 KDM4B protein O94953 UNIPROT AR protein P10275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23435229 f miannu KDM4B enzymatic activity is required to enhance AR transcriptional activity SIGNOR-254541 0.334 CREBBP protein Q92793 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity acetylation Lys390 QKTLTPEkGQSQGLI 9606 BTO:0000007 17923090 t lperfetto STAT2 is another important component of ISGF3 complex, and its acetylation was similar to IFNaR2 and IRF9 acetylation in many respects: CBP downregulation largely abolished STAT2 acetylation induction by IFNa (Figure 6A), and CBP was more potent than transferases tested in catalyzing STAT2 acetylation (Figure 6B). [...] Figure 6 (I) STAT2-K390R substitution has reduced activity in ISGF3 complex formation. SIGNOR-217891 0.552 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA2 protein Q9Y5H1 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265713 0.2 REL protein Q04864 UNIPROT CSRP1 protein P21291 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14522018 f We conclude that c-Rel regulates CRP expression without the requirement of binding to a kappaB site, and binds directly to C/EBPbeta to facilitate the binding of C/EBPbeta to the CRP promoter SIGNOR-254063 0.2 SET protein Q01105 UNIPROT NME1 protein P15531 UNIPROT down-regulates binding 9606 12628186 t miannu Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set. SIGNOR-99205 0.721 SP1 protein P08047 UNIPROT SCNN1A protein P37088 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 12684058 f Regulation of expression miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-251950 0.2 PRKACA protein P17612 UNIPROT STK24 protein Q9Y6E0 UNIPROT unknown phosphorylation Thr18 ALNKRRAtLPHPGGS 9606 BTO:0000007 BTO:0000142;BTO:0000671 10644707 t llicata Further experiments demonstrated that mst3b, but not mst3, was effectively phosphorylated by activation of cyclic amp-dependent protein kinase (pka) in both in vivo and in vitro assays. The mutation of thr-18 into ala in mst3b (t18a), a putative pka phosphorylation site that is absent in mst3, abolished its phosphorylation by pka. SIGNOR-74284 0.218 CDK1 protein P06493 UNIPROT DCTN6 protein O00399 UNIPROT up-regulates activity phosphorylation Thr186 KTMKGSStPVKN -1 23455152 t lperfetto Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin‐dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo‐like kinase 1 (Plk1) at kinetochores. SIGNOR-264777 0.309 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu82 REVFENTeRTTEFWK 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263695 0.675 PAK4 protein O96013 UNIPROT SNAI2 protein O43623 UNIPROT up-regulates quantity by stabilization phosphorylation Ser158 CDAQSRKsFSCKYCD -1 29849120 t miannu PAK4 bound and directly phosphorylated Slug at two previously unknown sites, S158 and S254, which resulted in its stabilization.  SIGNOR-277393 0.2 HES1 protein Q14469 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19129776 t gcesareni HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone SIGNOR-251674 0.2 IFNG protein P01579 UNIPROT DIO1 protein P49895 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 9397972 f scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5’-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-267487 0.2 PRKCA protein P17252 UNIPROT FERMT3 protein Q86UX7 UNIPROT up-regulates activity phosphorylation Ser484 LSLQRTGsGGPGNHP 9606 BTO:0000565 25609252 t miannu  PKC-induced phosphorylation events, as we have shown kindlin-3 to be a PKC phosphorylation target (Fig. 6C), are often followed by rapid activation of phosphatases (38).  SIGNOR-266415 0.2 PDGFRB protein P09619 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation 9606 8195171 t gcesareni In this study, we have characterized the interaction between the pdgf beta-receptor and shc. multiple autophosphorylation sites in the pdgf beta-receptor are responsible for the binding of shc. SIGNOR-36906 0.651 PIGBOS1 protein A0A0B4J2F0 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 31653868 f miannu We then confirmed via Western blot that TM treatment of PIGBOS-KD cells led to higher ATF4 and CHOP protein levels (Supplementary Fig. 13h). These data identified PIGBOS as a heretofore unknown mitochondrial regulator of UPR, and the only known microprotein linked to the regulation of cell stress or inter-organelle signaling. Upon UPR induction with TM, the loss of PIGBOS led to dramatic increases in the levels of all UPR target genes measured, indicating increased UPR signaling across all the branches (IRE1, PERK, and ATF6) (Fig. 6d and Supplementary Fig. 14a). Meanwhile, PIGBOS overexpressing cells showed the opposite effect, in which the UPR target genes showed less UPR activation, indicating a tunable modulation of ER stress by PIGBOS microprotein levels SIGNOR-261043 0.2 PPP2CA protein P67775 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248628 0.891 MAPKAPK2 protein P49137 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser82 RALSRQLsSGVSEIR 9606 BTO:0000938 12367505 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. gcesareni Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27. SIGNOR-94025 0.806 torkinib chemical CHEBI:90679 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258269 0.8 GNG2 protein P59768 UNIPROT GNB/GNG complex SIGNOR-C202 SIGNOR form complex binding 9606 23994464 t apalma Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the GŒ≤Œ≥ subunit SIGNOR-255005 0.939 GSK3B protein P49841 UNIPROT BLM protein P54132 UNIPROT down-regulates quantity by destabilization phosphorylation Ser175 SFVTPPQsHFVRVST 9606 BTO:0002181 26028025 t miannu We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. SIGNOR-276911 0.261 FZD4 protein Q9ULV1 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 18077588 t areggio Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. SIGNOR-258964 0.641 CSKMT protein A8MUP2 UNIPROT CS protein O75390 UNIPROT down-regulates activity methylation Lys395 LLEQGKAkNPWPNVD 34929314 t lperfetto A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate. SIGNOR-267637 0.2 TNFSF14 protein O43557 UNIPROT TNFRSF14 protein Q92956 UNIPROT up-regulates binding 9606 BTO:0000763 10894944 t gcesareni A member of the tumor necrosis factor (tnf) superfamily, human tnfsf14 (htnfsf14)/hvem-l (herpes virus entry mediator ligand) was isolated as a cellular ligand for hvem/tr2 and human lymphotoxin beta receptor (ltbetar). Tnfsf14 induces apoptosis and suppresses tumor formation SIGNOR-79328 0.856 PRKCA protein P17252 UNIPROT CDKN2D protein P55273 UNIPROT up-regulates phosphorylation Thr141 RRDARGLtPLELALQ 9606 22558186 t lperfetto Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively.we propose a sequential phosphorylation model for p19 in which modification at s76 would enable a second phosphorylation event at t141. The phosphorylation-induced structural changes could have functional implicancies for p19 in the dna damage response SIGNOR-197289 0.2 RFX complex complex SIGNOR-C104 SIGNOR HLA-DRB3 protein P79483 UNIPROT up-regulates quantity by expression transcriptional regulation -1 11258423 f The RFX complex is comprised of three proteins – RFX5, RFXB, and RFXAP – all of which are required for expression of MHCII genes|In our current studies, we have utilized electrophoretic mobility shift assays to characterize the DNA binding of the RFX5(1–330)2•RFXAP•RFXB complex to the proximal regulatory region from the HLA-DRα gene to gain insight into the DNA binding properties of the RFX complex SIGNOR-254001 0.2 SMARCD3 protein Q6STE5 UNIPROT MYOG protein P15173 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 f lperfetto We observed that the homeodomain factor pbx1, which cooperates with myod to stimulate myogenin expression, is constitutively bound to the myogenin promoter in a swi/snf-independent manner, suggesting a two-step mechanism in which myod initially interacts indirectly with the myogenin promoter and attracts chromatin-remodeling enzymes, which then facilitate direct binding by MyoD and other regulatory proteins. SIGNOR-136945 0.358 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 12213813 t lperfetto In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E SIGNOR-262994 0.663 MED10 protein Q9BTT4 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266656 0.846 SCF-betaTRCP complex SIGNOR-C5 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277344 0.488 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000007 14761950 t The effect has been demonstrated using P10636-8 lperfetto Casein kinase 1 delta phosphorylates tau and disrupts its binding to microtubules.Here we characterized the contribution of one ck1 isoform, ckidelta, to the phosphorylation of tau at residues ser202/thr205 and ser396/ser404 in human embryonic kidney 293 cells. SIGNOR-121717 0.378 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser78 NKDQHSIsYTLSRAQ 9606 BTO:0000007 12496252 t lperfetto In this article we demonstrate that pellino 1 is phosphorylated at multiple sites by irak1 or irak4 in vitro. The key residues involved in activation are located between residues 76 and 86 (ser-76, ser-78, thr-80, ser-82, and thr-86) and at thr-288 and ser-293, just n-terminal to the ring-like domain that carries the e3 ligase activity. Unusually, we found that the phosphorylation of ser-76 or thr-288 or ser-293 alone was sufficient for maximal activation SIGNOR-96743 0.761 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269371 0.721 NLGN1 protein Q8N2Q7 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264149 0.837 arformoterol chemical CHEBI:408174 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation -1 20655218 t Luana Table 1. Human β2- and β1-adrenoceptor binding and calculated log D7.4 values for formoterol, indacaterol, salmeterol, S1319 and the representative library members 11–41 SIGNOR-257881 0.8 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 18550549 t gcesareni Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144. SIGNOR-178888 0.274 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr548 KKVAVVRtPPKSPSS -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250088 0.512 NFE2L2 protein Q16236 UNIPROT HMOX1 protein P09601 UNIPROT up-regulates quantity transcriptional regulation 9606 31257023 f Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. SIGNOR-259334 0.673 ZNF165 protein P49910 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26567849 t Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. SIGNOR-266093 0.2 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser212 SSAGWKNsIRHNLSL 9606 18394876 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1. SIGNOR-252999 0.676 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition 9606 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262250 0.8 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 18593525 t gcesareni The increases in the membrane levels of nacholeate itself and of dag induce a translocation and overexpression of protein kinase c (pkc) and subsequent reductions of cyclin d, cyclin-dependent kinases 4 and 6 (cdks 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of e2f1 and knockdown of dihydrofolate reductase (dhfr) impairing dna synthesis. SIGNOR-179279 0.8 KDM6A protein O15550 UNIPROT ETS2 protein P15036 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 29736013 t miannu Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase SIGNOR-260035 0.2 CDK1 protein P06493 UNIPROT SUN1 protein O94901 UNIPROT down-regulates activity phosphorylation Ser334 FLLLAGLsLRGQGNF 9606 25482198 t miannu Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions. SIGNOR-263100 0.363 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 BTO:0000776 8657103 t lperfetto Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. SIGNOR-246572 0.768 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT up-regulates activity phosphorylation Ser297 PQKTSAKsPGPMRRS 9606 14741103 t llicata We identified that Ser297 is the major phosphorylation site by Cdk5. Phosphorylation of this site occurs in human. | Mutation of Ser297 blocks the effect of Dcx on migration in a fashion similar to pharmacological inhibition of Cdk5 activity. SIGNOR-250657 0.412 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR G2/M_transition phenotype SIGNOR-PH52 SIGNOR up-regulates 15549093 f lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary SIGNOR-251497 0.7 IDH3G protein P51553 UNIPROT IDH complex SIGNOR-C396 SIGNOR form complex binding 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the α2βγ heterotetramer, catalyzes the decarboxylation of isocitrate into α-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266247 0.693 methylnaltrexone chemical CHEBI:136007 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258147 0.8 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates activity phosphorylation Ser923 DELRDSDsVCDSGVE 9606 BTO:0000007 SIGNOR-C13 11158290 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-104803 0.85 FOXO proteinfamily SIGNOR-PF27 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252939 0.7 SHANK3 protein Q9BYB0 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264585 0.2 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 17997719 t gcesareni Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity. SIGNOR-159052 0.721 RAD9A protein Q99638 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 18594563 t gcesareni The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner SIGNOR-179382 0.823 IMPDH2 protein P12268 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity binding 9606 BTO:0001616 30518405 t miannu We further demonstrated that IMPDH2 overexpression accelerated G1/S phase cell cycle transition by inducing increased expression of cyclin D1 and Ki-67 and downregulation of p21Cip1 and p27Kip1. More importantly, G1/S phase cell cycle transition was triggered by IMPDH2 through activation of AKT activity, downregulation of mTOR and FOXO1 transcriptional activity. There is evidence that IMPDH2 interacts with the pleckstrin homology domain of PKB/AKT in the regulation of GTP biosynthesis. SIGNOR-260961 0.391 PCDHA6 protein Q9UN73 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265666 0.2 PRKCD protein Q05655 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Ser360 ELKALLQsSASRKTQ 9606 BTO:0000938 21145366 t gcesareni Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb SIGNOR-170348 0.496 MAPK3 protein P27361 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249479 0.574 ENAH protein Q8N8S7 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 18508258 f miannu Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance. SIGNOR-268392 0.7 JAK1 protein P23458 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260149 0.719 SEMA3C protein Q99985 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates activity binding 19666519 t lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. SIGNOR-253151 0.505 TNFRSF1A protein P19438 UNIPROT TRADD protein Q15628 UNIPROT up-regulates activity binding 9606 11502070 t lperfetto The death domain of tnfrsf1a provides a novel molecular interface that interacts specifically with the death domain of tradd. SIGNOR-109719 0.802 CSNK1D protein P48730 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo. SIGNOR-87441 0.616 AR protein P10275 UNIPROT TMPRSS2 protein O15393 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20308527 t lperfetto We demonstrate that CHD8 directly associates with AR and that CHD8 and AR simultaneously localize to the TMPRSS2 enhancer after androgen treatment. In the LNCaP cell line, reduction of CHD8 levels by small interfering RNA treatment severely diminishes androgen-dependent activation of the TMPRSS2 gene. We demonstrate that the recruitment of AR to the TMPRSS2 promoter in response to androgen treatment requires CHD8 SIGNOR-253686 0.588 MICU1 protein Q9BPX6 UNIPROT MCU_MICU1_variant complex SIGNOR-C500 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270867 0.691 MC5R protein P33032 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257070 0.251 PLK1 protein P53350 UNIPROT KIF2C protein Q99661 UNIPROT up-regulates activity phosphorylation Ser633 ELSSQMSsFNEAMTQ 9606 BTO:0000567 25504441 t miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. SIGNOR-276861 0.807 CAMK2A protein Q9UQM7 UNIPROT ITGB1BP1 protein O14713 UNIPROT up-regulates activity phosphorylation Thr38 GGLSRSStVASLDTD 9813144 t llicata The point mutation T38D localized within the optimal CaMKII recognition motif of ICAP-1alpha results in a strong defect in cell spreading which cannot be overcome by the inhibition of the endogenous CaMKII. This fact strongly suggests that the phosphorylation of Threonine 38 by CaMKII modulates the alpha5beta1 integrin function. Conversely, the mutation T38A produces an analog of ICAP-1alpha that cannot be phosphorylated and that stimulates cell spreading on fibronectin to a similar extent when CaMKII is inhibited. SIGNOR-250632 0.309 PPP3CA protein Q08209 UNIPROT NFATC3 protein Q12968 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-176376 0.527 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249318 0.758 PI4KA protein P42356 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269096 0.8 TLX3 protein O43711 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002504 22516263 t irozzo We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. SIGNOR-259098 0.368 CBX3 protein Q13185 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264494 0.2 PRKD1 protein Q15139 UNIPROT CACNA1C protein Q13936 UNIPROT up-regulates phosphorylation Ser1981 ASLGRRAsFHLECLK 9606 22100296 t gcesareni Both the expression of a dominant-negative mutant of pkd and the mutation of serine 1884 but not serine 1930, putative targets of pkd, strongly reduced l-type calcium currents and single channel activity without affecting the channel's expression at the plasma membrane. Our results suggest that serine 1884 is essential for the regulation of hcav1.2 by pkd. SIGNOR-177481 0.257 PRKCB protein P05771 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 BTO:0004737 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249090 0.285 A9/b1 integrin complex SIGNOR-C166 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269015 0.7 ABL1 protein P00519 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA 9606 12445832 t Manara In this report we describe for the first time that ABL1 and Btk physically interact and that ABL1 can phosphorylate tyrosine 223 in the SH3 domain of Btk. | This is presumably due to the negative regulatory effectof Btk SH3 domain phosphorylation caused by ABL1,which would result in a decreased catalytic activity ofBtk resulting in impaired autophosphorylation. SIGNOR-260801 0.34 POU2F1 protein P14859 UNIPROT MYH10 protein P35580 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238772 0.2 PCDH19 protein Q8TAB3 UNIPROT GABRA3 protein P34903 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C334 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267222 0.2 HNRNPU protein Q00839 UNIPROT IER3 protein P46695 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 17174306 f lperfetto In the present study, we show that hnRNP-U specifically enhances the expression of tumor necrosis factor alpha mRNA by increasing its stability, possibly through binding to the 3' untranslated region. We also show that hnRNP-U enhances the expression of several other genes as well, including GADD45A, HEXIM1, HOXA2, IER3, NHLH2, and ZFY, by binding to and stabilizing these mRNAs. SIGNOR-262285 0.2 MTCH2 protein Q9Y6C9 UNIPROT BID protein P55957 UNIPROT up-regulates relocalization 9606 20436477 t In the experiment they use a truncated BID (tBID)-interacting protein. gcesareni Mtch2/mimp (mitochondrial carrier homologue 2/met-induced mitochondrial protein), a novel truncated bid (tbid)-interacting protein, is a surface-exposed outer mitochondrial membrane protein that facilitates the recruitment of tbid to mitochondria SIGNOR-165081 0.307 MOB1B protein Q7L9L4 UNIPROT LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-169795 0.919 PLK1 protein P53350 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser24 GYLRKPKsMHKRFFV 9606 15849359 t lperfetto Phosphorylation of ser24 in the pleckstrin homology domain of insulin receptor substrate-1 by mouse pelle-like kinase/interleukin-1 receptor-associated kinase| irs-1 mutants s24d or s24e (mimicking phosphorylation at ser(24)) had impaired ability to associate with insulin receptors resulting in diminished tyrosine phosphorylation of irs-1 and impaired ability of irs-1 to bind and activate pi-3 kinase in response to insulin. SIGNOR-135688 0.27 long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI up-regulates quantity precursor of 9606 24269233 t ACSs catalyze the conversion of FAs to their active form acyl-CoAs. The human genome codes for 26 ACS isozymes, which are classified into six subfamilies based on their substrate specificities toward the chain length of FAs and on sequence similarity SIGNOR-267711 0.8 GSK3B protein P49841 UNIPROT FCAR protein P24071 UNIPROT down-regulates activity phosphorylation Ser284 LTFARTPsVCK 10090 BTO:0001516 30766540 t lperfetto GSK-3 is constitutively active in the absence of cytokine stimulation and can phosphorylate S263, keeping FcalphaRI in the inactive state. SIGNOR-264857 0.2 USP6 protein P35125 UNIPROT ARF6 protein P62330 UNIPROT up-regulates relocalization 9606 15509780 t miannu Here we show that tre17 (also called tre-2 and usp6), a founding member of the tbc family, targets the arf family gtpase arf6, which regulates plasma membrane-endosome trafficking. Surprisingly, tre17 does not function as a gap for arf6 but rather promotes its activation in vivo. Forced expression of tre17 promotes the localization of arf6 to the plasma membrane, leading to arf6 activation, presumably due to facilitated access to membrane-associated guanine nucleotide exchange factors (gefs). SIGNOR-130019 0.651 CDK1 protein P06493 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Thr143 AVSPGTLtPTGVVSG 26933062 t lperfetto Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis. SIGNOR-276588 0.432 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249123 0.348 RRAGD protein Q9NQL2 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor SIGNOR-162093 0.904 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PGR protein P06401 UNIPROT down-regulates phosphorylation 9606 BTO:0000150 10655479 t inferred from 70% family members gcesareni Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation. SIGNOR-270040 0.2 YWHAB protein P31946 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-252396 0.256 SLBP protein Q14493 UNIPROT H2AX protein P16104 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265405 0.2 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Ser246 CPRLRIFsHPNVLPV 9606 17420447 t lperfetto We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin. SIGNOR-154303 0.417 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4EBP1 protein Q13541 UNIPROT up-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0001109 36882522 t lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. SIGNOR-273114 0.2 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys68 ETSAAKLkRKYWWKN 9606 BTO:0000007 23353890 t miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. SIGNOR-272094 0.332 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t lperfetto Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity. SIGNOR-244337 0.2 CAV1 protein Q03135 UNIPROT SLC1A6 protein P48664 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 t miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. SIGNOR-264810 0.2 ELOC protein Q15369 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 BTO:0000672 22001063 t gcesareni Using proteomic techniques, several components of the elongin c complex were identified as candidate notch4(icd) interactors. Elongin c complexes can function as ubiquitin ligases capable of regulating proteasomal degradation of specific protein substrates. Our studies indicate that ectopic elongin c expression stimulates notch4(icd) degradation and inhibits its transcriptional activity in human kidney tubule hk11 cells. SIGNOR-176779 0.2 WNT9A protein O14904 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132070 0.613 IFNAR2 protein P48551 UNIPROT IFNAR complex SIGNOR-C243 SIGNOR form complex binding 9606 11278538 t miannu The human type I interferons, IFN-alpha, IFN-beta, and IFN-omega, induce somewhat different cellular effects but act through a common receptor complex, IFNAR, composed of subunits IFNAR-1 and IFNAR-2. Human IFNAR-2 binds all type I IFNs but with lower affinity and different specificity than the IFNAR complex. Human IFNAR-1 has low intrinsic binding of human IFNs but strongly affects the affinity and differential ligand specificity of the IFNAR complex. SIGNOR-260333 0.905 CDK1 protein P06493 UNIPROT PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) SIGNOR-275489 0.353 OPTN protein Q96CV9 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 27181519 f lperfetto Optineurin and TBK1 have also been discovered co-localizing in protein aggregates, and the phosphorylation of optineurin at serine 177 has been shown to be critical to its function in mediating clearance of aggregated proteins via autophagy SIGNOR-262275 0.7 PML protein P29590 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 15356634 t lperfetto Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome. SIGNOR-128738 0.537 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Ser828 EHDSAEGsHTSGQSN 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276512 0.374 PRRX1 protein P54821 UNIPROT MAFG protein O15525 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221961 0.342 MAPK1 protein P28482 UNIPROT TNKS1BP1 protein Q9C0C2 UNIPROT unknown phosphorylation Thr131 KEEPPPLtPPARCAA 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262782 0.2 PTPN6 protein P29350 UNIPROT PKM protein P14618 UNIPROT down-regulates activity dephosphorylation Tyr105 FASDPILyRPVAVAL 9606 26959741 t lperfetto SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs.|SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated hepatocellular carcinoma cells.|SHP-1 dephosphorylates p-PKM2Y105 and further affects the nucleus-related cell proliferation. SIGNOR-276997 0.2 AIM2 inflammasome complex SIGNOR-C222 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-263123 0.7 FBXO32 protein Q969P5 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001103 19319192 t gcesareni Here we present evidence that mafbx targets myod for degradation in several models of skeletal muscle atrophy. SIGNOR-184861 0.571 Collagen proteinfamily SIGNOR-PF103 SIGNOR ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 35268340 f miannu The extracellular matrix is a structure composed of many molecules, including fibrillar (types I, II, III, V, XI, XXIV, XXVII) and non-fibrillar collagens (mainly basement membrane collagens: types IV, VIII, X), non-collagenous glycoproteins (elastin, laminin, fibronectin, thrombospondin, tenascin, osteopontin, osteonectin, entactin, periostin) embedded in a gel of negatively charged water-retaining glycosaminoglycans (GAGs) such as non-sulfated hyaluronic acid (HA) and sulfated GAGs which are linked to a core protein to form proteoglycans (PGs). SIGNOR-269732 0.7 CENP-A nucleosome complex SIGNOR-C321 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 20566683 f miannu Centromeres contain specialized nucleosomes in which histone H3 is replaced by the histone variant centromere protein A (CENP-A). CENP-A nucleosomes are thought to act as an epigenetic mark that specifies centromere identity. SIGNOR-263703 0.7 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT up-regulates activity carboxylation Glu66 NLERECMeEKCSFEE 10090 BTO:0001103 11133752 t lperfetto The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing. SIGNOR-263690 0.675 GATA6 protein Q92908 UNIPROT SEMA3C protein Q99985 UNIPROT up-regulates quantity by expression transcriptional regulation 19666519 f lperfetto Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes. SIGNOR-253150 0.405 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Ser327 SEEDEMDsGTMVRAV 9534 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationwas also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues SIGNOR-247569 0.2 TLR2 protein O60603 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates activity 9606 BTO:0001025 19185596 f miannu S protein is a ligand for human TLR2. S protein utilizes toll-like receptor 2(TLR 2) to increase IL-8 production.Our results show that SARS S protein in a soluble form increased IL-8 production through hTLR2 ligand interaction. we have provided evidence that S protein induces IL-8 in PBMC in vitro and in THP-1 cells. The ability of S protein to increase IL-8 mRNA was mediated by activation of NF-κB possibly via TLR2 ligand and could be inhibited by the NF-κB inhibitor TPCK. The ability to detect elevated NF-κB transcription factor activity in the nucleus in response to S protein suggests that this most likely occurs by the mechanism of induction. Moreover increased secretion of IL-8 and IL-6 cytokines indicated that levels of proinflammatory mediators could be enhanced by S protein interaction with monocyte macrophages and could stimulate NK, neutrophil and monocyte migration to the site of infection. SIGNOR-260973 0.552 GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268591 0.2 GATA1 protein P15976 UNIPROT GP6 protein Q9HCN6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12359731 f miannu Deletion analyses and site-directed mutagenesis identified Sp1(227), GATA(177), and Ets(48) sites as essential for GPVI expression. We show that transcription factors GATA-1, Fli-1, and Sp1 can bind to and activate this promoter. SIGNOR-254158 0.284 MYC protein P01106 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity binding 10090 BTO:0000944 8266081 t miannu Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1. SIGNOR-268795 0.555 EXT2 protein Q93063 UNIPROT EXT1/EXT2 complex SIGNOR-C51 SIGNOR form complex binding 9606 11518722 t miannu Biochemical analysis shows that ext1 and ext2 are type ii transmembrane glycoproteins and form a golgi-localized hetero-oligomeric complex that catalyzes the polymerization of hs SIGNOR-109941 0.57 LRRC4 protein Q9HBW1 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264055 0.2 TGFBI protein Q15582 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR up-regulates activity 10090 BTO:0004093 25786978 t lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253283 0.343 CSNK2A2 protein P19784 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser321 LNSEDDVsDEEGQEL -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250998 0.379 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser338 RPRGQRDsSYYWEIE 9606 11733498 t lperfetto Interaction between active pak1 and raf-1 is necessary for phosphorylation and activation of raf-1. SIGNOR-112549 0.2 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268594 0.2 PRKACB protein P22694 UNIPROT TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation Ser116 LSGERRYsMPPLFHT 9606 31057087 t miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-259403 0.2 CDK1 protein P06493 UNIPROT RAB5B protein P61020 UNIPROT unknown phosphorylation Ser123 KELQRQAsPSIVIAL 9606 10403367 t lperfetto Cdc2 kinase preferentially phosphorylates ser-123 of rab5b. More work will be required to establish how phosphorylation of the three rab5 isoforms influences their function in the endocytic pathway SIGNOR-69233 0.329 WNT9A protein O14904 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-132073 0.65 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t Phosphorylation is the signal for ubiquitination lperfetto We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. SIGNOR-106808 0.84 PTPRJ protein Q12913 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates dephosphorylation 9606 18348712 t gcesareni As reduction of pi3k activity by cd148 or shp-1 [32] is not large (2540%), it is likely that these ptps may function as modulators of the pi3k pathway rather than suppressors. SIGNOR-178049 0.263 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 23764977 t miannu Seven PFCs [perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA)] were analyzed in vitro for their potential to affect estrogen receptor (ER) and androgen receptor (AR) transactivity as well as aromatase enzyme activity. The PFCs were assessed as single compounds and in an equimolar mixture. PFHxS, PFOS and PFOA significantly induced the ER transactivity, whereas PFHxS, PFOS, PFOA, PFNA and PFDA significantly antagonized the AR activity in a concentration-dependent manner.  SIGNOR-268760 0.8 EGF protein P01133 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 12297050 t lperfetto Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase. SIGNOR-186159 0.949 BCOR protein Q6W2J9 UNIPROT RNF2 protein Q99496 UNIPROT up-regulates activity binding 9606 17296600 t miannu BcoR and Fbxl10/Jhdm1B are among the most abundant Ring1B/Rnf2 interactors identified with the highest confidence, and their association has been validated by coimmunoprecipitation studies; hence we call this the Fbxl10-BcoR complex. In summary, we have widened the set of multiprotein complexes containing the Polycomb group protein Ring1B/Rnf2. The new interactors contain protein motifs whose enzymatic activities and binding properties would expand the regulatory potential and gene target diversity of Ring1B/Rnf2 complexes in terms of recruitment to and modification of chromatin SIGNOR-252241 0.555 DLGAP3 protein O95886 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264592 0.795 fingolimod chemical CHEBI:63115 ChEBI S1PR1 protein P21453 UNIPROT down-regulates chemical inhibition 9606 22225501 t gcesareni Sphingosine-1-phosphate (s1p(1)) receptor agonists such as fingolimod (fty-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. SIGNOR-195343 0.8 GAPDH protein P04406 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266495 0.8 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr989 VPSSRGDyMTMQMSC 10116 BTO:0000443 7651388 t lperfetto All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10). SIGNOR-235979 0.913 HTR2C protein P28335 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257405 0.279 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKM protein P08237 UNIPROT down-regulates activity phosphorylation -1 28607489 t miannu In vitro kinase reactions revealed that all three PFK1 isoforms (PFKP, PFKL, PFKM) and PKM2 were phosphorylated by cyclin D3-CDK6 (Extended Data Fig. 2a–d, Supplementary Table 4). SIGNOR-276452 0.2 Vps34 Complex II complex SIGNOR-C241 SIGNOR Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 30397185 f lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260326 0.7 MAPKAPK2 protein P49137 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates phosphorylation Ser387 SKLMRSAsFNTDPYV 9606 20626350 t gcesareni Mk2 was found to phopsphorylate in vitro the ago2 protein in ser387, which was identified as the major ago2 phosphorylation site in cells.and mutation of ser387 to alanineimpairsago2 localization to therna-containing granules termedprocessing bodies SIGNOR-166615 0.443 WHAMM protein Q8TF30 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261004 0.354 C5 protein P01031 UNIPROT C5AR2 protein Q9P296 UNIPROT up-regulates binding 9606 cleavage:Arg751;Arg677 HKDMQLGrLHMKTLL;KEILRPRrTLQKKIE 11773063 t complement C5a (anaphylatoxin) fragment: PRO_0000005988 gcesareni Here we report that the orphan receptor c5l2/gpr77, which shares 35% amino acid identity with cd88, binds c5a with high affinity. SIGNOR-113558 0.654 PDGFRB protein P09619 UNIPROT ABL2 protein P42684 UNIPROT up-regulates activity phosphorylation Tyr272 KCNKPTVyGVSPIHD -1 34144039 t miannu  PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. SIGNOR-277305 0.306 PTPRG protein P23470 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1003 VSNESVDyRATFPED -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254712 0.32 EXOSC9 protein Q06265 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261388 0.919 RANBP3 protein Q9H6Z4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity relocalization 9606 19289081 t lperfetto RanBP3 directly recognizes dephosphorylated Smad2/3, which results from the activity of nuclear Smad phosphatases, and mediates nuclear export of Smad2/3 in a Ran-dependent manner. SIGNOR-217634 0.443 lanreotide chemical CHEBI:135901 ChEBI SSTR2 protein P30874 UNIPROT up-regulates activity chemical activation 9606 25060168 t miannu Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. SIGNOR-259242 0.8 pregnenolone smallmolecule CHEBI:16581 ChEBI 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268648 0.8 IL6ST protein P40189 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 9716487 t lperfetto All IL-6-type cytokines recruit gp130to their receptot complexes They either signal via gp130 alone [8] or in combination with LIFR [9] or the recently cloned OSMR [10], which are all able to activate Jaks proteins. Two tyrosine residues at the corresponding positions of Jak2 (tyrosine-1007 and tyrosine-1008) were found to be phosphorylated, and a single mutation of tyrosine-1007 eliminated essentially all tyrosine kinase activity [59]. SIGNOR-238630 0.63 XRCC3 protein O43542 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity 9606 BTO:0000567 23438602 f lperfetto Interestingly, as with ATM (40, 41), XRCC3-deficient cells exhibited RDS and impaired CHK2 activation|Notably, early activation of CHK2 in S/G2 phase was downstream of XRCC3 recruitment as well as its phosphorylation at the sites of DSBs. NBS1 also has been shown to be involved in the early activation of CHK2 in response to IR (42). It is likely that NBS1-dependent CHK2 phosphorylation is mediated through XRCC3 activation. SIGNOR-263261 0.521 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Ser950 EGFHPRRsSQGATQM 10090 BTO:0000944 11581251 t lperfetto HSL activity is known to be regulated by phosphorylation (3). PKA increases HSL activity via phosphorylation at Ser563, Ser659, and Ser660 (14,15), although phosphorylation at Ser565 by glycogen synthase kinase, AMP-dependent protein kinase, or Ca2+/calmodulin-dependent protein kinase II has been reported to prevent activation of the enzyme SIGNOR-249203 0.592 PPP1CA protein P62136 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252603 0.432 DAPK1 protein P53355 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000776 17339337 t gcesareni Dna damage-activated protein kinases like chk1/2 modify the box-i domain of p53 at thr18 and ser20 (46) by an allosteric mechanism (10). SIGNOR-153491 0.569 PIM1 protein P11309 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates activity phosphorylation Ser269 PCNKRKYsLNGRQPP 9606 BTO:0001061 31730483 t miannu Phosphorylation of NFATC1 at PIM1 target sites is essential for its ability to promote prostate cancer cell migration and invasion. Here we have identified ten PIM1 target sites in NFATC1 and found that prevention of their phosphorylation significantly decreases the transcriptional activity as well as the pro-migratory and pro-invasive effects of NFATC1 in prostate cancer cells. SIGNOR-276769 0.634 CSNK2A1 protein P68400 UNIPROT NPHP1 protein O15259 UNIPROT up-regulates phosphorylation Ser123 EEEEESEsEDSEDSG 9606 16308564 t lperfetto Casein kinase 2 (ck2)-mediated phosphorylation of three critical serine residues within a cluster of acidic amino acids in nephrocystin mediates pacs-1 binding, and is essential for colocalization of nephrocystin with pacs-1 at the base of cilia. Inhibition of ck2 activity abrogates this interaction and results in the loss of correct nephrocystin targeting. SIGNOR-142347 0.2 ELOVL proteinfamily SIGNOR-PF93 SIGNOR palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267901 0.8 AMPK complex SIGNOR-C15 SIGNOR CTBP1 protein Q13363 UNIPROT down-regulates phosphorylation Ser158 REGTRVQsVEQIREV 9606 23291169 t lperfetto We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1 SIGNOR-216604 0.2 MEN1 protein O00255 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15640349 f irozzo Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. SIGNOR-255889 0.411 NFATC1 protein O95644 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001260 17079331 t lperfetto The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. SIGNOR-251730 0.423 Z-RNA stimulus SIGNOR-ST29 SIGNOR ZBP1 protein Q9H171 UNIPROT up-regulates activity binding 10090 32200799 t gianni Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. SIGNOR-266432 0.7 IRAK4 protein Q9NWZ3 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT up-regulates activity phosphorylation Thr342 ASEKFAQtVMTSRIV 9606 BTO:0000876 24567333 t lperfetto We show irak4 autophosphorylation occurs by an intermolecular reaction and that autophosphorylation is required for full catalytic activity of the kinase. Phosphorylation of any two of the residues thr-342, thr-345, and ser-346 is required for full activity SIGNOR-204657 0.2 MIF protein P14174 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 10090 17435771 t gcesareni We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. SIGNOR-252061 0.389 STXBP1 protein P61764 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9534 11036064 t miannu We propose that all these neurexin complexes can interact with Munc18. Both Mint1 and Mint2 could function as direct adaptors of Munc18 to neurexins, whereas Mint1 in addition could recruit Munc18 to CASK-neurexin (Fig. 5 B). SIGNOR-264040 0.515 IL1B protein P01584 UNIPROT IL1R2 protein P27930 UNIPROT down-regulates binding 9606 BTO:0000876 8332913 t gcesareni Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1 SIGNOR-38302 0.876 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser795 VPPARPGsRGPAPGP 9606 BTO:0000142 15287745 t lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. SIGNOR-127440 0.422 MAPK14 protein Q16539 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 12589053 f fspada Specific inhibitors for p38 kinase inhibited bmp2-induced adipocytic differentiation and transcriptional activation of ppargamma, whereas overexpression of smad6 had no effect on transcriptional activity of ppargamma.  SIGNOR-210090 0.402 DPF2 protein Q92785 UNIPROT ESRRA protein P11474 UNIPROT down-regulates activity binding 10090 BTO:0000165 25713408 t 1 miannu DPF2 directly bound to ERRalpha and suppressed the transactivation function of nuclear receptors such as androgen receptor. DPF2 was recruited to ERR target gene promoters in myoblast cells, and knockdown of DPF2 derepressed the level of mRNA expressed by target genes of ERRalpha. These results show that DPF2 acts as a nuclear receptor-selective co-repressor for ERRalpha by associating with both acetylated histone H3 and HDAC1. SIGNOR-239539 0.2 CFII complex complex SIGNOR-C387 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity cleavage 9606 30139799 t lperfetto Cleavage factor II (CF II) is a poorly characterized component of the multiprotein complex catalyzing 3' cleavage and polyadenylation of mammalian mRNA precursors. We have reconstituted CF II as a heterodimer of hPcf11 and hClp1. The heterodimer is active in partially reconstituted cleavage reactions SIGNOR-266121 0.8 ITGB1 protein P05556 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257700 0.703 CAMK2A protein Q9UQM7 UNIPROT FBXO43 protein Q4G163 UNIPROT up-regulates activity phosphorylation Ser192 NLEKNIPsSASGFSR -1 16407128 t Manara CaMKII and polo-like kinase 1 sequentially phosphorylate the cytostatic factor Emi2/XErp1 to trigger its destruction and meiotic exit. | these results implicate the 192RSST motif of Emi2 as a critical molecular target of CaMKII during CSF release SIGNOR-260907 0.39 Hexocyclium chemical CHEBI:5707 ChEBI CHRM5 protein P08912 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258399 0.8 JARID2 protein Q92833 UNIPROT MYOG protein P15173 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 23435416 t lperfetto JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells|Addition of Differentiation Media (DM) to human myoblasts was associated with the induction of MYOG, MYOD and MYL1 and a decrease in JARID2 RNA expression|Furthermore, we that showed JARID2 binds to and alters the methylation status of histone H3 lysine 27 in the promoter regions of MYOG and MYL1 and that the interaction of JARID2 at these promoters is dependent upon EED, a core component of the Polycomb Repressive Complex 2 (PRC2). Therefore JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS SIGNOR-249599 0.2 KLKB1 protein P03952 UNIPROT F12 protein P00748 UNIPROT up-regulates activity cleavage Arg353 EQPPSLTrNGPLSCG 9606 BTO:0000131 28966616 t lperfetto FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces. SIGNOR-263520 0.595 FYN protein P06241 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates phosphorylation Tyr353 NAQEKMVySLVSVPE 9606 14761954 t lperfetto We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm). SIGNOR-121795 0.496 CELF1 protein Q92879 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates activity binding 10090 BTO:0000759 16931514 t miannu These studies showed that both the increased levels of CUGBP1 and cdk4-mediated hyper-phosphorylation of CUGBP1 are involved in the age-associated induction of the CUGBP1-eIF2 complex. The CUGBP1-eIF2 complex is bound to C/EBPbeta mRNA in the liver of old animals, and this binding correlates with the increased amounts of liver-enriched activator protein and liver-enriched inhibitory protein. SIGNOR-262736 0.252 CTDSP1 protein Q9GZU7 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser204 NHSMDAGsPNLSPNP 9606 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248791 0.418 SOX9 protein P48436 UNIPROT OTX2 protein P32243 UNIPROT up-regulates activity binding 10090 20530484 t miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255184 0.355 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Thr739 SEGSGTAtPSALITT 9606 14744793 t lperfetto Transcriptional activation of p21(waf1/cip1) by alkylphospholipids: role of the mitogen-activated protein kinase pathway in the transactivation of the human p21(waf1/cip1) promoter by Sp1.|this activation promotes the phosphorylation of Sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased Sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-249481 0.644 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 8940173 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-247197 0.571 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG4-LLGL2_variant complex SIGNOR-C505 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270887 0.532 SIK2 protein Q9H0K1 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity phosphorylation Ser154 STLYRTQsSSNLAEL -1 27478041 t miannu The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells. SIGNOR-277269 0.325 MC1R protein Q01726 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 20371771 t lperfetto The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins SIGNOR-268697 0.467 axitinib chemical CHEBI:66910 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258075 0.8 BIRC3 protein Q13489 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys51 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272707 0.359 KAT2A protein Q92830 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269608 0.2 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates phosphorylation Thr533 TGSDNTDtEGS 9606 17936701 t lperfetto Pvhl acts as an adaptor to promote the inhibitory phosphorylation of the nf-kappab agonist card9 by ck2. The card9 c terminus contains multiple serine and threonine residues that resemble ck2 phosphorylation sites. Mass spectrometry analysis of myc-card9 recovered from hela cells revealed that these sites, including t531 and t533, were phosphorylated in vivo SIGNOR-158418 0.349 IL10 protein P22301 UNIPROT IL10RB protein Q08334 UNIPROT up-regulates binding 9606 BTO:0000671 11035029 t fspada The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10 SIGNOR-83191 0.708 canertinib chemical CHEBI:61399 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258095 0.8 NARS1 protein O43776 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270455 0.8 HNF4A protein P41235 UNIPROT PCSK9 protein Q8NBP7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000398 21123766 f miannu Recent studies have demonstrated that PCSK9 mRNA expression was upregulated to a greater extent than that of the LDL receptor in human hepatocytes in primary culture. Our findings also support the role of SREBP-2 as a transcriptional regulator of both the LDL receptor and PCSK9 in human enterocytes. SIGNOR-254451 0.27 ROCK2 protein O75116 UNIPROT MYL9 protein P24844 UNIPROT up-regulates activity phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 8702756 t miannu Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. SIGNOR-261718 0.639 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr187 FSEEIRFyQLGEEAM 9606 11812778 t gcesareni The shaker family k+ channel protein, kv1.3, is tyrosine phosphorylated by v-src kinase at tyr137 and tyr449 to modulate current magnitude and kinetic properties. SIGNOR-114641 0.314 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252523 0.909 NFE2L2 protein Q16236 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. SIGNOR-256652 0.7 ARHGAP22 protein Q7Z5H3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260476 0.553 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 15647376 t llicata N this study we have demonstrated that ezrin y145 is a direct target for phosphorylation by the tyrosine kinase src evidence from this study suggests that a positive feedback loop exists whereby src-mediated ezrin y145 phosphorylation sustains src activity._ SIGNOR-133227 0.64 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 8052307 t gcesareni In vivo, dominant negative ras mutant n17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in pc12 cells, and transfection of ras, but not raf, into cos cells results in a large elevation in the level of these lipids. Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-35878 0.923 AKT proteinfamily SIGNOR-PF24 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-244322 0.2 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT up-regulates activity phosphorylation Ser79 AGALYSGsEGDSESG -1 2046671 t llicata Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated. SIGNOR-250956 0.54 ketanserin chemical CHEBI:6123 ChEBI SLC18A2 protein Q05940 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000318 8643547 t miannu Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. SIGNOR-258494 0.8 PPM1D protein O15297 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 15870257 t lperfetto PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. SIGNOR-135980 0.569 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI TP53 protein P04637 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189999 0.8 PLK1 protein P53350 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by stabilization phosphorylation Ser234 GKFVLKAsLSAPGSE 9606 BTO:0002181 31281496 t miannu We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization. SIGNOR-277463 0.251 B2M protein P61769 UNIPROT Class I MHC complex SIGNOR-C425 SIGNOR form complex binding -1 28367149 t scontino One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER) SIGNOR-267777 0.2 COP1 protein Q8NHY2 UNIPROT ACACA protein Q13085 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271598 0.2 ECM stimulus SIGNOR-ST20 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259047 0.7 SSTR2 protein P30874 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256827 0.435 CSNK1A1L protein Q8N752 UNIPROT GLI2 protein P10070 UNIPROT up-regulates phosphorylation 9606 18698484 t gcesareni Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed SIGNOR-179972 0.337 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Thr181 PANSFVGtPYWMAPE 9534 BTO:0004055 10559204 t lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. SIGNOR-246298 0.2 CAST protein P20810 UNIPROT CAPN1 protein P07384 UNIPROT down-regulates activity binding 9606 BTO:0000590 25969760 t lperfetto In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain SIGNOR-251582 0.914 AATF protein Q9NY61 UNIPROT KLK3 protein P07288 UNIPROT up-regulates quantity by expression transcriptional regulation 23146908 t Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF. SIGNOR-253669 0.2 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236649 0.494 GPHN protein Q9NQX3 UNIPROT ARHGEF9 protein O43307 UNIPROT up-regulates activity binding 9606 25882190 t miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264973 0.617 AHR protein P35869 UNIPROT CYP1A1 protein P04798 UNIPROT up-regulates quantity by expression transcriptional regulation -1 9865727 t Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor|These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. SIGNOR-253639 0.678 RPS16 protein P62249 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262435 0.873 ARHGAP44 protein Q17R89 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260498 0.578 AKT3 protein Q9Y243 UNIPROT TBX3 protein O15119 UNIPROT up-regulates activity phosphorylation Ser719 AEKEAATsELQSIQR 9606 25595898 t miannu We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion. SIGNOR-223534 0.36 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PPM1D protein O15297 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser40 PTAEEKPsPRRSLSQ 33309518 t lperfetto Phosphorylation of multiple residues in the catalytic domain of PPM1D during mitosis, including Ser40 by Cyclin-dependent kinase 1 (CDK1), leads to ubiquitination of PPM1D and subsequent proteasomal degradation by Adenomatous polyposis coli (APC) and cell-division cycle protein 20 (CDC20) SIGNOR-275490 0.339 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 BTO:0001546 26690702 t gcesareni Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis. SIGNOR-173331 0.741 CSNK1G1 protein Q9HCP0 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser322 PRTSSNAsTISGRLS -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-250822 0.48 AKT2 protein P31751 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity 9606 16293724 f gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway. SIGNOR-141655 0.559 ETS1 protein P14921 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000948 22270366 f miannu VEGF-induced MMP-9 and MMP-13 promoter activities were down-regulated in ETS-1 siRNA-transfected cells. it is hypothesized that the activation of PI3K/AKT and p38 MAPK by VEGF results in ETS-1 gene expression, which activates MMP-9 and MMP-13, leading to the invasion and scattering of SKOV-3 cells. SIGNOR-254084 0.309 GGCX protein P38435 UNIPROT BGLAP protein P02818 UNIPROT up-regulates activity carboxylation 9606 31226734 t lperfetto Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation. SIGNOR-265922 0.679 SRC protein P12931 UNIPROT DNM2 protein P50570 UNIPROT down-regulates activity phosphorylation Tyr597 NTEQRNVyKDLRQIE 10090 BTO:0000944 33113375 t miannu We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G). SIGNOR-277539 0.569 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation Thr183 ACTNFMMtPYVVTRY -1 11062067 t MKK7 phosphorylates SAPK2a p38 exclusively at Tyr-182. Stress-activated protein kinase 1 (SAPK1), also called c-Jun N-terminal kinase (JNK), becomes activated in vivo in response to pro-inflammatory cytokines or cellular stresses. Its full activation requires the phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif, which can be catalysed by the protein kinases mitogen-activated protein kinase kinase (MKK)4 and MKK7. SIGNOR-251417 0.628 CHUK protein O15111 UNIPROT TRAF4 protein Q9BUZ4 UNIPROT down-regulates phosphorylation Ser426 KPGTWRGsLDESSLG 9606 22547678 t llicata Traf4 is atypical within its family because it is the only traf family member to negatively regulate innate immune signaling. Ikk_'s phosphorylation of serine-426 on traf4 was required for this negative regulation. SIGNOR-197253 0.389 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation 10029 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-235748 0.754 NF1 protein P21359 UNIPROT KRAS protein P01116 UNIPROT down-regulates activity binding 9606 BTO:0000007 32697994 t miannu Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS. SIGNOR-273661 0.715 RPL5 protein P46777 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262457 0.891 NEK6 protein Q9HC98 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 12023960 t miannu The present study is the first report of a protein kinase (NEK6) capable of phosphorylating the hydrophobic motif of SGK1, although our data suggest that NEK6 may not mediate this reaction in cells. Nevertheless, the phosphorylation of the hydrophobic motif of SGK1in vitro, coupled with the phosphorylation of the T-loop with PDK1, may be a useful way of generating fully active wild type SGK1. Ser377 and Ser422of SGK1, and the CDK7 T-loop peptide, which are phosphorylated by NEK6. SIGNOR-250297 0.341 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates 9606 BTO:0001103 20219869 t apalma Furthermore, NF-kB activation can cause destabilization of MyoD mRNA and degradation of MyoD protein (35, 49), which would further impede muscle differentiation SIGNOR-255352 0.282 PRKAA1 protein Q13131 UNIPROT FANCA protein O15360 UNIPROT up-regulates activity phosphorylation Ser347 VQMQREWsFARTHPL 9606 BTO:0001938 27449087 t miannu FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway.  SIGNOR-277264 0.336 F2 protein P00734 UNIPROT F8 protein P00451 UNIPROT up-regulates activity cleavage Arg1708 EDENQSPrSFQKKTR -1 10350471 t lperfetto Activation of factor VIII by thrombin occurs via limited proteolysis at R372, R740, and R1689. SIGNOR-263639 0.75 CDK1 protein P06493 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Ser613 EKKQITTsPITVRKN 9606 SIGNOR-C17 12372621 t lperfetto Warts is a serine/threonine kinase and a dynamic component of the mitotic apparatus. We have found that cdc2/cyclin b forms a complex with a fraction of warts in the centrosome and phosphorylates the ser613 site of warts during mitosisit can be speculated that phosphorylation of warts by cdc2/cyclin b promotes a protein complex formation on the mitotic apparatus at early mitosis, which may be required for subsequent activation of warts kinase at the metaphase-anaphase transition. SIGNOR-94160 0.394 D-serine smallmolecule CHEBI:16523 ChEBI NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity chemical activation 9606 BTO:0002609 12393813 t lperfetto D-serine acts in concert with L-glutamate (triangles) to activate NMDA receptors|D-serine released from astrocytes seems to be an endogenous ligand of the N-methyl-D-aspartate (NMDA) receptor (3, 8). Depletion of endogenous D-serine in slices and cultured cells strongly diminishes NMDA receptor responses measured biochemically and electrophysiologically SIGNOR-268279 0.8 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW -1 9218798 t SKK3 mediates the activation of SAPK4. Phosphorylation and activation of SAPK4 and SAPK2a by purified SKK3. SIGNOR-251424 0.651 AVPR1A protein P37288 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257077 0.448 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20584981 f fspada Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program. SIGNOR-166426 0.293 ACTN1 protein P12814 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity binding 9534 16291744 t lperfetto Consistent with the results obtained with COS-7 cells, coexpression of wild-type Œ±-actinin with PTP 1B in PTP 1B-null cells resulted in Src/Œ±-actinin binding and limited the interaction between FAK and Src SIGNOR-261799 0.562 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000944 11581251 t inferred from 70% family members lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. SIGNOR-270119 0.2 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9534 BTO:0000298 10880354 t miannu Ser(155) is phosphorylated preferentially by PKA in vitro and is the only residue in BAD that becomes phosphorylated when cells are exposed to cAMP-elevating agents. The phosphorylation of BAD at Ser(155) prevents it from binding to Bcl-X(L) and promotes its interaction with 14-3-3 proteins. SIGNOR-250338 0.529 MLL-AF9 fusion protein SIGNOR-FP5 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR up-regulates activity binding 9606 BTO:0005261 19956800 t irozzo Although the complex was initially termed ENL associated proteins (EAP), we now propose to redefine EAP as ‘‘elongation assisting proteins’’ to better reflect the function of this protein complex. In this report, we present evidence that the most frequently occurring MLL fusion proteins exploit molecular control mechanisms of transcriptional elongation to transform hematopoietic cells. MLL fusions become incorporated into an ‘‘elongation assisting protein’’ complex, recruit it to their respective target genes, and enforce ectopic transcription. SIGNOR-255876 0.2 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 BTO:0003807 11971971 t lperfetto Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-244788 0.2 Microprocessor complex complex SIGNOR-C356 SIGNOR NcRNA_processing phenotype SIGNOR-PH95 SIGNOR up-regulates 24581491 f lperfetto Microprocessor minimally comprises the ribonuclease DROSHA and its double-stranded RNA-binding partner DGCR8 (Denli et al., 2004; Gregory et al., 2004). Microprocessor recognizes pri-miRNA through the stem-loop (Zeng et al., 2005) and the stem-loop-ssRNA junction (Han et al., 2006), and cleaves both the 5′ and 3′ flanking segments to generate pre-miRNA. SIGNOR-264850 0.7 PPP2CA protein P67775 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity dephosphorylation Ser59 GGQESQPsPLALLAA 9606 24382322 t gcesareni These results indicate that the signals from TCDD or OP caused PP2A-mediated dephosphorylation of Sp1 at Ser-59 and induced CYP1A1 transcription SIGNOR-248223 0.266 UBE2I protein P63279 UNIPROT MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys137 KNGETSLkPEDFDFT 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275676 0.2 PRKCD protein Q05655 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Thr1224 RYVPPSStDRSPYEK 9606 11877440 t gcesareni We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin SIGNOR-115501 0.339 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11163210 t miannu Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.  SIGNOR-272940 0.867 EGLN2 protein Q96KS0 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates quantity by destabilization hydroxylation 9606 24990963 t lperfetto There are three EglN family members in humans and mice (EglN1, EglN2, and EglN3). Their enzymatic activity requires oxygen, ascorbic acid, iron, and α-ketoglutarate (α-KG). Under hypoxic conditions, EglNs lose their activity and fail to hydroxylate HIFα, which leads to HIFα stabilization SIGNOR-261999 0.853 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser253 APRRRAVsMDNSNKY 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252863 0.76 PICK1 protein Q9NRD5 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity binding 10116 BTO:0003036 16554470 t miannu We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. SIGNOR-268178 0.799 MAPK12 protein P53778 UNIPROT RCSD1 protein Q6JBY9 UNIPROT down-regulates activity phosphorylation Ser108 LPGASPKsPGLKAMV -1 15850461 t miannu Peptide T2 was sequenced and shown to comprise residues 79–112 of CapZIP, phosphorylated at Ser-108 (Figure 2B). The identity of peptide T1 is unknown. These experiments established that the SAPK3/p38γ substrate was CapZIP. Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown). An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ. SIGNOR-263083 0.513 SREBF1 protein P36956 UNIPROT ACACA protein Q13085 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11994399 f Luana SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]). SIGNOR-267957 0.464 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203588 0.773 MAPK3 protein P27361 UNIPROT THRB protein P10828 UNIPROT down-regulates activity phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-102224 0.415 MMP24 protein Q9Y5R2 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272368 0.7 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity. SIGNOR-252898 0.402 PSTPIP1 protein O43586 UNIPROT DNM2 protein P50570 UNIPROT down-regulates binding 9606 18480402 t miannu We show that pstpip1 associates with the regulator of endocytosis, dynamin 2, and pstpip1 expression impairs transferrin uptake and endocytosis SIGNOR-178628 0.379 ITGAV protein P06756 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253205 0.913 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18621737 t lperfetto Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2. SIGNOR-179456 0.892 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9Y4C0 UNIPROT up-regulates activity binding 9606 BTO:0000142 11470830 t miannu In brain, dystroglycan and dystrophin are expressed on neurons and astrocytes, and some muscular dystrophies cause cognitive dysfunction. Our data indicate that dystroglycan is a physiological ligand for neurexins and that neurexins' tightly regulated interaction could mediate cell adhesion between brain cells. these results suggest that α- and β-neurexins represent ligands for dystroglycan via interactions of their LNS domains, analogous to interaction of the LNS-domain in laminin, agrin, and perlecan with dystroglycan. SIGNOR-265451 0.304 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA -1 10949026 t gcesareni Survival factors, acting through kinases such as Akt and PKA, induce endogenous BAD phosphorylation at two evolutionarily conserved sites, Ser-112 and Ser-136, which leads to the translocation of BAD from the mitochondria to the cytoplasm and the inhibition of BAD-dependent death SIGNOR-67400 0.418 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Ser104 SQQQFGYsPGQQQTH 9606 17310276 t lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 SIGNOR-153300 0.345 L-serine chemical CHEBI:17115 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 10090 BTO:0000142 12393813 t lperfetto High levels of d-serine occur in the brain, challenging the notion that d-amino acids would not be present or play a role in mammals. d-serine levels in the brain are even higher than many l-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others. d-serine is synthesized by a serine racemase (SR) enzyme, which directly converts l- to d-serine. We now report that SR is a bifunctional enzyme, producing both d-serine and pyruvate in cultured cells and in vitro. Transfection of SR into HEK 293 cells elicits synthesis of d-serine and augmented release of pyruvate to culture media. SIGNOR-268269 0.8 paliperidone chemical CHEBI:82978 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258565 0.8 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs. SIGNOR-248603 0.2 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248923 0.668 MYC protein P01106 UNIPROT IMPDH2 protein P12268 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18677108 t miannu Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation. SIGNOR-267375 0.297 NPTX1 protein Q15818 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control SIGNOR-260411 0.2 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr312 ISYDIPPtPGNTYQI 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249399 0.591 TEK protein Q02763 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto the effects of the angiopoietins are not specific for vascular endothelial cells, as their receptors (Tie1, Tie2) are known to be expressed in hematopoietic cells and they have also recently been shown to be expressed in skeletal muscle cellsExogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241541 0.2 GRB10 protein Q13322 UNIPROT IGF1R protein P08069 UNIPROT down-regulates binding 9606 21659604 t gcesareni Grb10 negatively regulates growth factor signaling. It binds the insulinand insulin-like growth factor 1 (igf-1) receptors, and mice without grb10 are larger and exhibit enhanced insulin sensitivity SIGNOR-174062 0.733 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 17110930 t Barakat Upon TNFα stimulation, MEKK1, ASK1, and TAK1 phosphorylate and activate MKK7, which in turn activates JNK SIGNOR-274148 0.583 orantinib chemical CHEBI:91088 ChEBI FGFR1 protein P11362 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207435 0.8 Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 16440056 f lperfetto The most abundant cytoplasmic dynein complex, cytoplasmic dynein 1, is involved in functions as diverse as spindle-pole organization and nuclear migration during mitosis, the positioning and functioning of the endoplasmic reticulum, the Golgi apparatus, and the nucleus, and also the minus-end-directed transport of vesicles, including endosomes and lysosomes, along microtubules and retrograde axonal transport in neurons. SIGNOR-265058 0.7 SEC13 protein P55735 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265296 0.844 ATR protein Q13535 UNIPROT MCM2 protein P49736 UNIPROT unknown phosphorylation Ser108 DVEELTAsQREAAER 9606 15210935 t lperfetto Atm phosphorylates mcm3 on s535 in response to ionizing radiation. Second, atr phosphorylates mcm2 on s108 in response to multiple forms of dna damage and stalling of replication forksthe functional consequences of mcm2 s108 and mcm3 s535 phosphorylation are not clear SIGNOR-126363 0.702 WNK1 protein Q9H4A3 UNIPROT OXSR1 protein O95747 UNIPROT up-regulates phosphorylation Ser325 VRRVPGSsGRLHKTE 9606 17190791 t gcesareni Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1) SIGNOR-151659 0.491 PIM2 protein Q9P1W9 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-249604 0.396 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser276 VHPATPIsPGRASGM 9606 17015473 t The effect has been demonstrated using Q01196-8. gcesareni Aml1/runx1 phosphorylation by cyclin-dependent kinases regulates the degradation of aml1/runx1 by the anaphase-promoting complex. SIGNOR-149972 0.345 EXOC3 protein O60645 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270786 0.959 MAPK3 protein P27361 UNIPROT KRT8 protein P05787 UNIPROT unknown phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 22344252 t llicata Our data suggested a close relationship between k8(s431) phosphorylation and keratin reorganization in epithelial tumor cells. SIGNOR-196141 0.425 ATM protein Q13315 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates phosphorylation Thr491 PQQRNALtPTTIPDG 9606 18769144 t lperfetto Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively SIGNOR-180755 0.409 KDR protein P35968 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity relocalization 9825 BTO:0004007 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 9405464 t VEGF pathway Gianni In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function. SIGNOR-261949 0.704 GATA1 protein P15976 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10523830 f irozzo Our results suggest that Spi-1 and GATA-1 might play a key role in the regulation of Fli-1. Most notably, we observed that the GATA/EBS dual element near the Fli-1 CAP sites had an enhancer activity in HEL cells. Spi-1 and GATA-1 were both found to bind to this sequence and hence both factors could represent potential regulators of Fli-1 expression. SIGNOR-256053 0.528 Phenylalanyl-tRNA synthetase complex SIGNOR-C473 SIGNOR phenylalanine smallmolecule CHEBI:28044 ChEBI down-regulates quantity chemical modification 9606 20223217 t miannu Here we report crystal structure of hcPheRS complexed with phenylalanine at 3.3 Å resolution. An essential feature of hcPheRS is a novel fold formed by the N-terminal part of the α subunit, whose functional role in tRNAPhe binding and complex formation was studied by truncation mutagenesis. Phenylalanine activation and formation of Phe-tRNAPhe catalyzed by modified hcPheRS have been compared with those of the wild-type enzyme. HcPheRS is a heterotetramer built of two αβ heterodimers. SIGNOR-270439 0.8 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273075 0.635 KDM3B protein Q7LBC6 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. SIGNOR-266636 0.2 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Ser74 TVNQSLLsPLVLEVD 9606 BTO:0000586 19115206 t the cytoskeletal intermediate filament keratin 8 (KRT8) was identified as a physiological PRL-3-interacting protein. Indeed, treatment with the PRL-3 inhibitor effectively suppressed the phosphorylation of KRT8 at S73 and S431|The site-specific phosphorylation of keratins induces the disassembly of these filaments, and the balance between their phosphorylation and dephosphorylation controls the continuous exchange of intermediate filament subunits between a soluble pool and polymerized filaments SIGNOR-248340 0.274 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr161 DDYHNPGyLVVLPDS 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247022 0.765 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1231 HSLAARYyNWVSFPG 9606 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104076 0.2 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR LEFTY2 protein O00292 UNIPROT up-regulates quantity by expression transcriptional regulation 31583686 t SimoneGraziosi Both SOX2 and SOX17 are able to partner with OCT4 and, as a consequence, recognize and bind specific binding motifs.6, 7 In human and mouse ESCs, SOX2/OCT4 bind to canonical motifs (CTTTGTCATGCAAAT-like), which are composite SOX (CATTGTC-like) and OCT (ATGCAAAT-like) motifs|This way SOX17 and SOX2 regulate a common set of pluripotency and GC-related genes (PRDM14, DPPA4, TDGF1, NANOG, LIN28A, TRIM71, OTX2, PIM2) (Fig. 6). Additionally, in TCam-2 cells SOX17 binds to compressed motifs or SOX motifs (not bound by SOX2 in ECs), thereby regulating the PGC specifiers PRDM1 and TFAP2C, the GC-related genes NANOS3 and BMP7 and the cancer-related genes MYC and IGF1 (Fig. 6). In 2102EP cells, SOX2 further binds canonical elements or SOX motifs (not bound by SOX17 in TCam-2), regulating additional pluripotency genes (GDF3, LEFTY2, SALL4, SOX2 and POU5F1) (Fig. 6). SIGNOR-269251 0.426 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267904 0.8 ASNS protein P08243 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-267534 0.8 GART protein P22102 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI down-regulates quantity chemical modification 9606 11381136 t miannu The third step is catalyzed by the enzyme glycinamide ribonucleotide transformylase (GAR Tfase). The two folate-requiring reactions, glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole ribonucleotide transformylase (AICAR Tfase), have attracted particular attention because some of the most successful anticancer drugs to date have been folate antimetabolites such as methotrexate (3). These two enzymes carry out similar chemistry in catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to the amino group of the substrates GAR and AICAR to form fGAR and fAICAR. SIGNOR-267303 0.8 CEP72 protein Q9P209 UNIPROT CDK5RAP2 protein Q96SN8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically. SIGNOR-271720 0.655 GABRB1 protein P18505 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263766 0.634 INTS1 protein Q8N201 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261468 0.891 C5AR2 protein Q9P296 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 9108406 f lperfetto We report here that the anaphylatoxins C3a and C5a are chemotactic factors for the human mast cell line HMC-1, human cord blood-derived mast cells (CBMC) and cutaneous mast cells in vitro. SIGNOR-263459 0.7 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ala) smallmolecule CHEBI:29170 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269480 0.8 CAD protein P27708 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267424 0.8 POU5F1 protein Q01860 UNIPROT SOX17/POU5F1 complex SIGNOR-C451 SIGNOR form complex binding 23474895 t SimoneGraziosi Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm|We show that Sox17 partners with Oct4 and binds to a unique ‘compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical' binding sites. SIGNOR-269221 0.621 MYCL protein P12524 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0000724 7882978 f irozzo These observations indicate that continued late-stage expression of L-myc affected differentiation processes directly, rather than indirectly through deregulated growth control, whereas constitutive c-myc expression inhibited proliferative arrest, but did not appear to disturb differentiation. SIGNOR-259202 0.7 HIF1A protein Q16665 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271571 0.269 NFE2L3 protein Q9Y4A8 UNIPROT PLA2G7 protein Q13093 UNIPROT up-regulates quantity by expression transcriptional regulation 22247257 t lperfetto Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene. SIGNOR-268979 0.369 SMURF1 protein Q9HCE7 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates activity monoubiquitination 9615 BTO:0000837 32010791 t miannu  Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation. SIGNOR-277507 0.2 CCND1 protein P24385 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000575 11731443 f Cyclin D1 regulates mitogen-dependent progression through G1 phase in cultured cells, and its overexpression in malignant cells is thought to contribute to autonomous proliferation in vivo. SIGNOR-260014 0.7 ARPP19 protein P56211 UNIPROT PPP2R2D protein Q66LE6 UNIPROT down-regulates activity binding -1 phosphorylation:Ser62 KGQKYFDsGDYNMAK 21164014 t gcesareni We identified cyclic adenosine monophosphate€“regulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry. SIGNOR-243731 0.687 NOG protein Q13253 UNIPROT GDF5 protein P43026 UNIPROT down-regulates activity binding 9606 19956691 t Regulation miannu We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. SIGNOR-251865 0.688 Diprenorphine chemical CHEBI:4650 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258789 0.8 CSNK2A2 protein P19784 UNIPROT PTPN1 protein P18031 UNIPROT unknown phosphorylation -1 9600099 t llicata In this study, we demonstrate that HPTP1B are multiple phosphorylated on threonine and tyrosine as well as serine near its N-terminus by CKII and p60c-src in vitro. SIGNOR-251028 0.345 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT down-regulates activity phosphorylation Thr2446 NKRSRTRtDSYSAGQ 9606 15905173 t lperfetto Importantly, phosphorylation of mTOR by S6K1 occurs at threonine 2446/serine 2448. This region has been shown previously to be part of a regulatory repressor domain. These sites are also constitutively phosphorylated in the breast cancer cell line MCF7 carrying an amplification of the S6K1 geneit has been proposed that other inputs, in addition to phosphorylation of Thr-2446/Ser-2448 by S6K1, are part of the mechanism involved in inhibiting this repressor domain SIGNOR-137255 0.2 CEBPE protein Q15744 UNIPROT CEBPG protein P53567 UNIPROT up-regulates activity binding 9606 BTO:0000007 15588942 t miannu C/EBP-epsilon interacts with C/EBP-gamma through the leucine-zipper containing domain. C/EBP-epsilon and C/EBP-gamma synergistically activate transcription of lactoferrin promoter SIGNOR-224900 0.378 PCM1 protein Q15154 UNIPROT NEK2 protein P51955 UNIPROT up-regulates relocalization 9606 15659651 t miannu Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1 SIGNOR-133337 0.41 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t gcesareni Although sh2 domains have not been reported previously to be phosphorylated, the tensin-3 sh2 domain is a physiologic substrate for src. Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. SIGNOR-187854 0.414 TUBE1 protein Q9UJT0 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-267178 0.7 RORC protein P51449 UNIPROT Th17 phenotype SIGNOR-PH94 SIGNOR up-regulates 9606 16990136 f MARCO ROSINA Our results demonstrate that RORgt is the transcription factor that directs the differentiation of inflammatory Th17 cells SIGNOR-255028 0.7 CLTB protein P09497 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260666 0.764 NPLOC4 protein Q8TAT6 UNIPROT UFD1 protein Q92890 UNIPROT up-regulates activity binding 9606 20442859 t miannu These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes. SIGNOR-252422 0.2 STAT3 protein P40763 UNIPROT IL1RN protein P18510 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000130;BTO:0000876 20032313 f miannu The interleukin 1 receptor antagonist (IL-1ra) is an important negative regulator of the inflammatory response, whose genetic deficiency has been recently shown to cause a severe autoinflammatory syndrome in humans. In this study we characterized the molecular mechanisms whereby interleukin 10 (IL-10) potentiates IL-1ra transcription in LPS-stimulated monocytes and neutrophils. our findings uncover a novel mechanism whereby IL-10-activated STAT3 modulates IL-1ra transcription in LPS-treated phagocytes by making IL-1ra promoter accessible to readily available nuclear NF-kappaB. SIGNOR-254795 0.494 ATM protein Q13315 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser696 NVLSVALsQRTTVPE 9606 21095582 t lperfetto Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability SIGNOR-169999 0.439 RPLP2 protein P05387 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262449 0.812 SRC protein P12931 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates 9606 BTO:0000142 11782488 f gcesareni C-src was suggested to be involved in bmk1 activation from the experiments with herbimycin a and pp2, specific inhibitors of src family kinases. SIGNOR-113779 0.349 CSDE1 protein O75534 UNIPROT FOS protein P01100 UNIPROT down-regulates quantity post transcriptional regulation 10090 BTO:0000944 15314026 t By testing different classes of mammalian poly(A) nucleases, we identified CCR4 as a poly(A) nuclease involved in the mCRD-mediated rapid deadenylation in viv SIGNOR-261145 0.298 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser696 PNKELPPsPEKKTKP 9606 BTO:0000567 9398320 t lperfetto Map4 is phosphorylated by cdc2 kinase in mitotic hela/ phosphorylation by cdc2 kinase decreased the microtubule-stabilizing ability of map4, suggesting that there are critical phosphorylation sites among the five major cdc2 kinase-dependent phosphorylation sites [spots 4 (ser-696), 5, 6, 9, and 10 (ser-787)]. SIGNOR-53735 0.507 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr775 QGWVPSNyITPVNSL 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260811 0.2 COL6A3 protein P12111 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t Muscle basement membrane consists primarily of a type IV collagen network, however types VI, XV, and XVIII are also present. SIGNOR-254675 0.7 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10029 15069075 t lperfetto Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results. SIGNOR-236760 0.719 ARHGAP31 protein Q2M1Z3 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260488 0.517 INS protein P01308 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates activity 9606 BTO:0000887 9415393 f lperfetto Studies in adipose cells have demonstrated that insulin stimulates its receptor to phosphorylate tyrosine residues in irs-1, leading to activation of phosphatidylinositol 3-kinase, which plays a necessary role in mediating the translocation of the insulin-responsive glucose transporter glut4 to the cell surface. SIGNOR-236781 0.506 GMPS protein P49915 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI down-regulates quantity chemical modification 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267337 0.8 IL3RA protein P26951 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 15795318 f gcesareni We previously demonstrated that integrin-dependent adhesion activates stat5a, a well known target of il-3-mediated signaling SIGNOR-134862 0.563 DVL1P1 protein P54792 UNIPROT DAAM1 protein Q9Y4D1 UNIPROT up-regulates binding 9606 23151663 t gcesareni Importantly, daam1 binds to disheveled (dvl) and thus functions downstream of the frizzled receptors. Little is known of how daam1 is localized and functions in mammalian cells. SIGNOR-199451 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RXRA protein P19793 UNIPROT down-regulates activity phosphorylation 9606 17604322 t inferred from 70% family members lperfetto In colon cancer cells, the Ras/mitogen‚Äêactivated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‚Äêmutated RXRalpha T82A/S260A, which mimics the unphosphorylated form of RXRalpha, can form a heterodimer with PPARgamma and thereby activate target gene expression by binding to the PPRE SIGNOR-269995 0.2 DEF6 protein Q9H4E7 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 18976935 t lperfetto Furthermore, membrane targeting of the SLAT Dbl-homology (catalytic) domain was sufficient to trigger TCR-mediated NFAT activation and Th1 and Th2 differentiation in a Cdc42-dependent manner. SIGNOR-253369 0.398 PRKACA protein P17612 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser99 NRQAAKLsKPTLENL 9606 15703181 t lperfetto We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195. SIGNOR-133888 0.2 IRX1 protein P78414 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261651 0.2 DDIT3 protein P35638 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 31226023 f miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260171 0.7 ATR protein Q13535 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser407 SSSIIYSsQEDVKEF 9606 BTO:0002552 14654783 t lperfetto We found that a major kinase responsible for s407 phosphorylation is atrs407 phosphorylation of mdm2 by atr reduces mdm2-dependent export of p53 from nuclei to cytoplasm. SIGNOR-119546 0.51 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser860 NRAVSLDsPVSVGSS 9606 BTO:0000093 15383283 t miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. SIGNOR-250105 0.513 DAXX protein Q9UER7 UNIPROT AIRE protein O43918 UNIPROT down-regulates activity binding 9606 BTO:0000567 20185822 t 1 miannu The interaction between AIRE and DAXX has been validated by in vivo coimmunoprecipitation analysis and colocalization study in mammalian cells. The interaction has been further confirmed by showing in transactivation assays that DAXX exerts a strong repressive role on the transcriptional activity of AIRE. SIGNOR-239287 0.338 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 11729179 t lperfetto Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no. SIGNOR-216445 0.265 FUBP1 protein Q96AE4 UNIPROT CCND2 protein P30279 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19637194 f irozzo A positive cell cycle regulator that we found down-regulated in Hep3B cells upon FBP1 inactivation was cyclin D2. In addition, Cyclin D2 mRNA levels were diminished in the FBP1 knockdown cells, whereas the amount of Cyclin D1 mRNA remained unaffected. Numerous studies have classified D-type cyclins as cell cycle–promoting oncoproteins important for cellular transformation, and our results suggest that cyclin D2 is a candidate FBP1-regulated oncoprotein in HCC. SIGNOR-259124 0.2 ZNF804A protein Q7Z570 UNIPROT ANKRD1 protein Q15327 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269461 0.2 DVL3 protein Q92997 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12533515 t gcesareni Wnt/fz activation of rac and rho is inhibited by rac-n17 and rho-n19, respectively (figs. _(figs.1d,1d, _d,5c,d;5c,d;habas et al. 2001), and requires different dvl domains wnt signaling induces complex formation between dvl and rac. SIGNOR-97409 0.453 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT down-regulates activity phosphorylation Thr2074 VTPSPPGtVLTSALS 9606 BTO:0000007 12794074 t lperfetto We show that gsk-3beta directly binds at c-terminal of the notch2 ankyrin repeats and phosphorylates thr-2068 and/or ser-2070, thr-2074, and thr-2093. SIGNOR-101574 0.49 AP1 complex SIGNOR-C154 SIGNOR CCND1 protein P24385 UNIPROT up-regulates transcriptional regulation 9606 BTO:0000762 12509763 f lperfetto Substrates for ERK1/2 include nuclear proteins such as C-JUN, this leads to activation of the AP-1 transcription factor, which is made up of FOS-JUN heterodimers.|As a result of stimulating these transcriptional regulators, key cell-cycle regulatory proteins, such as D-type cyclins, are expressed, which enables the cell to progress through the G1 phase of the cell-cycle. SIGNOR-253215 0.612 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1173 QDTSKFWyKADISRE 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187843 0.414 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates 9606 19491292 f gcesareni Nuclear pgc-1alpha and foxo3a respond in a reciprocal manner following aicar treatment. SIGNOR-186058 0.399 EGFR protein P00533 UNIPROT LRRK1 protein Q38SD2 UNIPROT down-regulates activity phosphorylation Tyr971 TQQTEEQyFQFLAKF 9534 BTO:0000298 22337768 t miannu In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity. SIGNOR-262856 0.347 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK8 protein P45983 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-189702 0.8 ZM447439 chemical CHEBI:91376 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207926 0.8 PTPN2 protein P17706 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates activity dephosphorylation Tyr1021 PNEGDNDyIIPLPDP 10090 BTO:0002572 14966296 t The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP. SIGNOR-248390 0.553 AGK protein Q53H12 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267708 0.368 KDM6A protein O15550 UNIPROT HOXC8 protein P31273 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260029 0.31 PRRX1 protein P54821 UNIPROT MAFF protein Q9ULX9 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221890 0.358 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267313 0.8 PRKN protein O60260 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000793 20871098 t miannu Parkin and PINK1 are required for ubiquitination of MFN-1 and MFN-2.  Decreases in MFN-1 and MFN-2 protein levels seen at later timepoints are difficult to interpret as it is unclear whether this is due to degradation by the proteasome and/or loss of whole mitochondria by mitophagy. SIGNOR-272779 0.2 KRAS protein P01116 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 BTO:0000797 27340238 f These alterations corresponded to mutant KRAS and BRAF-dependent increases in glucose uptake and lactate production. Metabolic reprogramming and glucose conversion to lactate in RKO cells were proportional to levels of BRAF V600E protein. SIGNOR-259372 0.7 ABI1 protein Q8IZP0 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems SIGNOR-253571 0.843 iron-sulfur cluster smallmolecule CHEBI:30408 ChEBI SDHB protein P21912 UNIPROT up-regulates activity chemical activation 26083061 t lperfetto Succinate dehydrogenase subunit B contains three Fe-S clusters |The enzymatic activity of both proteins depends on the presence of intact Fe-S clusters SIGNOR-262133 0.8 CASP8 protein Q14790 UNIPROT RNF31 protein Q96EP0 UNIPROT down-regulates activity cleavage Asp348 GTGGLEPdLARGRWA 9606 BTO:0005111 32122970 t miannu We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages. Reciprocally, caspase-1, as well as caspase-8, regulated LUBAC activity by proteolytically processing HOIP at Asp-348 and Asp-387 during the execution of cell death. SIGNOR-272194 0.319 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275788 0.274 ZFYVE26 protein Q68DK2 UNIPROT TTC19 protein Q6DKK2 UNIPROT up-regulates activity binding 9606 BTO:0000567 20208530 t miannu We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. FYVE-CENT interacts with KIF13A and TTC19 SIGNOR-265538 0.471 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 21808241 t Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs. gcesareni Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators SIGNOR-175787 0.691 PKNOX1 protein P55347 UNIPROT SYP protein P08247 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20864515 f miannu Prep1 overexpression in HepG2 liver cells upregulated SYP and SHP1 and inhibited insulin-induced IR and IRS1/2 phosphorylation and was accompanied by reduced glycogen content. SIGNOR-254923 0.2 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity binding 9606 22326956 t lperfetto TGF-beta signaling mediates a wide range of biological activities in development and disease. TGF-beta ligands signal through heterodimeric type I and type II receptors (TGF-beta receptor type I [TbetaRI, also known as ALK5 and TGFBR1] and TbetaRII) that are members of the serine/threonine kinase family. SIGNOR-196022 0.842 YAP1 protein P46937 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21233212 f miannu We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling. SIGNOR-263660 0.37 AKT1 protein P31749 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser230 LKRNRYLsFHFKSGS 15870194 t lperfetto Site-directed mutagenesis, mass spectrometry, and kinetic analyses identified S(230) in hBVR (225)RNRYLSF sequence as the Akt1 target. SIGNOR-275517 0.3 KLF4 protein O43474 UNIPROT SOD1 protein P00441 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002104 23370975 f miannu The expression of superoxide dismutase (SOD) 1 in both mRNA and protein levels was found to be decreased by overexpressing KLF4, while increased by knockdown of KLF4 SIGNOR-254545 0.294 ACVR2B protein Q13705 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 10090 21966641 t areggio It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains SIGNOR-254984 0.771 NARS1 protein O43776 UNIPROT Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270456 0.8 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr252 HDGTVTHtFCGTIEY -1 9445476 t gcesareni The results presented here are consistent with PDK1 as the in vivo kinase responsible for mediating Thr252 phosphorylation in the catalytic domain of p70s6k. SIGNOR-243338 0.719 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser399 DNITLPPsQPSPTGG -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274095 0.403 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Arg94 IGFQEAYrRFYGPV -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256322 0.2 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). SIGNOR-176487 0.275 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 11041858 t lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases . The ser-51 mutant showed little covalent modification by the endogenous enzymes. Phosphorylation of the serine 51 residue in the alpha-subunit of translational initiation factor 2 in eukaryotes (eif2 alpha) impairs protein synthesis presumably by sequestering eif2b, a rate-limiting pentameric guanine nucleotide exchange protein which catalyzes the exchange of gtp for gdp in the eif2-gdp binary complex SIGNOR-83226 0.888 FAD(3-) chemical CHEBI:57692 ChEBI ETF complex SIGNOR-C463 SIGNOR form complex binding 9606 33450351 t miannu Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. SIGNOR-269469 0.8 EN1 protein Q05925 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription SIGNOR-265776 0.461 GPR161 protein Q8N6U8 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 23332756 t Shh signaling directs Gpr161 to be internalized from cilia, preventing its activity. SIGNOR-259936 0.381 clozapine chemical CHEBI:3766 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258516 0.8 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 BTO:0000568 16890161 t gcesareni Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin. SIGNOR-148671 0.786 ZRSR2/U2AF2 complex SIGNOR-C81 SIGNOR Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11739736 f miannu The essential splicing factor U2AF (U2 auxiliary factor) is a heterodimer composed of 65-kDa (U2AF(65)) and 35-kDa (U2AF(35)) subunits. U2AF(35) has multiple functions in pre-mRNA splicing. First, U2AF(35) has been shown to function by directly interacting with the AG at the 3' splice site. Second, U2AF(35) is thought to play a role in the recruitment of U2AF(65) by serine-arginine-rich (SR) proteins in enhancer-dependent splicing. SIGNOR-263946 0.7 MAPK14 protein Q16539 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Thr182 IDQGDLMtPQFTPYY 9606 BTO:0000567 9628874 t lperfetto In hela cells, prak was activated in response to cellular stress and proinflammatory cytokines. Prak activity was regulated by p38alpha and p38beta both in vitro and in vivo and thr182 was shown to be the regulatory phosphorylation site. SIGNOR-58135 0.627 TCF3 protein P15923 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 BTO:0000887 1649701 t E12/E47-like proteins interact in vivo with the myogenic HLH proteins MyoD and myogenin lperfetto In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators. SIGNOR-20540 0.801 PICK1 protein Q9NRD5 UNIPROT ASIC1 protein P78348 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 11802773 t miannu we found that the PDZ domain-containing protein PICK1 (protein interacting with C kinase) interacts specifically with the C-termini of BNC1 and ASIC. Our studies showing association of recombinant PICK1 with ASIC and BNC1, and the presence of both PICK1 and ASIC in the synaptosomal fraction SIGNOR-223417 0.548 ADORA3 protein P0DMS8 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256671 0.446 AMPK complex SIGNOR-C15 SIGNOR AMPK complex SIGNOR-C15 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 17728241 t lperfetto Mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of ampk by a-769662 in cells and in vitro, while only partially reducing activation by ampk SIGNOR-216411 0.798 SOSTDC1 protein Q6X4U4 UNIPROT BMP2 protein P12643 UNIPROT down-regulates activity 10090 18032587 f lperfetto SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7 SIGNOR-242746 0.589 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI HNF4A protein P41235 UNIPROT down-regulates quantity by repression 9606 9792724 f miannu Retinoic acid mediates down-regulation of the alpha-fetoprotein gene through decreased expression of hepatocyte nuclear factors. The levels of HNF1 and HNF4 mRNA were also decreased following RA treatment. SIGNOR-254445 0.8 BAZ1B protein Q9UIG0 UNIPROT WICH complex SIGNOR-C449 SIGNOR form complex binding 9606 16603771 t miannu We show here that the WICH complex (WSTF-SNF2h) interacts with several nuclear proteins as follows: Sf3b155/SAP155, RNA helicase II/Gualpha, Myb-binding protein 1a, CSB, the proto-oncogene Dek, and nuclear myosin 1 in a large 3-MDa assembly, B-WICH, during active transcription. Our results show that a WSTF-SNF2h assembly is involved in RNA polymerase III transcription, and we suggest that WSTF-SNF2h-NM1 forms a platform in transcription while providing chromatin remodeling. SIGNOR-268828 0.924 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM1 protein P0DP23 UNIPROT up-regulates chemical activation 10090 10448861 t lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-235590 0.8 COL2A1 protein P02458 UNIPROT A2/b1 integrin complex SIGNOR-C160 SIGNOR up-regulates binding 9606 7688313 t gcesareni Both a2b1- and a1b1- integrins are implicated in chondrocyte adhesion to native collagene i and ii SIGNOR-31881 0.46 PEX12 protein O00623 UNIPROT UBE2D1 protein P51668 UNIPROT up-regulates activity binding -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253024 0.617 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2137 EDRTVPStPTLVVPH 9606 18794356 t miannu Tpr is phosphorylated by erk2 at four different sites. / because phosphorylation of tpr by activated erk stabilizes their interaction, we hypothesize that this phosphorylation is not part of a signal amplification cascade but rather positions activated erk to perform a continuing function in the nuclear pore. SIGNOR-181022 0.379 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252856 0.909 ARID1A protein O14497 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270689 0.802 CTNND2 protein Q9UQB3 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252134 0.454 STAT6 protein P42226 UNIPROT ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma Cytokines like IL-4 or IL-13 lead to STAT6 phosphorylation with consecutive arginase expression and varying further aspects of M2 polarization (mannose receptor, Ym1, Fizz1) SIGNOR-255557 0.414 MAPK1 protein P28482 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Thr388 VYFKPSLtPSGEFRK 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188127 0.394 CDK2 protein P24941 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR form complex binding 9606 19056339 t lperfetto We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2. SIGNOR-182569 0.977 ESR2 protein Q92731 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 11517191 f ER beta and ER alpha induced the expression of several endogenous genes such as pS2, TGF alpha, or the cyclin kinase inhibitor p21 but, in contrast to ER alpha, ER beta was unable to regulate c-myc proto-oncogene expression SIGNOR-253943 0.294 PRKCA protein P17252 UNIPROT PPP1R16B protein Q96T49 UNIPROT down-regulates activity phosphorylation Ser331 SQLRHKSsLSRRTSS -1 27939168 t done miannu PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function. SIGNOR-273802 0.2 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270896 0.537 EPAS1 protein Q99814 UNIPROT KDM5C protein P41229 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271579 0.28 NF90-NF45 complex SIGNOR-C443 SIGNOR CDKN1A protein P38936 UNIPROT down-regulates quantity by repression 10116 25566957 f miannu In the present study, we investigated the expression profiles of NF45 in the sciatic nerve of adult rats following crush injury.  in the TNF-α-induced Schwann cell proliferation assay, protein level of NF45 and cyclin E was elevated while expression of p21 was down-regulated. Further, when NF45 was knocked down, Schwann cell proliferation was interrupted and the expression of cyclin E was attenuated, while the expression of p21 was up-regulated. To repress the expression of p21 is one of the basic mechanisms for NF45-regulated cell proliferation. SIGNOR-268491 0.249 PRKCB protein P05771 UNIPROT TNNI3 protein P19429 UNIPROT down-regulates phosphorylation Ser44 KKSKISAsRKLQLKT 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134628 0.2 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 11160424 t gcesareni The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity. u0126 was found to functionally antagonize ap-1 transcriptional activity via noncompetitive the dual specificity kinase mek with an ic50 of 0.07 microm for mek 1 and 0.06 microm for mek 2. SIGNOR-104939 0.8 LPAR5 protein Q9H1C0 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256997 0.2 MLN protein P12872 UNIPROT MLNR protein O43193 UNIPROT up-regulates binding 9606 BTO:0000938 10381885 t gcesareni A heterotrimeric guanosine triphosphate-binding protein (g protein)-coupled receptor for motilin was isolated from human stomach SIGNOR-68721 0.766 GTF2I protein P78347 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19097122 f miannu Transcription factor TFII-I causes transcriptional upregulation of GRP78 synthesis in prostate cancer cells. SIGNOR-254221 0.377 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 17389598 t lperfetto Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2. SIGNOR-153944 0.684 STAT1 protein P42224 UNIPROT CIITA protein P33076 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001103 9551976 f Federica Ferrentino A role for STAT1 in regulation of the CIITA promoter is shown by the rescue of IFN-gamma induction by expression of STAT1 in STAT1-defective U3A cells SIGNOR-255752 0.53 GAS6 protein Q14393 UNIPROT MERTK protein Q12866 UNIPROT up-regulates binding 9606 BTO:0000975 8939948 t gcesareni We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily. SIGNOR-44953 0.757 PTPN6 protein P29350 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75934 0.363 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr326 TSSSQLStPKSKQSP 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250659 0.412 GABPB1 protein Q06547 UNIPROT HCFC1 protein P51610 UNIPROT down-regulates activity binding 9606 BTO:0000567 10675337 t miannu The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation SIGNOR-221377 0.331 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser688 SKGVDFEsSEDDDDD -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265893 0.2 IGF1 protein P05019 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 17200203 f Regulation of expression miannu Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts SIGNOR-251862 0.294 PIK-90 chemical CID:6857685 PUBCHEM PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206226 0.8 PTPRG protein P23470 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity dephosphorylation Tyr576 RYMEDSTyYKASKGK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254719 0.245 CALM3 protein P0DP25 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266340 0.534 BLOC-2 complex SIGNOR-C252 SIGNOR KIF13A protein Q9H1H9 UNIPROT up-regulates activity binding 9606 30404817 t lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. SIGNOR-260702 0.259 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR CCL7 protein P80098 UNIPROT up-regulates quantity 10090 32283152 f miannu The rapid replication of SARS-CoV in BALB/c mice induces the delayed release of IFN-α/β, which is accompanied by the influx of many pathogenic inflammatory mononuclear macrophages. The accumulated mononuclear macrophages receive activating signals through the IFN-α/β receptors on their surface and produce more monocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages. SIGNOR-260963 0.7 GRB7 protein Q14451 UNIPROT RND1 protein Q92730 UNIPROT up-regulates binding 9606 BTO:0000150 10664463 t gcesareni We would like to propose that when cells are driven to divide by growth factor stimulation, grb7 relocalizes at the membrane, in the same subcellular compartment as rnd1, where they could interact in vivo. SIGNOR-74914 0.605 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR LEF1 protein Q9UJU2 UNIPROT up-regulates transcriptional regulation 9606 10890911 f lperfetto Coexpression of smad2 and smad4, smad3 alone, or smad3 and smad4 resulted in strong enhancement of lef1-dependent transcriptional activity SIGNOR-217169 0.603 PRKACA protein P17612 UNIPROT HSF1 protein Q00613 UNIPROT up-regulates phosphorylation Ser320 ASPGRPSsVDTLLSP 9606 21085490 t lperfetto Protein kinase a binds and activates heat shock factor 1hsf1 binds avidly to the catalytic subunit of pka, (pkac_) and becomes phosphorylated on a novel serine phosphorylation site within its central regulatory domain (serine 320 or s320), both in vitro and in vivo. Intracellular pkac_ levels and phosphorylation of hsf1 at s320 were both required for hsf1 to be localized to the nucleus, bind to response elements in the promoter of an hsf1 target gene SIGNOR-169853 0.318 SMAD7 protein O15105 UNIPROT SMURF2 protein Q9HAU4 UNIPROT up-regulates activity relocalization 9606 19352540 t lperfetto Smad7 also recruits the HECT type of E3 ubiquitin ligases, Smurf1 and Smurf2. It binds to Smurfs in the nucleus and translocates into the cytoplasm in response to TGF-_ and recruits the ubiquitin ligases to the activated type I receptor ALK5/T_RI, leading to the degradation of the receptor through the proteasomal pathway. SIGNOR-168450 0.867 JAK2 protein O60674 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 8977526 t lperfetto JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation. SIGNOR-249503 0.521 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser784 GVEKCSDsQSWEDIA 9606 12697768 t llicata To examine whether the respective sq sites become phosphorylated in vivo, we raised polyclonal antibodies against phosphorylated ser-6 (anti-s6p), phosphorylated ser-25 and ser-29 (anti-s25p/29p), and phosphorylated ser-784 (anti-s784p). All affinity-purified antisera recognized 53bp1 SIGNOR-100653 0.871 MARCHF9 protein Q86YJ5 UNIPROT LILRB1 protein Q8NHL6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271534 0.2 PDPK1 protein O15530 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Thr507 FGESRAStFCGTPDY 9606 BTO:0000007 9748166 t miannu PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. PKCδ was also phosphorylated in the activation loop site (T505) SIGNOR-250269 0.565 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 15664191 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity. previous studies have shown that phosphorylation is required for raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated erk SIGNOR-133345 0.625 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity 10090 BTO:0000887 24145169 f The BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling SIGNOR-256487 0.2 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118027 0.711 (+)-pilocarpine chemical CHEBI:8207 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258626 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 BTO:0000222 14749395 t lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. SIGNOR-216920 0.323 THRA protein P10827 UNIPROT RARA protein P10276 UNIPROT up-regulates binding 9606 15650024 t gcesareni We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs. SIGNOR-133240 0.417 MAPK10 protein P53779 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 20220133 t gcesareni Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset. SIGNOR-164085 0.246 XL765 chemical CHEBI:71958 ChEBI PIK3CA protein P42336 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207872 0.8 mono(2-ethylhexyl) phthalate chemical CHEBI:17243 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu MEHP and MiNP exhibit potent activation of hCAR2 and hPXR with higher affinities for these receptors than for the hPPARs. The rank order potency for MEHP and MiNP was hCAR2 > hPXR > hPPARs. SIGNOR-268785 0.8 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser283 RSVPEPLsPVSSLQA -1 16027724 t GSK-3, p38 and CDK2 can phosphorylate Cdx2 through the 4S motif in vitro, but only CDK2 was shown to be active in vivo. the compound mutant 4S>A (serines 281, 285, 289 and 293 replaced by alanines) SIGNOR-251227 0.385 Alamandine chemical CID:44192273 PUBCHEM MRGPRD protein Q8TDS7 UNIPROT up-regulates activity binding 10029 BTO:0000246 23446738 t Luana Alamandine produces several physiological actions that resemble those produced by angiotensin-(1-7), including vasodilation, antifibrosis, antihypertensive, and central effects. Interestingly, our data reveal that its actions are independent of the known vasodilator receptors of the RAS, Mas, and angiotensin II type 2 receptor. Rather, we demonstrate that alamandine acts through the Mas-related G-protein-coupled receptor, member D. SIGNOR-262308 0.8 CERS6 protein Q6ZMG9 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI up-regulates quantity chemical modification 9606 26887952 t done miannu  Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity.  SIGNOR-273997 0.8 PCDH10 protein Q9P2E7 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-269034 0.2 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser392 ERLRLSPsPTSQRSR 9606 18815303 t gcesareni Phosphorylation by mitotic cdc2 kinase at ser-22, ser-390, and ser-392 residues on lamin a/c, or by protein kinase c (pkc) during apoptosis, leads to the depolymerization of lamin (disassembly of the nuclear lamina), which may lead to their release from the inm SIGNOR-181318 0.546 KCNJ3 protein P48549 UNIPROT KCNJ5/KCNJ3 complex SIGNOR-C56 SIGNOR form complex binding 9606 BTO:0000562 22362083 t miannu The muscarinic k(+) channel (i (k,ach)) is a heterotetramer composed of girk1 (kir3.1) andgirk4(kir3.4) subunits of a g protein-coupled inwardly rectifying channel, and plays an important role in mediating electrical responses to the vagal stimulation in the heart. SIGNOR-196202 0.478 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT down-regulates activity phosphorylation Ser231 FGDDEDDsGTEES 9606 BTO:0000567 11546811 t lperfetto The ubiquitin-conjugating enzyme, cdc34, has been implicated in the ubiquitination of a number of vertebrate substrates, including p27(kip1), ikappabalpha, wee1, and myod. We show that mammalian cdc34 is a phosphoprotein that is phosphorylated in proliferating cells. Phosphorylation of cdc34 by the associated kinase maps predominantly to residues 203 and 222. Mutation of cdc34 at ck2-targeted residues, ser-203, ser-222, ser-231, thr-233, and ser-236, abolishes the phosphorylation of cdc34 observed in vivo and markedly shifts nuclearly localized cdc34 to the cytoplasm. SIGNOR-110399 0.399 WNK1 protein Q9H4A3 UNIPROT SYT2 protein Q8N9I0 UNIPROT up-regulates activity phosphorylation Thr199 ETKVHRKtLNPAFNE 9606 BTO:0000007 15350218 t miannu Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells. Phosphorylation by WNK1 increases the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of threonine 202, a WNK1 phosphorylation site, partially prevents this change. These findings suggest that phosphorylation of Syts by WNK1 can regulate Ca2+ sensing and the subsequent Ca2+-dependent interactions mediated by Syt C2 domains. . In contrast, WNK1 phosphorylated Syt2 on T202 and T386 within the C2 domains (Figure 6B). SIGNOR-263049 0.615 EP300 protein Q09472 UNIPROT CPT1B protein Q92523 UNIPROT up-regulates quantity by expression transcriptional regulation 9534 BTO:0001538 15199055 f Furthermore, we show that the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. SIGNOR-254260 0.2 PCSK2 protein P16519 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT up-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270335 0.2 SMARCB1 protein Q12824 UNIPROT CDC6 protein Q99741 UNIPROT down-regulates 9606 12226744 f miannu We show that the ectopic expression of wild-type hsnf5/ini1, but not that of truncated versions, leads to a cell cycle arrest by inhibiting the entry into s phase of mrt cells. This g1 arrest is associated with down-regulation of a subset of e2f targets including cyclin a, e2f1 and cdc6. SIGNOR-92785 0.317 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr69 PVPNQPVyNQPVYNQ 9606 11390389 t lperfetto C-abl tyrosine kinase binds and phosphorylates phospholipid scramblase 1. Phosphorylation was abolished by mutation of tyr residues tyr(69)/tyr(74) within the tandem repeat sequence (68)vynqpvynqp(77) of plscr1 SIGNOR-86013 0.39 TRIM13 protein O60858 UNIPROT AKT2 protein P31751 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21333377 t miannu Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT.  We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro. SIGNOR-271853 0.2 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000742 15568017 t gcesareni We demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for Wnt-directed myogenic gene expression. SIGNOR-255799 0.57 PRLHR protein P49683 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257280 0.265 INS protein P01308 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 11279134 f lperfetto The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-235619 0.498 VRK2 protein Q86Y07 UNIPROT DTNBP1 protein Q96EV8 UNIPROT down-regulates quantity by destabilization phosphorylation Ser299 RAKPPSSsSTCTDSA -1 30062698 t miannu  We show that VRK2 phosphorylates Ser 297 and Ser 299 of dysbindin using in vitro kinase assay. In addition, we found that VRK2-mediated phosphorylation of dysbindin enhanced ubiquitination of dysbindin and consequently resulted in the decrease in its protein stability through western blotting.  SIGNOR-277404 0.2 HOXD13 protein P35453 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16314414 f miannu We show that hoxd13 andhoxa13activate transcription from the epha7 promoter and that a mutation of thehoxa13/hoxd13 binding site was sufficient to abolish activation. SIGNOR-142453 0.274 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191009 0.8 CHD8 protein Q9HCK8 UNIPROT SOX7 protein Q9BT81 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268922 0.2 Hemoglobin complex SIGNOR-C209 SIGNOR hb:hp complex SIGNOR-C149 SIGNOR form complex binding 9606 11854029 t miannu CD163 was identified as the endocytic receptor binding hemoglobin (Hb) in complex with the plasma protein haptoglobin (Hp). This specific receptor-ligand interaction leading to removal from plasma of the Hp-Hb complex-but not free Hp or Hb-now explains the depletion of circulating Hp in individuals with increased intravascular hemolysis. SIGNOR-255284 0.743 CSNK2A1 protein P68400 UNIPROT OTUB1 protein Q96FW1 UNIPROT up-regulates activity phosphorylation Ser16 QKQEPLGsDSEGVNC 34785775 t lperfetto Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. |Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec SIGNOR-276527 0.322 INS protein P01308 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates 9606 15209375 f gcesareni The interaction ofinsulin and growth factors with their receptors on the outside surface of a cell, leads to the activation of phosphatidylinositol 3-kinase (pi 3-kinase) and generation of the phosphatidylinositol 3,4,5-trisphosphate (ptdins(3,4,5)p3) second messenger at the inner surface of the cell membrane. SIGNOR-126063 0.339 GSK3B protein P49841 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates quantity by destabilization phosphorylation Thr265 ATYHHNStTTWTGSR 10090 BTO:0000944 25373906 t miannu In the presence of FGF, Wnt potentiates TGF-β signaling by preventing Smad4 GSK3 phosphorylations that inhibit a transcriptional activation domain located in the linker region.  SIGNOR-276442 0.404 ID3 protein Q02535 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241134 0.54 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr94 SSLPEGYyEEAVPLS 9534 9655255 t lperfetto In this report, site-directed mutagenesis and a transient expression system that permits co-expression of activated pp60c-src (Src527F) and AFAP-110 in Cos-1 cells were used to identify the SH2-binding motif in AFAP-110. Four tyrosine residues, two in the amino terminus (Y93 and Y94) and two in the carboxy terminus (Y451 and Y453), were mutated to phenylalanine, significantly reducing overall steady-state levels of tyrosine phosphorylation and preventing Src527F from forming a stable complex with AFAP-110. SIGNOR-246363 0.583 MATK protein P42679 UNIPROT LYN protein P07948 UNIPROT down-regulates activity phosphorylation Tyr508 YTATEGQyQQQP -1 9171348 t miannu In vitro phosphorylation assays showed that Chk suppressed Lyn activity by phosphorylating its C-terminal negative regulatory tyrosine. SIGNOR-250177 0.336 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR BIN1 protein O00499 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136399 0.28 (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-6-(phenylmethylene)-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one chemical CHEBI:125500 ChEBI OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258775 0.8 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257607 0.793 SPAG1 protein Q07617 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270938 0.389 MYT1L protein Q9UL68 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 29397565 f miannu Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. SIGNOR-266779 0.7 ANGPT1 protein Q15389 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000222 26042050 f lperfetto Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. SIGNOR-241560 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr37 EECDQNWyKAELNGK 9606 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246289 0.2 MSH release-inhibiting hormone smallmolecule CID:56842142 PUBCHEM MC1R protein Q01726 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257536 0.8 NTN1 protein O95631 UNIPROT UNC5C protein O95185 UNIPROT up-regulates binding 9606 10399920 t gcesareni We provide evidence that netrin-1 triggers the formation of a receptor complex of dcc and unc5 proteins and simultaneously derepresses the interaction between their cytoplasmic domains, thereby converting dcc-mediated attraction to unc5/dcc-mediated repulsion. SIGNOR-69047 0.829 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid chemical CHEBI:125628 ChEBI AURKA protein O14965 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194527 0.8 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser342 SKLTHSLsTSDITAI 9606 16163388 t lperfetto Phosphorylation of s342 and s367 in vivo require the chk2 kinase. Chk2 also stimulates mdmx ubiquitination and degradation by mdm2 SIGNOR-140417 0.717 CDK1 protein P06493 UNIPROT MPLKIP protein Q8TAP9 UNIPROT up-regulates phosphorylation Thr120 QGSPRTStPFGSGRV 9606 17310276 t lperfetto Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1 SIGNOR-153308 0.345 PRKDC protein P78527 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001949 18439899 t gcesareni DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform SIGNOR-252447 0.748 CTSG protein P08311 UNIPROT C3 protein P01024 UNIPROT up-regulates activity cleavage Arg748 ASHLGLArSNLDEDI 9606 BTO:0001412 1861080 t miannu Plasma membrane elastase and cathepsin G from U937 cells cleave C3 into C3a- and C3b-like fragments; further incubation leads to C3c- and C3dg-like fragments, as judged from SDS-PAGE analysis of the digests. Sequencing of the C3b-like fragment purified by reverse phase chromatography indicates that initial cleavage of C3 by purified cathepsin G occurs at two positions in the amino-terminal part of the alpha-chain, at a Arg-Ser bond located between residues 748 and 749 and at a Leu-Asp bond between residues 751 and 752. These proteases are, thus, able to generate, on the U937 surface, active fragments of C3, which are likely to be involved in cell-protein and cell-cell interactions. SIGNOR-256347 0.588 TYMS protein P04818 UNIPROT dUMP(2-) smallmolecule CHEBI:246422 ChEBI down-regulates quantity chemical modification 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268234 0.8 SLC6A8 protein P48029 UNIPROT creatine smallmolecule CHEBI:16919 ChEBI up-regulates quantity relocalization 9606 18652074 t miannu CRT is essential for normal brain function as mutations in the CRT gene (SLC6A8) result in X-linked mental retardation, associated with the almost complete lack of creatine in the brain, severe speech and language delay, epilepsy, and autistic behaviour. SIGNOR-265808 0.8 EGFR protein P00533 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates phosphorylation Tyr570 SSNFDSIyICPSTFA 9606 20029029 t gcesareni A negative feedback loop consisting of egfr-mediated phosphorylation of hdac6 tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. SIGNOR-162431 0.448 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1623 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248780 0.437 GSK3B protein P49841 UNIPROT NEB protein P20929 UNIPROT down-regulates phosphorylation 9606 21798082 t gcesareni Gsk3b is able to phosphorylate nebulin at two ser sites in the c-terminal region of nebulin localized to the z-disk, thus preventing the interaction of nebulin with neuronal wiscott-aldrich syndrome protein (nwasp), a ubiquitously expressed member of the wasp family, which is involved in actin assembly. SIGNOR-175659 0.31 PRKCZ protein Q05513 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Thr110 SHSRQAStDAGTAGA 9606 BTO:0002181 25660024 t miannu  Yap and β-catenin are direct substrates of PKCζ.We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation.Consistent with MS/MS analysis, mutation to alanine of these two sites completely abolished Yap phosphorylation by PKCζ. Interestingly, S109 and T110 sites were highly conserved among species (Figure S3B), which suggested an important role in Yap regulation. SIGNOR-276877 0.279 ELOVL5 protein Q9NYP7 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267898 0.8 PTPN11 protein Q06124 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation Tyr1016 DVVDADEyLIPQQGF 9534 BTO:0004055 12582165 t lperfetto Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not SIGNOR-236424 0.867 PELI1 protein Q96FA3 UNIPROT HPD protein P32754 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0003036 31537781 t lperfetto Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. SIGNOR-272959 0.2 TP53 protein P04637 UNIPROT HR protein O43593 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15489903 f miannu P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases. SIGNOR-255436 0.345 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates activity phosphorylation Thr317 PTQRMTItEFMNHPW -1 7592979 t miannu In Vitro Activation of MAPKAP Kinase 2 by p38/40. the constitutively active mutant T205E,T317E shows no changes in activity after treatment with the p38/40 fraction SIGNOR-250102 0.763 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser717 VYKSPVVsGDTSPRH 9606 BTO:0000590 12387894 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249355 0.733 PCSK2 protein P16519 UNIPROT OXT protein P01178 UNIPROT down-regulates quantity cleavage 9606 BTO:0001073 11690596 t miannu Oxytocin-extended form is further cleaved by enzymatic activity to yield the nine-amino-acid active peptide, OT. The proteolysis may involve several pro-hormone convertases, convertase 2 (PC2) (20p11-1-11.2) and convertase 5 (PC5) (9q21.3) (Gabreels et al 1998). Both enzymes are found in OT neurosecretory vesicles and are a part of a family of subtilisen/kexinlike convertases (Seidah et al 1994). It is a product of the OT gene located at human gene locus 20p13 (Rao et al 1992). The processing cascade results in the production of neurophysin I and OT extended form (OT-X), which is OT with a C-terminal, three-amino-acid extension. SIGNOR-270328 0.267 N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylpropanamide chemical CHEBI:91617 ChEBI AR protein P10275 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190323 0.8 LAMC1 protein P11047 UNIPROT Laminin-10 complex SIGNOR-C182 SIGNOR form complex binding 11821406 t lperfetto The laminin (LN) family of large heterotrimeric extracellular matrix glycoproteins has multiple functions: LNs take part in the regulation of processes such as cell migration, differentiation, and proliferation, in addition to contributing to the structure of basement membranes. LN-10, composed of alpha5, beta1, and gamma1 chains, is widely distributed in most basement membranes of both epithelia and endothelia. SIGNOR-253231 0.699 ERN1 protein O75460 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity phosphorylation Tyr628 EHPNVIRyFCTEKDR -1 25968568 t miannu IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures.  SIGNOR-275417 0.2 VEZF1 protein Q14119 UNIPROT CITED2 protein Q99967 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001086 29794136 t miannu The transcription factor Vezf1 represses the expression of the antiangiogenic factor Cited2 in endothelial cells SIGNOR-266883 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262995 0.2 TGFA protein P01135 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity binding 9606 BTO:0000584 16585207 t Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines gcesareni Our data indicate that a subset of cell lines is dependent on TGF-_-mediated activation of the EGFR for cell proliferation and strongly suggest that pancreatic tumors expressing high levels of TGF-_ and phosphorylated (activated) EGFR are EGFR-dependent in vitro and in vivo. SIGNOR-93199 0.897 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser518 LSASPRMsGFIYQGK 9606 25009260 t lperfetto Pkc_ directly phosphorylates _pix at ser583 and indirectly at ser340 in cells. herefore, we propose that pkc_ positively modulates dopamine release through _2pix phosphorylation. The pkc_-_pix-cdc42/rac1 phosphorylation axis may provide a new therapeutic target for the treatment of parkinsonian syndrome SIGNOR-205234 0.2 PRKCB protein P05771 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates phosphorylation Ser40 SREVFDFsQRRKEYE 9606 12198130 t miannu Phosphorylation of nrf2 at ser-40 by protein kinase c regulates antioxidant response element-mediated transcription / recently we reported evidence for the involvement of protein kinase c (pkc) in phosphorylating nrf2 and triggering its nuclear translocation in response to oxidative stress SIGNOR-91830 0.403 sabcomeline chemical CHEBI:134846 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10116 9399977 t miannu SB 202026 (R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2] octane-3-acetonitrile) displaced [3H]-oxotremorine-M from muscarinic receptors in the rat brain with high affinity (IC50 = 14 nM), a potency similar to that of oxotremorine-M itself (IC50 = 13 nM), but exhibited low affinity for cholinergic nicotinic receptors and other neuroreceptors. In studies using cloned human muscarinic receptors, SB 202026 possessed approximately equal affinity in displacing [3H]-quinuclidinyl benzilate from all muscarinic receptor subtypes SIGNOR-258677 0.8 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A1 protein P30531 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206960 0.8 MAPK1 protein P28482 UNIPROT NEFH protein P12036 UNIPROT up-regulates activity phosphorylation Ser532 KSPAEAKsPEKEEAK 10116 9592082 t lperfetto The fraction containing Erk2, as well as bacterially expressed Erk1 and Erk2, phosphorylated all types of KSP motifs in peptides (KSPXK, KSPXXK, KSPXXXK, and KSPXXXXK) derived from NF-M and NF-H. They also phosphorylated an expressed 24 KSPXXXK repeat NF-H polypeptide, an expressed NF-H as well as dephosphorylated native rat NF-H, and NF-M proteins with accompanying decreases in their respective electrophoretic mobilities. |Our data on primary hippocampal cells also showed an inhibition of neurite outgrowth by the drug that was accompanied by inhibition of MAP, NF-H, and NF-M phosphorylation. SIGNOR-249425 0.372 CREBBP protein Q92793 UNIPROT MYBL1 protein P10243 UNIPROT up-regulates activity binding 9534 9210395 t 2 miannu CBP co-operates functionally with A-Myb SIGNOR-240984 0.488 CDK1 protein P06493 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1. SIGNOR-178202 0.52 MEF2C protein Q06413 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates activity binding 9606 9418854 t lperfetto Myod-e protein heterodimers interact with mef2 proteins to synergistically activate myogenesis. SIGNOR-54089 0.737 BMP1 protein P13497 UNIPROT COL1A1 protein P02452 UNIPROT up-regulates activity cleavage 9534 BTO:0000298 11283002 t miannu BMP-1myc Expressed in COS-7 Cells Exhibits Procollagen C-proteinase Activity. Bone morphogenetic protein (BMP)-1, which belongs to the tolloid subgroup of astacin-like zinc metalloproteinases, cleaves the C-propeptides of procollagen at the physiologic site and is, therefore, a procollagen C-proteinase (PCP). Cleavage occurs between a specific alanine or glycine residue (depending on the procollagen chain) and an invariant aspartic acid residue in each of the three chains of procollagen. SIGNOR-256342 0.673 MTA1 protein Q13330 UNIPROT MBD2/NuRD complex complex SIGNOR-C337 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263842 0.803 TAOK3 protein Q9H2K8 UNIPROT TAOK3 protein Q9H2K8 UNIPROT up-regulates activity phosphorylation Tyr183 NSFVGTPyWMAPEVI 9534 BTO:0004055 10559204 t lperfetto These data indicate that JIK is indeed the protein kinase present in the immune complex responsible for autophosphorylation and for the phosphorylation of the exogenous substrate. Moreover, our observations suggest that JIK (A181F183) acts as the catalytically inactive mutant of JIK, which is no longer able to potently undergo autophosphorylation and dramatically phosphorylate MBP, as compared with the wild type JIK. SIGNOR-246302 0.2 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates activity phosphorylation Ser422 AEAFLGFsYAPPTDS -1 10191262 t miannu The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp SIGNOR-250274 0.64 GALR2 protein O43603 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257226 0.291 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252358 0.787 SSTR5 protein P35346 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256690 0.483 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-216868 0.343 LRIG1 protein Q96JA1 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates ubiquitination 9606 16123311 t gcesareni We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation. SIGNOR-139954 0.598 CDK1 protein P06493 UNIPROT PIK3C2A protein O00443 UNIPROT down-regulates activity phosphorylation Ser259 KVSNLQVsPKSEDIS 9606 12719431 t lperfetto Mitotic and stress-induced phosphorylation of HsPI3K-C2alpha targets the protein for degradation. Stress-dependent and mitotic phosphorylation of hspik3-c2alpha occurs on the same serine residue (ser259) within a recognition motif for proline-directed kinases. Mitotic phosphorylation of hspik3-c2alpha can be attributed to cdc2 activity, and stress-induced phosphorylation of hspik3-c2alpha is mediated by jnk/sapk SIGNOR-100903 0.283 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser689 KGVDFESsEDDDDDP -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265895 0.2 CDH3 protein P22223 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265865 0.847 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser515 SGDRSGYsSPGSPGT 9606 BTO:0000590 9832145 t lperfetto Sequencing of 32P-labeled trypsin phosphopeptides from tau prephosphorylated by A-kinase (using unlabeled ATP) and further phosphorylated by GSK-3 in the presence of [gamma-32P]ATP revealed that Ser-195, Ser-198, Ser-199, Ser-202, Thr-205, Thr-231, Ser-235, Ser-262, Ser-356 and Ser-404 are phosphorylated, whereas if tau is not prephosphorylated by A-kinase, GSK-3 phosphorylates it at Thr-181, Ser-184, Ser-262, Ser-356 and Ser-400. These data suggest that (i) prephosphorylation of tau by A-kinase makes additional and different sites accessible for phosphorylation by GSK-3; (ii) phosphorylation of tau at these additional sites further inhibits the biological activity of tau in its ability to bind to microtubules and promote microtubule assembly. SIGNOR-249354 0.733 PRKAA2 protein P54646 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 SIGNOR-C15 22137581 t lperfetto Using this approach for ppp1r12c, baiap2, and cdc27, we found that mutation of a single serine to alanine (s452, s366, and s379 respectively) resulted in almost a complete loss of ampk phosphorylation in these proteins. Termination of irsp53 function is suggested to occur following cdc42 dissociation, kinase phosphorylation of t340 and t360, and subsequent 14-3-3 binding, which competes for sh3 partners, thus allowing filopodial retraction SIGNOR-195102 0.2 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI 2-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58289 ChEBI up-regulates quantity precursor of 9606 24786789 t miannu Phosphoglycerate mutase (PGAM) is a glycolytic enzyme that catalyzes the reversible conversion of 3-phosphoglycerate (3-PG) to 2-phosphoglycerate (2-PG; ref. 4). Human genome contains two PGAM genes, PGAM1 (also known as PGAM-B), which is expressed in brain and most other tissues, and PGAM2 (also known as PGAM-M), which is highly expressed in muscle. SIGNOR-266510 0.8 DYRK1B protein Q9Y463 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0000165;BTO:0000222;BTO:0001946 BTO:0000887;BTO:0001760 15851482 f lperfetto Mirk diminishes the extent of myoblast apoptosis during the differentiation process, at least in part by direct modulation of p21cip1 localization. SIGNOR-235731 0.7 MASP1 protein P48740 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263423 0.668 N-hydroxy-2-[4-[[(1-methyl-3-indolyl)methylamino]methyl]-1-piperidinyl]-5-pyrimidinecarboxamide chemical CHEBI:94771 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193513 0.8 FIS1 protein Q9Y3D6 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) SIGNOR-272976 0.7 imatinib chemical CHEBI:45783 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258227 0.8 isoprenaline chemical CHEBI:64317 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 8982677 t miannu K i values of the agonists for [~25I]iodocyanopindolol binding to the COS-7 cell membranes are shown in Table 1. In the membranes expressing one of the 13-adrenoceptor subtypes, both isoproterenol and T-0509 caused monophasic dis- placement of [~25I]iodocyanopindolol, suggesting a single binding site of the agonists. SIGNOR-258578 0.8 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 9606 23431053 t milica Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-201282 0.846 CDK1 protein P06493 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 SIGNOR-C17 20937773 t lperfetto In this study, we demonstrate that procaspase-8 is phosphorylated in mitotic cells by cdk1na interference-mediated silencing of cyclin b1 or treatment with the cdk1 inhibitor ro-3306 enhances the fas-mediated activation and processing of procaspase-8 in mitotic cells/cyclin b1 on ser-387 SIGNOR-168446 0.367 MAS1 protein P04201 UNIPROT AGTR1 protein P30556 UNIPROT down-regulates activity binding 9606 BTO:0000007 15809376 t miannu our findings demonstrate that the protein encoded by the Mas proto-oncogene exhibits direct antagonistic properties on the AT1 receptor in vitro and that this oligomeric interaction may represent a natural state for these receptors in vivo in some tissues. the present findings in native tissues suggest that the Mas receptor can act as an in vivo functional antagonist of the AT1 receptor owing to formation of a hetero-oligomeric complex SIGNOR-260626 0.279 MAPK1 protein P28482 UNIPROT NUP50 protein Q9UKX7 UNIPROT down-regulates activity phosphorylation Ser315 TQSKPVSsPFPTKPL 9606 19767751 t llicata Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-188135 0.2 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol 4-phosphate smallmolecule CHEBI:17526 ChEBI up-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269103 0.8 CDK5RAP2 protein Q96SN8 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity binding 9606 BTO:0000567 19282672 t Giulio We show here that inhibition of CDK5RAP2 expression causes chromosome mis-segregation, fails to maintain the spindle checkpoint, and is associated with reduced expression of the spindle checkpoint proteins BUBR1 and MAD2 and an increase in chromatin-associated CDC20.|We found that the APC activator CDC20, but not others we exam-ined, was present in the CDK5RAP2 immunocomplex in HeLa cell extracts (Fig. 3A). CDK5RAP2 was detected in the CDC20 immunocomplex as well (Fig. 3B). SIGNOR-260311 0.316 SIL1 protein Q9H173 UNIPROT HSPA5 protein P11021 UNIPROT up-regulates activity binding 9534 BTO:0001538 12356756 t Simone BAP, a Mammalian BiP-associated Protein, Is a Nucleotide Exchange Factor That Regulates the ATPase Activity of BiP. In addition,BAP was associated with BiP in mammalian cells and inter-acted with BiP functionallyin vitro. BAP stimulated the ATPase activity of BiP when added alone or together with the ER DnaJ protein, ERdj4, by promoting the release of ADP from BiP. Together, these data demonstrate that BAP serves as a nucleotide exchange factor for BiP and provide insights into the mechanisms that control protein folding in the mammalian ER. SIGNOR-261045 0.588 ADAM17 protein P78536 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity cleavage 9606 10882063 t gcesareni ... here we show that an additional processing event occurs in the extracellular part of the receptor, preceding cleavage by the gamma-secretase-like activity. Purification of the activity accounting for this cleavage in vitro shows that it is due to tace (tnfalpha-converting enzyme), a member of the adam (a disintegrin and metalloprotease domain) family of metalloproteases. SIGNOR-78903 0.733 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65273 0.449 MAPK14 protein Q16539 UNIPROT FGFR1 protein P11362 UNIPROT down-regulates phosphorylation Ser777 SMPLDQYsPSFPDTR 9606 20626350 t gcesareni Fgfr1 translocation requires p38 mapk activation which phosphorylates the c-term tail of fgfr1 on ser777 SIGNOR-166598 0.277 MICU3 protein Q86XE3 UNIPROT MCU_MICU3_variant complex SIGNOR-C501 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270872 0.638 FPR1 protein P21462 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256682 0.419 PPP3CC protein P48454 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity dephosphorylation Ser637 VPVARKLsAREQRDC 9606 18838687 t When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis. SIGNOR-248506 0.264 PAK1 protein Q13153 UNIPROT PREX2 protein Q70Z35 UNIPROT down-regulates activity phosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu P21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase. PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277181 0.372 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t lperfetto We have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl SIGNOR-99215 0.2 MTOR protein P42345 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser293 SSGYFSSsPTLSSSP 9606 22017875 t llicata Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome. SIGNOR-176849 0.751 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 10581258 t lperfetto P38 regulates p53, but also in p53-defective tumor cells rewire their checkpoint response and become dependent in the p38/mk2 pathway in mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72695 0.768 OPRK1 protein P41145 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256710 0.461 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser155 FPLRKTVsEPNLKLR 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. SIGNOR-248646 0.32 MYC protein P01106 UNIPROT ST3GAL3 protein Q11203 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22547830 f We provide evidence that ST3GAL1/3/4 and FUT3 are transcriptionally up-regulated by c-Myc with probable involvement of Ser62 phosphorylation, and that FUT2 is transcriptionally down-regulated through the attenuation of CDX2. SIGNOR-253962 0.2 KDM5A protein P29375 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265334 0.2 CAV3 protein P56539 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255997 0.5 MAPK3 protein P27361 UNIPROT TRPV3 protein Q8NET8 UNIPROT up-regulates activity phosphorylation Thr264 EGFYFGEtPLALAAC 9606 BTO:0000552 29084846 t done miannu We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis. SIGNOR-273672 0.2 PP2CA_R1A_R2A complex SIGNOR-C132 SIGNOR DOCK6 protein Q96HP0 UNIPROT down-regulates activity phosphorylation Ser1194 GQRSRLAsMLDSDTE 23462102 t lperfetto Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching SIGNOR-275668 0.2 CCND1 protein P24385 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates 9606 BTO:0000150 BTO:0000149 20443831 f gcesareni The mechanism by which cyclin d1 enhances notch1 activity in different cell types remains to be determined;the current studies demonstrate for the first time that notch1 activity is induced by cyclin d1. The expression of cyclin d1 sirna reduced notch1 activity. SIGNOR-165189 0.63 ECM stimulus SIGNOR-ST20 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259044 0.7 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249120 0.332 HIF-1 complex complex SIGNOR-C418 SIGNOR LDHA protein P00338 UNIPROT up-regulates quantity transcriptional regulation 9606 7673128 t Deletional and mutational analysis of the function of mouse LDH-reporter fusion gene constructs in transient transfection assays defined three domains, between -41 and -84 base pairs upstream of the transcription initiation site, which were crucial for oxygen-regulated expression. The most important of these, although not capable of driving hypoxic induction in isolation, had the consensus of a hypoxia-inducible factor 1 (HIF-1) site, and cross-competed for the binding of HIF-1 with functionally active Epo and phosphoglycerate kinase-1 sequences SIGNOR-267479 0.649 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr643 GVHHIDYyKKTSNGR 9606 BTO:0001130 18670643 t lperfetto Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4. SIGNOR-179780 0.2 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT down-regulates activity phosphorylation Ser18 SVHSKRRsRADLTAE 9606 BTO:0001939 25086031 t miannu Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes). SIGNOR-263160 0.2 MAPK10 protein P53779 UNIPROT APP protein P05067 UNIPROT up-regulates phosphorylation Thr743 VEVDAAVtPEERHLS 9606 24610780 t lperfetto Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. is regulated by jnk3 via phosphorylation of app at thr668 SIGNOR-204671 0.572 CHEK1 protein O14757 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates activity phosphorylation Ser331 KSKGRASsSGNQESS 9606 BTO:0000567 19861535 t lperfetto In vitro and in vivo experiments show that phosphorylation of s331 is mediated by chk1, the s-phase checkpoint kinase implicated in the fanconi anemia dna repair pathway. phosphorylation at this site is dependent on chk1, signifying the importance of the s-phase checkpoint in the activation of fanconi anemia pathway. SIGNOR-107042 0.597 CCND1 protein P24385 UNIPROT MSI1 protein O43347 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20443831 f gcesareni We hypothesized that cyclin d1 may induce notch1 activity either by repressing numb or by inducing musashi 1 expression SIGNOR-165186 0.286 F2RL1 protein P55085 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256895 0.2 FGF14 protein Q92915 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253445 0.245 ATM protein Q13315 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser1039 NSNHGSQsPRNVEER 29939287 t phosphorylation site remapping based on Fig 1 lperfetto To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. SIGNOR-273434 0.2 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Thr409 GQGEKSAtPSRKILD 9606 SIGNOR-C17 15037602 t lperfetto Here, we show that rangap1 is phosphorylated on residues t409, s428, and s442. Phosphorylation occurs before nuclear envelope breakdown and is maintained throughout mitosis. The m-phase kinase cyclin b/cdk1 phosphorylates rangap1 efficiently in vitro, and t409 phosphorylation correlates with nuclear accumulation of cyclin b1 in vivo. SIGNOR-123524 0.481 HSF1 protein Q00613 UNIPROT HSPA6 protein P17066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12813038 f miannu These experiments suggest that HSF2 is involved in the stress response, but unlike the ubiquitous HSF1 operates in a cell-line specific manner through differential expression of alternatively spliced isoforms. Curiously, HSF2A could not be activated by heat shock in cells deficient in functional HSF1 and required the expression of HSF1 for heat induction of the hsp70B gene in cells. SIGNOR-254477 0.436 SMARCC1 protein Q92922 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270606 0.794 CSNK2A1 protein P68400 UNIPROT FANCD2 protein Q9BXW9 UNIPROT down-regulates activity phosphorylation Ser898 SECDPTPsHRGQLNK 9606 BTO:0000567 31167143 t miannu Here, we report a cluster of phosphosites on FANCD2 whose phosphorylation by CK2 inhibits both FANCD2 recruitment to ICLs and its monoubiquitination in vitro and in vivo. We have found that phosphorylated FANCD2 possesses reduced DNA binding activity, explaining the previous observations.  SIGNOR-276729 0.2 EGFR protein P00533 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19882665 f miannu We show that egfr-mediated signaling promotes sox2 expression, which in turn binds to the egfr promoter and directly upregulates egfr expression. SIGNOR-189033 0.489 CTNNB1 protein P35222 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity 9606 16510874 f Luana Beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo. H3k4 trimethylation in vivo requires prior ubiquitination of h2b, and we find that ubiquitin is necessary for transcription initiation on chromatin but not nonchromatin templates in vitro. Chromatin immunoprecipitation experiments reveal that beta-cat recruits pygopus, bcl-9/legless, and mll/set1-type complexes to the c-myc enhancertogether with the negative wnt regulators, apc, and betatrcp. SIGNOR-265358 0.2 SCF-betaTRCP complex SIGNOR-C5 SIGNOR RAPGEF2 protein Q9Y4G8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 24290981 t miannu Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. SIGNOR-276607 0.2 NOTCH1 protein P46531 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 16256737 t lperfetto The notch intracellular domain interacts with hif-1alpha and hif-1alpha is recruited to notch-responsive promoters upon notch activation under hypoxic conditions. SIGNOR-141315 0.64 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr988 RVDSDNAyIGVTYKN 9823 BTO:0004007 7535778 t miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. SIGNOR-250252 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser703 MSRARIGsDPLAYEP 9606 10400637 t gcesareni The results indicate that p90rsk phosphorylates serine 703 of nhe-1, and this phosphorylation is required for growth factor stimulation of na+/h+ exchange. SIGNOR-252792 0.2 HTR2A protein P28223 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256742 0.352 MEF2C protein Q06413 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0002320 21598020 t miannu GATA-4 and MEF2C are known to bind to the GATA box 2 in the major promoter of CTNNA3 and this element is essential in directly regulating expression of CTNNA3 in cardiac muscle cells. The co-transfection of GATA-4 with MEF2C leads to a synergistic activation of the CTNNA3 promoter SIGNOR-265816 0.48 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Thr658 VGGVVIAtVIVITLV -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261792 0.497 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 18362890 t inferred from 70% family members gcesareni These findings indicate that the phosphorylation of mob1 at thr74 by mst2 is essential to make a complex of mob1, mst2 and ndr1, and to fully activate ndr1 SIGNOR-270220 0.2 PIN1 protein Q13526 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 BTO:0000150 23716601 t esanto Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated myc and its coactivators to select promoters during gene activation. SIGNOR-202134 0.562 PRKAA1 protein Q13131 UNIPROT ULK1 protein O75385 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 SIGNOR-C15 21460634 t lperfetto Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition. SIGNOR-173038 0.56 PHF12 protein Q96QT6 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates activity binding 9606 BTO:0000007 11390640 t miannu We have cloned and characterized a new member of the PHD zinc finger family called Pf1 that interacts with two global transcription corepressors: mSin3A and TLE. Pf1 interacts with TLE. The Groucho/TLE proteins are members of an abundant corepressor family, and we hypothesized that Pf1 might interact with TLE family members. Together, these data suggest that in the absence of interactions with mSin3A, Gal4-Pf1 (102–273 L212P/A216P)-dependent repression can be attributed to interaction with endogenous TLE. SIGNOR-266994 0.2 SOSTDC1 protein Q6X4U4 UNIPROT WNT7A protein O00755 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242710 0.273 ASXL1 protein Q8IXJ9 UNIPROT RXRA protein P19793 UNIPROT up-regulates activity binding 9606 BTO:0000567 16606617 t irozzo In this study, we demonstrate that mammalian ASXL1 interacts with the AF-2 AD core of RAR (and RXR) through a novel, promiscuous NR box (LVMQLL) and enhances transcriptional activity of the receptors in certain cells. SIGNOR-255911 0.286 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20651737 t lperfetto Engagement of cd40 with its ligand cd40l results in the recruitment of the TRAF3/TRAF2/cIAP Complex to the receptor. At the receptor, traf3 undergoes ciap-dependent k48-linked polyubiquitylation (ub) that targets it for proteasomal degradation. In the absence of traf3, nik protein levels accumulate as it can no longer be recruited to the TRAF2/cIAP Complex. SIGNOR-167057 0.87 PTGDR protein Q13258 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256755 0.582 FGFR1 protein P11362 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates 9606 12270934 f lperfetto  Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors SIGNOR-218010 0.313 CDH11 protein P55287 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR up-regulates activity binding 9606 10029089 t miannu Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin SIGNOR-265825 0.506 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258730 0.8 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270695 0.832 HRH1 protein P35367 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257376 0.412 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Ser170 RDSEGFNsPKQCDSS -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265958 0.525 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates quantity by destabilization phosphorylation Ser69 GPLAPPAsPGPFATR 10090 15486195 t miannu Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination. SIGNOR-250132 0.754 FGF2 protein P09038 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 f miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. SIGNOR-252191 0.259 HPX protein P02790 UNIPROT HBB protein P68871 UNIPROT down-regulates activity 9606 20617898 f Regulation miannu The endogenous molecule hemoglobin and its derivative heme are often released into tissue compartments where there is infection in the presence of degrading blood. We found that hemoglobin synergizes with multiple TLR agonists to induce high levels of tumor necrosis factor and interleukin-6 from macrophages and that this synergy is independent of TLR4 and MyD88. In contrast, heme synergized with some but not all TLR agonists studied. Furthermore, the synergy of both hemoglobin and heme with lipopolysaccharide was suppressed by hemopexin, a plasma heme-binding protein. SIGNOR-251811 0.493 RNF4 protein P78317 UNIPROT KDM5C protein P41229 UNIPROT up-regulates activity sumoylation 9606 33859667 t SaraGualdi Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015). SIGNOR-271576 0.2 MDM2 protein Q00987 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity binding 9606 17700533 t miannu Since HDM2, a key negative regulator of p53, also binds to and inhibits p73, we asked whether p73 could mediate Nutlin-3-induced apoptosis. SIGNOR-255470 0.833 p38 proteinfamily SIGNOR-PF16 SIGNOR CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276362 0.2 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT down-regulates phosphorylation Tyr54 HTVEAVAyAPKKELI 9606 9461559 t llicata Here we demonstrate that c-abl interacts constitutively with rad51. We show that c-abl phosphorylates rad51 on tyr-54 in vitro. The results also show that treatment of cells with ionizing radiation induces c-abl-dependent phosphorylation of rad51. Phosphorylation of rad51 by c-abl inhibits the binding of rad51 to dna and the function of rad51 in atp-dependent dna strand exchange reactions. SIGNOR-55482 0.767 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 BTO:0000150 18372406 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-178137 0.663 NPTX1 protein Q15818 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity 9606 BTO:0004168;BTO:0003227 31113871 f lperfetto We found that the protein levels of BCL2-associated agonist of cell death (BAD) and BCL2-associated X protein (BAX) were increased in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control cells. In contrast, decreased levels of myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) were found in NPTX1-overexpressing SMMC-7721 and MHCC-97h cells relative to control SIGNOR-260413 0.2 IL1B protein P01584 UNIPROT ITGA2 protein P17301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001596 1744142 f lperfetto TGF-beta 1 decreases the biosynthesis of alpha 3 subunit but increases the production of alpha 2 subunit. IL-1 beta potentiates the effects of TGF-beta 1. Furthermore, in the presence of TGF-beta 1 the increase in the expression of alpha 1 subunit by IL-1 beta is even larger. Thus, IL-1 beta and TGF-beta 1, which usually have antagonistic functions in connective tissue, can regulate integrin expression in a synergistic way. SIGNOR-253356 0.276 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t lperfetto The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival SIGNOR-236236 0.965 KIF5B protein P33176 UNIPROT JAKMIP1 protein Q96N16 UNIPROT up-regulates activity relocalization 10090 17532644 t SARA Marlin-1 is associated with kinesin-I and suggest that the movement of Marlin-1 is mediated by plus end microtubuledependent molecular motors SIGNOR-260989 0.2 LINC complex complex SIGNOR-C303 SIGNOR NPC complex SIGNOR-C263 SIGNOR up-regulates activity binding 9606 BTO:0000567 28831067 t lperfetto The NXF1:NXT1 complex and NUP153 interact with the amino terminus of SUN1 |In analogy to a proposal made by Chang et al.4, Nesprins could help anchoring SUN1 near the NPC to enable it to fulfill its task in mRNA export. SIGNOR-263292 0.2 SMARCC2 protein Q8TAQ2 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270735 0.832 FYN protein P06241 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276371 0.361 SOST protein Q9BQB4 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 f Interacts with LRP4 (via the extracellular domain);the interaction facilitates the Wnt signaling. Interacts with LRP5 (via the first two YWTD-EGF repeat domains);the interaction inhibits Wnt-mediated signaling. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream mole-cules of bmp signaling to inhibit canonical wnt sig-naling and therefore negatively regulate bone mass SIGNOR-195684 0.574 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser272 EEPSPLPsPTASPNH 9606 BTO:0000142 15262992 t lperfetto Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd SIGNOR-126843 0.402 Jervine chemical CHEBI:6088 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 BTO:0000149 16112412 t gcesareni Here, we demonstrate that cyclopamine and jervine, two structurally related inhibitors of smo, force ciliary translocation of smo. SIGNOR-139865 0.8 TMPRSS2 protein O15393 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25122198 t miannu we identified pro-hepatocyte growth factor (HGF) as a TMPRSS2 substrate and confirmed that HGF and it’s cognate receptor c-Met are activated in prostate cancers expressing TMPRSS2, a finding that also associated with the acquisition of a pro-invasive mesenchymal gene expression program. SIGNOR-263657 0.2 ITCH protein Q96J02 UNIPROT BID protein P55957 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20392206 t miannu The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid SIGNOR-271415 0.356 COL1A2 protein P08123 UNIPROT A11/b1 integrin complex SIGNOR-C168 SIGNOR up-regulates activity binding 10090 BTO:0000165 12496264 t lperfetto Modeling of the alpha I domain-collagen peptide complexes could partially explain the observed preference of different I domains for certain GFOGER sequence variations. In summary, our data indicate that the GFOGER sequence in fibrillar collagens is a common recognition motif used by alpha(1)beta(1), alpha(2)beta(1), and also alpha(11)beta(1) integrins. SIGNOR-253346 0.464 Erythrocytic spectrin complex SIGNOR-C384 SIGNOR Membrane_disruption phenotype SIGNOR-PH151 SIGNOR down-regulates 9606 24302288 f lperfetto Spectrin is multifunctional, and spectrin-based networks are important for maintaining the shape and mechanical properties of erythrocytes. SIGNOR-266028 0.7 AKT2 protein P31751 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-235852 0.671 PDGFRB protein P09619 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 11896619 t miannu The gtpase activating protein (gap) of ras binds only to beta-receptors / we have previously shown that the binding site for gtpase activating protein of ras (rasgap) in the pdgf beta-receptor, tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of pdgf alpha- and beta-receptors, compared to the pdgf beta-receptor homodimer. / the decreased recruitment of the rasgap to the receptor leads to prolonged activation of the ras/map kinase pathway SIGNOR-115843 0.569 MAP2K7 protein O14733 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 9606 BTO:0000975 17360977 t lperfetto Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase SIGNOR-217920 0.375 FGF11 protein Q92914 UNIPROT SCN4A protein P35499 UNIPROT down-regulates activity binding 9606 BTO:0001103 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253434 0.2 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t miannu Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-264963 0.8 AKT1 protein P31749 UNIPROT KDM5A protein P29375 UNIPROT up-regulates activity phosphorylation Ser1255 CLTERAMsWQDRARQ -1 27292631 t miannu We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment. SIGNOR-274059 0.307 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203544 0.773 ESRRA protein P11474 UNIPROT RNF208 protein Q9H0X6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 31862882 t Gianni Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner SIGNOR-269052 0.2 EEF1A1P5 protein Q5VTE0 UNIPROT Val-tRNA(Val) smallmolecule CHEBI:29164 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269559 0.8 MAPK3 protein P27361 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Thr709 PKRLGAHtP 9606 14697653 t lperfetto Thus, fe65 has at least two apparently disparate functions and may also be involved in the pathogenesis of alzheimer's disease. The mechanisms by which fe65 trafficking and metabolism are regulated to fulfil these different roles are unclear. Our findings reported here, which demonstrate that fe65 is a phosphoprotein that is targeted by erk1/2 and which identify four in vivo phosphorylation sites, provide one possible mechanism whereby functional diversity might be achieved. SIGNOR-120483 0.27 CSNK1D protein P48730 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization phosphorylation Ser31 PGAMLGPsPGPSPGS 9606 BTO:0001225 30177679 t miannu  We reveal that CK1δ phosphorylates Brg1 at Ser31/Ser35 residues to facilitate the binding of Brg1 to FBW7, leading to ubiquitination-mediated degradation.  SIGNOR-277408 0.2 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr336 TQTSDTAtNSTLPSA -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249686 0.2 sunitinib chemical CHEBI:38940 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 21993628 t gcesareni The action of kit kinase inhibitors, especially imatinib, sunitinib, dasatinib and pkc412, on different primary and secondary mutants is discussed. SIGNOR-176760 0.8 DLX2 protein Q07687 UNIPROT MSX2 protein P35548 UNIPROT down-regulates activity binding 10090 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240911 0.397 FANCF protein Q9NPI8 UNIPROT Fanconi anemia core complex complex SIGNOR-C300 SIGNOR form complex binding 9606 BTO:0000567 17396147 t lperfetto This complex includes not only the five known FA proteins (FANC‐A, C, E, F, and G), but also four new polypeptides, which are named FAAPs for FANCA‐associated polypeptides. |Thus, eight of the nine components of the FA core complex are FA proteins (FANC‐A, B, C, E, F, G, L, and M). Furthermore, two of the newly discovered FA proteins have enzymatic activities: FANCL is a ubiquitin ligase essential for FANCD2 monoubiquitination in vivo  SIGNOR-263242 0.907 TOP1 protein P11387 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000944 22904072 t miannu We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation.  Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition.  SIGNOR-277354 0.347 AGTR1 protein P30556 UNIPROT NPHS1 protein O60500 UNIPROT down-regulates activity 10116 21982880 f miannu Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. These findings indicate that Ang II induces nephrin dephosphorylation and podocyte injury through a caveolin-1-dependent mechanism. SIGNOR-253342 0.368 PLK1 protein P53350 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Ser1525 PIKYLEEsDEDDLF 9606 19098900 t gcesareni Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin SIGNOR-182844 0.489 TUBG1 protein P23258 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 19029337 f miannu It has been reported that NEDD1 directly interacts with and recruits the γ-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly SIGNOR-261423 0.7 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT down-regulates activity cleavage Pro21 FLLSYAVpSCGRSVE -1 8753751 t lperfetto Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. | Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments. SIGNOR-270546 0.428 CSNK1A1 protein P48729 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 16061179 t gcesareni FADD is essential for death receptor (DR)-induced apoptosis.|Phosphorylation of FADD at serine 194 by CKIalpha regulates its nonapoptotic activities SIGNOR-139307 0.336 COLGALT2 protein Q8IYK4 UNIPROT COL4A1 protein P02462 UNIPROT up-regulates activity glycosylation -1 19075007 t Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues. SIGNOR-261159 0.437 CD3 complex SIGNOR-C432 SIGNOR NCK1 protein P16333 UNIPROT up-regulates activity relocalization 9606 12110186 t We present strong evidence that ligand engagement of TCR-CD3 induces a conformational change that exposes a proline-rich sequence in CD3ϵ and results in recruitment of the adaptor protein Nck. SIGNOR-259935 0.341 LEF1 protein Q9UJU2 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19653274 f irozzo Expression of Lef-1 FL, but not the newly identified Lef-1 Deltaexon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with beta-catenin and it enhanced cell proliferation SIGNOR-256281 0.591 fentanyl chemical CHEBI:119915 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258939 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000848 18246127 t lperfetto To understand the mechanisms underlying B-RAF effects on cell survival we initially analysed the Bcl-2 family protein, Bad, that is phosphorylated by RSK1 at the inhibitory serine-75 residue in a MEK-dependent manner in melanoma cells SIGNOR-252784 0.2 CSNK2A1 protein P68400 UNIPROT F5 protein P12259 UNIPROT down-regulates activity phosphorylation Ser692 IPDDDEDsYEIFEPP -1 9525959 t llicata Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). | The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart. SIGNOR-250862 0.309 SDH complex SIGNOR-C400 SIGNOR succinate(2-) smallmolecule CHEBI:30031 ChEBI down-regulates quantity chemical modification 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. SIGNOR-266276 0.8 POU2F1 protein P14859 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 23836662 f miannu This PER2-OCT1 interaction effectively converted OCT1 sites, which normally activate expression, into repressor sites by recruitment of a polycomb repressor complex including EZH2 and SUZ12, as well as HDAC2. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. SIGNOR-254152 0.259 ETV4 protein P43268 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24983502 f miannu Transcriptional activation of oct4 by the ets transcription factor pea3 in nccit human embryonic carcinoma cells SIGNOR-205173 0.384 CDK6 protein Q00534 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1035 NMDAPPLsPYPFVRT 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. all three residues selectively targeted by cdk4(6), t401 (n-terminus), s672 (spacer region) and s1035 (c-terminus) SIGNOR-104711 0.673 MAP3K11 protein Q16584 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates phosphorylation Ser281 WHKTTQMsAAGTYAW 9606 11053428 t gcesareni These residues within the activation loop are critical for mlk-3 autophosphorylation and activation. In addition, when the thr277 and ser281 residues were mutated to negatively charged glutamic acid to mimic phosphorylated serine/threonine residues, the resulting mutants were fully functional, implying that these two residues may serve as the autophosphorylation sites. SIGNOR-83407 0.2 ACP1 protein P24666 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates activity dephosphorylation 9606 12815062 t miannu Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity.  4000254={CellProcess=4107155 CellType=10000184}}|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways. SIGNOR-277064 0.279 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Ser452 PVKTLPFsPSQFLNF BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250735 0.714 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr204 LTRYTRPtPVQKHAI 9606 SIGNOR-C17 16280325 t lperfetto Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis. SIGNOR-141565 0.299 RPS6KA3 protein P51812 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002181 23608533 t miannu We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. SIGNOR-276464 0.2 sertindole chemical CHEBI:9122 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258542 0.8 F2R protein P25116 UNIPROT LATS2 protein Q9NRM7 UNIPROT down-regulates 9606 BTO:0000007 22972936 f milica Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase. SIGNOR-192048 0.2 CDK2 protein P24941 UNIPROT HIRA protein P54198 UNIPROT up-regulates activity phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 BTO:0001938 SIGNOR-C16 11238922 t lperfetto Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle. SIGNOR-105548 0.329 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MBP protein P02686 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 16401070 t inferred from 70% family members lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-270100 0.2 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. SIGNOR-146897 0.814 CSNK2A1 protein P68400 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates phosphorylation Ser423 CEEEFSDsEEEGEGG 9606 11602581 t gcesareni Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1. SIGNOR-111015 0.614 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr41 GIHSGATtTAPSLSG 9606 19667122 t lperfetto Specifically, we provide evidence that jnk binds to e-cadherin/beta-catenin complex and phosphorylates beta-catenin at serine 37 and threonine 41, the sites also phosphorylated by gsk-3beta. SIGNOR-187582 0.2 KLF11 protein O14901 UNIPROT HBE1 protein P02100 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10207080 f Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. SIGNOR-251829 0.28 PRKAA2 protein P54646 UNIPROT TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 SIGNOR-C15 16959574 t gcesareni We have observed that ampk directly phosphorylates tsc2, and the ampk-dependent phosphorylation of tsc2 is critical for the coordination between cell growth and cellular energy levels. SIGNOR-149388 0.567 CSNK2A1 protein P68400 UNIPROT SLC29A1 protein Q99808 UNIPROT up-regulates activity phosphorylation Ser254 ETKLDLIsKGEEPRA -1 17520485 t miannu These data suggest that inhibition of CK2-mediated phosphorylation at Ser254 had the same effect on transporter function as the actual loss of Ser254 in mENT1a, implying that this site is constitutively phosphorylated by CK2.  SIGNOR-276063 0.2 HTR4 protein Q13639 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256912 0.365 CLK3 protein P49761 UNIPROT SRSF1 protein Q07955 UNIPROT up-regulates activity phosphorylation -1 8617202 t miannu In vitro, Clk/Sty efficiently phosphorylated the SR family member ASF/SF2 on serine residues located within its serine/arginine-rich region (the RS domain). Overexpression of the active Clk/Sty kinase caused a redistribution of SR proteins within the nucleus. These results suggest that Clk/Sty kinase directly regulates the activity and compartmentalization of SR splicing factors. SIGNOR-273859 0.539 CAMK2A protein Q9UQM7 UNIPROT DLG1 protein Q12959 UNIPROT down-regulates activity phosphorylation Ser232 ITLERGNsGLGFSIA 9534 BTO:0000298 12933808 t llicata Synapse-associated protein 97 (SAP97), a member of membrane-associated guanylate kinase protein family, has been implicated in the processes of targeting ionotropic glutamate receptors at postsynaptic sites. | We show here that SAP97 is directly associated with NR2A through its PDZ1 domain, and CaMKII-dependent phosphorylation of SAP97-Ser-232 disrupts NR2A interaction both in an in vitro pull-out assay and in transfected COS-7 cells. Moreover, expression of SAP97(S232D) mutant has effects similar to those observed upon constitutively activating CaMKII. SIGNOR-250618 0.639 SNAI2 protein O43623 UNIPROT JAG1 protein P78504 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 20509143 f miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. SIGNOR-255151 0.424 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid chemical CHEBI:95066 ChEBI SGK3 protein Q96BR1 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0003136 25458846 t lperfetto A catalytic small molecule pan-SGK inhibitor, GSK650394 (Sherk et al., 2008) also significantly blocks MCF7, ZR-75-1, and T47D cell migration (Figure 5C, Figures S4B–C). Finally, ectopic expression of SGK3 also promotes invasive migration through Matrigel (Figure 5D). Therefore, SGK3 protein kinase activity promotes migration of breast cancer cells that display elevated levels of INPP4B. SIGNOR-262019 0.8 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 21205641 t lperfetto In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy. SIGNOR-216453 0.477 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257927 0.8 PRKCA protein P17252 UNIPROT RAB37 protein Q96AX2 UNIPROT down-regulates activity phosphorylation Thr172 YGVPFLEtSAKTGMN 9606 BTO:0002877 29312551 t done miannu We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility.  SIGNOR-273803 0.2 3-[4-[4-[2-[3-[(dimethylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-3-pyrazolyl]phenyl]-1,1-dimethylurea chemical CHEBI:91362 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition 9606 19567821 t miannu The protein kinases, Aurora A, B, and C have critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. GSK1070916, is a novel ATP competitive inhibitor that is highly potent and selective for Aurora B/C kinases. SIGNOR-262225 0.8 mTORC1 complex SIGNOR-C3 SIGNOR APOB protein P04114 UNIPROT down-regulates quantity by repression translation regulation 9606 23721961 f miannu Activation of mTORC1 also has dual effects on ApoB synthesis: it inhibits ApoB secretion by decreasing ApoB translation, but promotes ApoB secretion by inhibiting sortilin. SIGNOR-252117 0.273 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269335 0.721 TFAP2A protein P05549 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 t miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 SIGNOR-253636 0.261 PRKCQ protein Q04759 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 26284074 t Barakat PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins SIGNOR-274144 0.359 JNK proteinfamily SIGNOR-PF15 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 18931691 f miannu JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. SIGNOR-260178 0.7 LFNG protein Q8NES3 UNIPROT DLL1 protein O00548 UNIPROT up-regulates binding 9606 11346656 t gcesareni The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng SIGNOR-107699 0.455 desipramine chemical CHEBI:47781 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition -1 9400006 t miannu In the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.in the SERT, the TCAs amitriptyline, nortriptyline, imipramine, desipramine and chloroimipramine were 4.5 to 10 times more potent (table 3) at the human SERT.Thus, amitriptyline, imipramine, nortriptyline and desipramine showed high affinity for the SERT, particularly the human version, and for the NET in which the secondary amines were more potent. SIGNOR-258679 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-251470 0.2 AKT1 protein P31749 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-217460 0.649 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide chemical CHEBI:125569 ChEBI PPARG protein P37231 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001950 27489280 t lperfetto We performed reporter assays to examine the effect of NeoB on the transcriptional activity of specific nuclear hormone receptors, including PPARs, retinoic acid receptor (RAR), ER, and LXR, in uninfected Huh7-25 cells (Fig. 3A). NeoB did not have a significant effect [...] in contrast to the transcriptional repression by known antagonists as positive controls (GW6471, GSK0660, FH535, Ro41-5253, and 4-hydroxytamoxifen) (Fig. 3A) SIGNOR-262015 0.8 RAPGEF3 protein O95398 UNIPROT RAP1A protein P62834 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 10777494 t miannu Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. SIGNOR-263956 0.703 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Tyr564 SKHKEDVyENLHTKN 9606 8692915 t Manara The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites. SIGNOR-260821 0.419 KLF10 protein Q13118 UNIPROT TGFBI protein Q15582 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 18359287 t lperfetto Analyzing the mechanism of TGFBI up-regulation in clear cell carcinoma, we identified a novel VHL target, a Kruppel-like transcriptional factor 10 (KLF10). The TGFBI promoter, which we isolated and studied in Luc-reporter assay, was induced by KLF10 but not hypoxia. SIGNOR-253212 0.243 AKT1 protein P31749 UNIPROT PDE3B protein Q13370 UNIPROT up-regulates activity phosphorylation Ser295 VIRPRRRsSCVSLGE 10090 BTO:0000944 10454575 t PDE3B is a physiological substrate of Akt and that Akt-mediated phosphorylation of PDE3B on serine-273 is important for insulin-induced activation of PDE3B SIGNOR-252573 0.682 RHOQ protein P17081 UNIPROT EXOC7 protein Q9UPT5 UNIPROT up-regulates binding 9606 12687004 t gcesareni Here we show that tc10 interacts with one of the components of the exocyst complex, exo70. SIGNOR-100486 0.626 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT up-regulates activity phosphorylation Thr255 ITTPELTtPCGSAEY 9606 BTO:0000093 17130135 t We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation SIGNOR-253015 0.2 DLC1 protein Q96QB1 UNIPROT MYH9 protein P35579 UNIPROT down-regulates activity binding 9606 BTO:0004006 phosphorylation:Ser1943 RKGAGDGsDEEVDGK 26977077 t miannu Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. Dlc1 interacts with phosphorylated Myh9 (Ser-1943). This association of Dlc1 with S1943 phosphorylated Myh9, suggests that Dlc1 may be involved in reduced Myh9 filament stability. SIGNOR-269283 0.2 CHIR 99021 chemical CHEBI:91091 ChEBI GSK3A protein P49840 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190997 0.8 PPP1R14B protein Q96C90 UNIPROT PPP1CB protein P62140 UNIPROT down-regulates activity binding -1 12144526 t lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin SIGNOR-265743 0.289 HLF protein Q16534 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 23415677 f miannu Ectopic hlf expression inhibits apoptosis in murine and human cells, suggesting that hlf is regulating a conserved transcriptional program that inhibits cell death. SIGNOR-256647 0.7 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276099 0.266 AURKB protein Q96GD4 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 23712260 t lperfetto Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization. SIGNOR-202130 0.48 TRIM41 protein Q8WV44 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 17893151 t miannu RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear. SIGNOR-271667 0.32 CSNK2A1 protein P68400 UNIPROT CLIP1 protein P30622 UNIPROT up-regulates phosphorylation Ser1364 DDLNNYDsDDQEKQS 9606 20664522 t lperfetto Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis SIGNOR-167168 0.296 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 20145185 t gcesareni In vivo, azd8931 inhibited xenograft growth in a range of models while significantly affecting egfr, erbb2, and erbb3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. SIGNOR-163730 0.8 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR KDM5B protein Q9UGL1 UNIPROT down-regulates activity 9606 35217626 t SaraGualdi Our transcriptomic profiling in AML further identified Kdm5b (also known as Jarid1b, Plu-1, or RBP2-H1), a multifunctional demethylase that can remove histone H3 lysine 4 tri/di-methylation (H3K4me3/2), to be a critical downstream target repressed by PRC2. SIGNOR-271577 0.367 TWIST2 protein Q8WVJ9 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255509 0.2 SETBP1 protein Q9Y6X0 UNIPROT SET protein Q01105 UNIPROT up-regulates binding 9606 22566606 t miannu Setbp1 was shown to form a complex with set and pp2a, enhancing the stability of set and its inhibition of pp2a. SIGNOR-197324 0.487 OGA protein O60502 UNIPROT PFKL protein P17858 UNIPROT up-regulates activity deglycosylation Ser529 CVIPATIsNNVPGTD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267608 0.2 LRRK2 protein Q5S007 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Thr127 KVLSSLVtLNKVTAD 9606 21048939 t gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence SIGNOR-169221 0.463 EZH2 protein Q15910 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260070 0.445 TCF3 protein P15923 UNIPROT BBC3 protein Q96PG8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23684607 f miannu The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. SIGNOR-255386 0.274 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr740 TGESDGGyMDMSKDE -1 8195171 t miannu Synthetic peptide analysis revealed that certain autophosphorylation sites in the PDGF beta-receptor (Tyr-579, Tyr-740, Tyr-751, and Tyr-771) were able to mediate the specific binding of the Shc SH2 domain as well as intact Shc proteins. SIGNOR-250257 0.2 EREG protein O14944 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4. SIGNOR-147859 0.7 EEF1A1P5 protein Q5VTE0 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269561 0.8 SYK protein P43405 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9606 11514608 t lperfetto BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation. SIGNOR-246567 0.351 SRP19 protein P09132 UNIPROT SRP54 protein P61011 UNIPROT up-regulates activity binding -1 30649418 t miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. SIGNOR-261168 0.962 SH3RF1 protein Q7Z6J0 UNIPROT MAP3K12 protein Q12852 UNIPROT up-regulates binding 9606 BTO:0000938 12514131 t gcesareni One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks SIGNOR-97060 0.381 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr371 LLAKLEEtKEYQEPE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276211 0.2 STAT5A protein P42229 UNIPROT PIM2 protein Q9P1W9 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15769897 t The serine-threonine kinase Pim-2 is a functionally relevant downstream target of STAT5. Here, we observed only a weak induction of Pim-2 by Flt3-D835Y compared to the effects of Flt3-ITD. SIGNOR-261543 0.417 PRKCE protein Q02156 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Ser775 EGVKRTLsFSLRSSR 9534 BTO:0000298 14523239 t lperfetto We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. SIGNOR-249231 0.2 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000938 9771888 t The effect has been demonstrated using P10636-8 gcesareni Tau is phosphorylated by gsk-3 at several sites found in alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by a-kinase. SIGNOR-60659 0.438 MDH2 protein P40926 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266288 0.8 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates activity phosphorylation Thr208 TFGNKLDtFCGSPPY -1 18424437 t miannu MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. SIGNOR-276165 0.576 GATA2 protein P23769 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24583263 f irozzo We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression. SIGNOR-256007 0.589 Immunoglobulin mu heavy chain protein P0DOX6 UNIPROT BCR-Ml complex SIGNOR-C434 SIGNOR form complex binding 9606 BTO:0000776 32323265 t scontino An antibody is composed of two identical HCs and two identical LCs (either kappa or lambda ), consisting of variable (V) and constant (C) regions linked by disulfide bonds. Pro- genitor B cells rearrange their Ig heavy chain (HC) genes to differentiate into precursor B (pre- B) cells that express μ HCs. SIGNOR-268191 0.2 PPM1A protein P35813 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 27419230 t miannu In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG). SIGNOR-277152 0.249 TGFB1 protein P01137 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR down-regulates activity 9606 10611320 f lperfetto Tgf-beta treatment resulted in the specific inactivation of cyclin cdk2 complexes caused by absence of the activating thr(160) phosphorylation on cdk2. SIGNOR-217502 0.278 TNKS2 protein Q9H2K2 UNIPROT CASC3 protein O15234 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263382 0.2 AS-605240 chemical CID:5289247 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189921 0.8 ADSS1 protein Q8N142 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 10496970 f miannu Adenylosuccinate synthetase catalyzes the first committed step in the de novo biosynthesis of AMP, thermodynamically coupling the hydrolysis of GTP to the formation of adenylosuccinate from l-aspartate and IMP. SIGNOR-267835 0.7 SRC protein P12931 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t miannu Src-dependent pdk1 tyr373/376 tyrosine phosphorylation. / optimal activation of pdk1 requires phosphorylation of tyr373/376 SIGNOR-166722 0.573 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120260 0.319 CDH1 protein P12830 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 21255999 t miannu At its C-terminus, cadherin interacts with β-catenin, which dynamically associates with α-catenin, a direct binding partner of filamentous actin SIGNOR-265863 0.96 CAMK2B protein Q13554 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000938 20841359 t gcesareni Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival. SIGNOR-167962 0.294 RUNX3 protein Q13761 UNIPROT TXN2 protein Q99757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002384 17956589 f miannu Comprehensive analysis using a cDNA microarray showed that RUNX3 upregulated 17 apoptosis-related genes (including FADD, TRAF6, caspase-2, ING1, ING4, Calpain 10, and DNase1) and downregulated 135 apoptosis-related genes (including FLIP, PEA15, TXN2, HSPD1, IKK, and TIAL1) in MKN-1 cells. SIGNOR-255093 0.2 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser280 YKKVKKNsSPPLSLY 9606 19833968 t miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 SIGNOR-268047 0.355 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Thr1226 LRSLRRNtKKPKPKP 9534 BTO:0000298 19103606 t miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells SIGNOR-276178 0.421 MLL Fusion fusion protein SIGNOR-FP14 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t miannu Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-260095 0.2 GTF2I protein P78347 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity relocalization 9606 21282467 t lperfetto Moreover, the inhibitory effect of TFII-I on transcription is mediated by its ability to recruit corepressor complexes, including histone deacetylase 3 (HDAC3) (25, 133), histone H3K4-specific demethylase LSD1 (48), and components of the polycomb repressor complex SIGNOR-268540 0.411 haloperidol chemical CHEBI:5613 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258838 0.8 PPP3CB protein P16298 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248381 0.261 STK4 protein Q13043 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity phosphorylation Thr187 KRNTVIGtPFWMAPE 9534 BTO:0004055 12223493 t lperfetto Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylationWe define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. SIGNOR-247581 0.2 AEP complex complex SIGNOR-C117 SIGNOR HOXA9 protein P31269 UNIPROT up-regulates quantity by expression 9606 20854876 f irozzo Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. SIGNOR-255879 0.414 SEC61G protein P60059 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-265278 0.89 MYD88 protein Q99836 UNIPROT DHX36 protein Q9H2U1 UNIPROT up-regulates activity binding 9606 BTO:0002042 20696886 t miannu We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing. SIGNOR-260956 0.512 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20551323 f gcesareni One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf SIGNOR-166163 0.465 DRD5 protein P21918 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257418 0.265 TLX1 protein P31314 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates activity binding 9606 BTO:0000661 15897879 t 2 miannu HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade. SIGNOR-240719 0.311 CDK8 protein P49336 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation Ser2513 EHPFLTPsPESPDQW -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273176 0.541 HOXA10 protein P31260 UNIPROT IGFBP1 protein P08833 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003697 17350963 f miannu The functional role of HOXA10 in IGFBP1 expression was further explored using human endometrial stromal cells (HSC). Overexpression of HOXA10 in HSC resulted in a decrease of IGFBP1 mRNA, whereas silencing HOXA10 caused an increase of IGFBP1 mRNA, even in the presence of H + dbcAMP. These data demonstrate that HOXA10 negatively influences IGFBP1 expression in decidualizing cells. SIGNOR-254467 0.416 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr180 EFKNIFGtPEFVAPE 9606 15611134 t gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. SIGNOR-132459 0.2 MYC protein P01106 UNIPROT SLC2A1 protein P11166 UNIPROT up-regulates quantity transcriptional regulation 10116 10823814 t C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-259987 0.438 DRD5 protein P21918 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257043 0.291 SCF-betaTRCP complex SIGNOR-C5 SIGNOR GBF1 protein Q92538 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 29898406 t miannu We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation. SIGNOR-277399 0.252 APH1B protein Q8WW43 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 12522139 t gcesareni Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity. SIGNOR-97107 0.909 SRC protein P12931 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 16619028 t lperfetto Src kinase phosphorylates caspase-8 on tyr380: a novel mechanism of apoptosis suppressionwe identified caspase-8 as a new substrate for src kinase. Phosphorylation occurs on tyr380, situated in the linker region between the large and the small subunits of human procaspase-8, and results in downregulation of caspase-8 proapoptotic function SIGNOR-146127 0.462 PPBP protein P02775 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258413 0.368 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269620 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RRAS protein P10301 UNIPROT up-regulates activity phosphorylation Ser201 QEQELPPsPPSAPRK 9606 BTO:0002181 27086924 t miannu  In this study, we report that TC21 and R-Ras are phosphorylated on a conserved serine, Ser186 and Ser201, respectively, in intact cells. This residue is located in the C-terminal hypervariable region of the proteins and is not conserved in M-Ras. We show that the MAP kinases ERK1/2 phosphorylate TC21 and R-Ras on this C-terminal serine residue both in vitro and in vivo.  SIGNOR-277219 0.2 DMTF1 protein Q9Y222 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261587 0.2 mTORC1 complex SIGNOR-C3 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t azuccotti Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain [..]. Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255842 0.472 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 10090 BTO:0000944 SIGNOR-C14 SIGNOR-C13 11297557 t lperfetto The i b kinase (ikk) complex rapidly phosphorylates nf- b1 p105 on serine 927 in the pest region romashkova et al. demonstrated that akt binds to and activates inhibitor of kappa b kinase-alfa (ikkalfa), which in turn phosphorylates and thereby promotes the degradation of the inhibitory cofactor of nf-kb, i-kb the scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk. SIGNOR-235438 0.741 SLBP protein Q14493 UNIPROT H2BE1 protein A0A2R8Y619 UNIPROT up-regulates quantity by expression translation regulation 9606 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265380 0.2 PTEN protein P60484 UNIPROT DVL2 protein O14641 UNIPROT down-regulates activity dephosphorylation Ser143 FHPNVSSsHENLEPE 9606 26399523 t miannu This showed that while both PTEN WT and the lipid phosphatase-inactive G129E mutant suppressed phosphorylation of DVL2 on serine 143 that accumulated upon PTEN knockdown, the C124S and Y138L mutants did not .|Finally, it is important to point out that while our studies show that PTEN can directly dephosphorylate DVL2 in vitro, it is possible that regulation of serine 143 phosphorylation of DVL2 by PTEN in cells may require additional protein factors, or post-translational modifications. SIGNOR-277035 0.322 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage 9606 14585074 t lperfetto Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation SIGNOR-90397 0.628 TERB1 protein Q8NA31 UNIPROT TERF1 protein P54274 UNIPROT up-regulates activity relocalization 9606 BTO:0000007 SIGNOR-C305 SIGNOR-C306 33015044 t lperfetto The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1 SIGNOR-263315 0.2 SYK protein P43405 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates activity phosphorylation Tyr105 FGIKPDDyLYSICSE 9534 BTO:0004055 19553680 t miannu We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kbeta kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KbetaY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kbeta.  SIGNOR-276227 0.2 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT up-regulates activity carboxylation Glu79 EDSDKTNeFWNKYKD -1 9538022 t lperfetto This report describes the expression, purification, and characterization of a series of recombinant factor Xa variants bearing aspartate substitutions for each of the glutamate residues which normally undergo gamma-carboxylation. |We have produced fully active recombinant human factor Xa and demonstrated that gla residues 16, 26, and 29 are critical for normal activity of factor Xa.|This observation suggests that, for wild-type r-fX expressed in HEK cells, carboxylation by the gamma-glutamyl carboxylase proceeds to completion once initiated; | 11 amino terminal glutamic acid residues of fX which normally undergo gamma-carboxylation (glas 6, 7, 14, 16, 19, 20, 25, 26, 29, 32, 39). SIGNOR-263674 0.605 MAPK12 protein P53778 UNIPROT NUP62 protein P37198 UNIPROT down-regulates quantity by destabilization phosphorylation Thr269 GAASGTStTTSTAAT 9606 BTO:0000007 30401435 t miannu We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1).  SIGNOR-277415 0.2 ABL1 protein P00519 UNIPROT AHSA1 protein O95433 UNIPROT up-regulates activity phosphorylation Tyr223 LTSPEELyRVFTTQE 9606 26235616 t Manara Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity SIGNOR-260938 0.253 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation -1 19168263 t Luana Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a β2 adrenoceptor agonist | After that, in vitro assays were carried out and the Kd value obtained for BR-AEA was compared with reported in vitro data for salbutamol and other well-known ligands. SIGNOR-257814 0.8 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide chemical CHEBI:94489 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207681 0.8 BTK protein Q06187 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000007 10068673 t done miannu These results demonstrate that WASP, under this experimental condition, can be tyrosine-phosphorylated by the kinase activity of Btk and that the direct interaction between WASP and the SH3 domain of Btk is required for this phosphorylation to occur. SIGNOR-273958 0.736 HOXA10 protein P31260 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 f miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. SIGNOR-254215 0.2 GNG12 protein Q9UBI6 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000586 16293724 t gcesareni We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein)coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. SIGNOR-252681 0.384 CACNA2D3 protein Q8IZS8 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 31746409 f miannu Overexpression of CACNA2D3 reduced proliferation and migration, but increased apoptosis and Ca2+ influx in Ishikawa and RL95-2 cells. SIGNOR-266854 0.7 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr384 ACQVYFTyDPYSEED -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251376 0.635 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRB protein P10828 UNIPROT up-regulates activity chemical activation 10116 BTO:0000759 2158622 t miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-258384 0.8 RAD23B protein P54727 UNIPROT ERCC5 protein P28715 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275702 0.631 ACTL6B protein O94805 UNIPROT Muscle cell-specific SWI/SNF SMARCA4 variant complex SIGNOR-C483 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu We have also found that, of the two human SWI/2/SNF2 family-related ATPases, the PBAF complex contains only BRG1 but not hbrm (Xue et al., submitted). In contrast, the BAF complex isolated by BAF250 can include either BRG1 or hbrm (Fig. ​(Fig.4b).4b). These data underscore the distinctness of the two human complexes and suggest that BAF250 is a signature subunit that may confer specificity to the BAF complex. SIGNOR-270740 0.704 GRK5 protein P34947 UNIPROT GRK5 protein P34947 UNIPROT up-regulates activity phosphorylation Thr485 LDIEQFStVKGVNLD -1 8144599 t Autophosphorylation of GRK5 occurs primarily at residues Ser-484 and Thr-485. Phospholipid-stimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5. SIGNOR-251202 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 1651322 t inferred from 70% family members lperfetto It is likely that the map2 and ert kinases account for the phosphorylation of the egf receptor at thr669 (egf receptor (krel veplt669psgeapnqallr)) observed in cultured cells.Phosphorylation at ser-695 is partial and occurs only if thr-693 is phosphorylated. Phosphorylation at thr-678 and thr-693 by prkd1 inhibits egf-induced mapk8/jnk1 activation. SIGNOR-270017 0.2 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates quantity by destabilization phosphorylation Ser266 QYLGSIAsPSVHPAT 9606 BTO:0002181 16046550 t miannu We have identified four phosphorylation sites on AML1c that are necessary for transcriptional activity of AML1c in K562 and 293T cells (27).4 Mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein. The presence of these mutations results in an increase in the amount of ubiquitinated AML1c in the matrix, and increases the half-life of this insoluble AML1c. One possible model to explain these observations is that phosphorylation might be necessary for the normal process of both proteasome degradation and transcriptional activation. SIGNOR-268219 0.2 PTPN2 protein P17706 UNIPROT STAT6 protein P42226 UNIPROT down-regulates activity dephosphorylation 9606 17210636 t gcesareni These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors SIGNOR-235192 0.671 FOXO3 protein O43524 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12913110 f lperfetto In addition, we find that FKHRL1 (FOXO3a) directly activates the bim promoter via two conserved FOXO binding sites and that mutation of these sites abolishes bim promoter activation after NGF withdrawal. SIGNOR-209657 0.766 PCDH15 protein Q96QU1 UNIPROT TMC2 protein Q8TDI7 UNIPROT up-regulates activity binding 9606 BTO:0000007 BTO:0000630 25114259 t lperfetto Although several studies show that the tip links, composed of PCDH15 and CDH23, are required for normal mechanotransduction, it is unclear how they are coupled to the transduction machinery. Likewise, it has been demonstrated that the transmembrane channel-like proteins TMC1 and TMC2 are required for mechanosensitive responses in hair cells, but how they interact with other components of the mechanotransduction complex is not known. Here, we show that TMC1 and TMC2 can interact with PCDH15, thereby establishing a critical connection between the tip link and these putative components of the mechanotransduction channel in hair cells. SIGNOR-262583 0.444 DUSP5 protein Q16690 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10224087 t inferred from 70% of family members gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-269932 0.777 ABCC8 protein Q09428 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 t lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. SIGNOR-262056 0.646 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser272 RSRLTPVsPESSSTE 9606 BTO:0000551 20974803 t lperfetto Here we show that cdk1 phosphorylates p62 in vitro and in vivo at t269 and s272, which is necessary for the maintenance of appropriate cyclin b1 levels and the levels of cdk1 activity necessary to allow cells to properly enter and exit mitosis. SIGNOR-216932 0.353 EIF3E protein P60228 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 f irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. SIGNOR-259156 0.2 retinol smallmolecule CHEBI:50211 ChEBI retinal smallmolecule CHEBI:15035 ChEBI up-regulates quantity precursor of 9606 21621639 t lperfetto Currently, at least three RDH seem physiologically involved in converting all-trans-retinol into all-trans-retinal: RDH1, RDH10 and DHRS9 SIGNOR-265115 0.8 CCKAR protein P32238 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000551 11313903 t gcesareni These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways. SIGNOR-106998 0.451 RAB5A protein P20339 UNIPROT PIK3R4 protein Q99570 UNIPROT up-regulates activity binding 10090 27411398 t lperfetto Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity SIGNOR-260708 0.429 BIRC2 protein Q13490 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18997794 t lperfetto Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3. SIGNOR-182128 0.87 RALA protein P11233 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates activity phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 11689711 t gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. SIGNOR-249665 0.2 NR1D1 protein P20393 UNIPROT ARNTL protein O00327 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24577401 t miannu A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription. SIGNOR-268005 0.664 WDR62 protein O43379 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates activity relocalization 10090 30566428 t lperfetto In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis SIGNOR-271717 0.2 MAPK8IP3 protein Q9UPT6 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates binding 9606 10523642 t gcesareni Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct. SIGNOR-71468 0.622 RUVBL2 protein Q9Y230 UNIPROT R2SP co-chaperone complex SIGNOR-C517 SIGNOR form complex binding 9606 29844425 t miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270940 0.51 Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 22303254 f Polycomb group (PcG) and Trithorax group (TrxG) proteins are epigenetic regulators that control gene expression through modulating chromatin structure and addition of posttranslational modifications (PTMs) on histones SIGNOR-268625 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR YBX1 protein P67809 UNIPROT up-regulates phosphorylation Ser102 NPRKYLRsVGDGETV 9606 BTO:0000150 19036157 t lperfetto Phosphorylation of yb-1 at the serine 102 residue is required for transcriptional activation of growth-enhancing genes, such as egfr. Herein, we illustrate that activated akt binds to and phosphorylates the yb-1 cold shock domain at ser102 SIGNOR-182493 0.2 SB-202190 chemical CHEBI:79090 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206697 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1882 SPTSPTYsPTTPKYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269349 0.721 SMARCD2 protein Q92925 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270745 0.774 FLT4 protein P35916 UNIPROT SHC1 protein P29353 UNIPROT unknown phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 9927207 t llicata We have investigated which of the shc tyrosine residues are targeted by the vegfr3/ flt4 kinase and the role of the shc ptb and sh2 domains in this process. Our results show that y239/ y240 and y313 are simultaneously phosphorylated by the kinase, creating grb2 binding sites. SIGNOR-64076 0.581 SMARCC2 protein Q8TAQ2 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR form complex binding 9606 15627498 t miannu We discuss recent insights in the functional differences between two evolutionary conserved subclasses of swi/snf-related chromatin remodeling factors. Onesubfamily comprises yeast swi/snf, fly bap and mammalian baf, whereas the other subfamily includes yeast rsc, fly pbap andmammalian pbaf. We review the subunit composition, conserved protein modules and biological functions of each of these subclasses ofswi/snf remodelers. SIGNOR-132936 0.867 PRKCQ protein Q04759 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates activity phosphorylation Ser323 LCLQKDPsKRPTAAE -1 14988727 t miannu Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. SIGNOR-276007 0.473 PPP3CB protein P16298 UNIPROT FLNA protein P21333 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation. SIGNOR-248362 0.2 STK39 protein Q9UEW8 UNIPROT SLC12A3 protein P55017 UNIPROT down-regulates activity phosphorylation Thr55 SSTFCMRtFGYNTID 10090 25651566 t lperfetto SPAK directly phosphorylates NCC and its effects on NCC are universally associated with phosphorylation|This adds to the evidence that SPAK-mediated phosphorylation acts primarily to increase activity of individual cotransporters without affecting the amount of NCC on the surface| the kinase (SPAK) that phosphorylates NCC at T53 SIGNOR-264623 0.494 GNAS protein P63092 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR up-regulates activity binding 9606 17652154 t gcesareni Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR SIGNOR-267848 0.735 CHD8 protein Q9HCK8 UNIPROT MAP2 protein P11137 UNIPROT down-regulates quantity transcriptional regulation 10090 32839322 t Gianni Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells SIGNOR-268916 0.2 KNL1 protein Q8NG31 UNIPROT KNL1 complex complex SIGNOR-C363 SIGNOR form complex binding 27881301 t lperfetto KNL1C (known as Spc105 complex in S. cerevisiae) contains the KNL1 and ZWINT subunits. SIGNOR-265193 0.2 RMDN3 protein Q96TC7 UNIPROT VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR form complex binding 10116 BTO:0000142 30841933 t lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. SIGNOR-262119 0.619 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192901 0.8 MAPK7 protein Q13164 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates phosphorylation Thr319 TPVVSVTtPSLPPQG 9606 BTO:0000567 10849446 t lperfetto We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo. SIGNOR-236579 0.704 RASGEF1B protein Q0VAM2 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 19201597 t gcesareni Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras. SIGNOR-183835 0.299 BAK1 protein Q16611 UNIPROT CYCS protein P99999 UNIPROT up-regulates relocalization 9606 11175253 t Translocation from Mitochondria to Cytosol amattioni Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux SIGNOR-105206 0.556 GABRA6 protein Q16445 UNIPROT GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263762 0.6 CDK1 protein P06493 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Thr34 FLEGCACtPERMAEA 9606 11861764 t gcesareni Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo SIGNOR-115129 0.677 LNX1 protein Q8TBB1 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 11782429 t esanto Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation. SIGNOR-112201 0.734 CSNK2A1 protein P68400 UNIPROT AQP4 protein P55087 UNIPROT down-regulates activity phosphorylation Ser316 EKKGKDQsGEVLSSV 9615 BTO:0000837 11742978 t llicata We found that the stress-induced kinase casein kinase (CK)II phosphorylates the Ser276 immediately preceding the tyrosine motif, increasing AQP4-mu 3A interaction and enhancing AQP4-lysosomal targeting and degradation. AQP4 phosphorylation by CKII may thus provide a mechanism that regulates AQP4 cell surface expression. | To determine whether Ser276 is an actual CKII substrate, we used GST–AQP4-Cter proteins in which only one out of the three C-terminal CKII consensus sites was sequentially conserved (Ser276, Ser285 and Ser315, respectively). Figure 7B (right panel) shows that the three serine residues, including Ser276, were indeed efficiently phosphorylated by CKII. SIGNOR-250828 0.422 LAMP2 protein P13473 UNIPROT Chaperone-mediated autophagy phenotype SIGNOR-PH118 SIGNOR up-regulates activity 10029 BTO:0000977 8662539 f Here, the lysosomal membrane glycoprotein LGP96 was identified as a receptor for the selective import and degradation of proteins within lysosomes. Specific substrates of this proteolytic pathway bound to the cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different binding assays. SIGNOR-259990 0.7 HTR6 protein P50406 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257073 0.251 Tubulin proteinfamily SIGNOR-PF46 SIGNOR Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-266827 0.7 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT down-regulates activity dephosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 18819921 t Using substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both phosphatases interact with Met and that these interactions require phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of the Met kinase domain.|Using small interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the absence of either PTP1B or TCPTP and further elevated upon loss of both phosphatases. SIGNOR-248388 0.487 FLCN protein Q8NFG4 UNIPROT RRAGC protein Q9HB90 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000007 24095279 t The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur SIGNOR-256503 0.69 CELF6 protein Q96J87 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0001109 31534127 t miannu CELF6 binds to the 3'UTR of p21 transcript and increases its mRNA stability. Depletion of CELF6 promotes cell cycle progression, cell proliferation and colony formation whereas overexpression of CELF6 induces G1 phase arrest. SIGNOR-269044 0.2 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-128268 0.424 NF1 protein P21359 UNIPROT AFP protein P02771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 7549116 f miannu Our results pointed to a key role that NF1 might play in the functioning of the AFP promoter. Indeed, overexpression of NF1 induced a specific decrease in the activity of the AFP promoter. Competition between NF1 and HNF-1 for binding to their overlapping binding sites on the AFP promoter would be critical for modulating its activity. SIGNOR-254636 0.274 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163458 0.471 SPTAN1 protein Q13813 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates activity 19102630 f lperfetto We have shown that in the nucleus alphaRIISp is involved in repair of DNA interstrand cross-links (13,14). It binds to purified DNA containing an interstrand crosslink; it colocalizes with the cross-link repair protein, XPF, in damage-induced nuclear foci after treatment of cells with a DNA interstrand cross-linking agent, and it is needed for the production of incisions by XPF at the site of an interstrand cross-link SIGNOR-263276 0.288 ZNF804A protein Q7Z570 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 23434502 t miannu ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3). SIGNOR-269464 0.2 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT down-regulates activity phosphorylation Ser436 TCSPLRHsFQKQQRE -1 8810272 t miannu Protein kinase A phosphorylates -adducin at three sites in the neck domain (Ser-408, ’436, and ’481) in addition to the MARCKS-related domain of both subunits. Phosphorylation by PKA, in contrast to PKC, reduced affinity of erythrocyte adducin for spectrin-F-actin complexes as well as activity of adducin in promoting binding of spectrin to F-actin. SIGNOR-250330 0.314 BTRC protein Q9Y297 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates ubiquitination 9606 BTO:0000785 24469040 t lperfetto _-trcp ubiquitinates ezh2 and jak2-mediated phosphorylation on y641 directs _-trcp-mediated ezh2 degradation. SIGNOR-204481 0.381 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 15469984 t gcesareni Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering scfbetatrcp-dependent destruction of the apc inhibitor emi1. SIGNOR-129813 0.778 PRKCA protein P17252 UNIPROT EGLN2 protein Q96KS0 UNIPROT down-regulates phosphorylation Ser234 QRAIPPRsIRGDQIA 9606 18710826 t tpavlidou Thus, recombinant phd1 was examined for in vitro phosphorylation using protein kinase a, protein kinase calpha, casein kinase i and ii and erk2. The protein was most strongly phosphorylated by protein kinase calpha, and the phosphorylation sites were found to be ser-132, ser-226 and ser-234.Mutation Of ser-132 or ser-234 to asp or glu diminished the enzymatic activity to 25-60%, while mutation of ser-226 scarcely influenced the activity. SIGNOR-180203 0.349 heme smallmolecule CHEBI:30413 ChEBI HBA1 protein P69905 UNIPROT up-regulates activity chemical activation 9606 26557657 t miannu Heme is a prosthetic group comprising ferrous iron (Fe2+) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. SIGNOR-251909 0.8 BLM protein P54132 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 28912125 f miannu The BLM gene product, BLM, is a RECQ helicase that is involved in DNA replication and repair of DNA double-strand breaks by the homologous recombination (HR) pathway. During HR, BLM has both pro- and anti-recombinogenic activities, either of which may contribute to maintenance of genomic integrity. SIGNOR-261824 0.7 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR JUN protein P05412 UNIPROT up-regulates binding 9606 18174238 t lperfetto Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment SIGNOR-216337 0.578 Gbeta proteinfamily SIGNOR-PF4 SIGNOR PAK1 protein Q13153 UNIPROT down-regulates phosphorylation 9606 14993270 t inferred from 70% family members gcesareni Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation. SIGNOR-270086 0.2 VRK1 protein Q99986 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 BTO:0000567 10951572 t gcesareni Vrk1 phosphorylates murine p53 in threonine 18. This threonine is within the p53 hydrophobic loop (residues 13-23) required for the interaction of p53 with the cleft of its inhibitor mdm-2. SIGNOR-81222 0.533 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Thr290 NKLKPPGtPPPSSRK 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248526 0.261 S1RA chemical CID:44247568 PUBCHEM SIGMAR1 protein Q99720 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000195 22784008 t Simone Vumbaca The most selective compounds were further profiled, and compound 28, 4-{2-[5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862) emerged as the most interesting candidate. Compound 28 is a highly selective σ1R antagonist and has successfully completed phase I safety and pharmacokinetic evaluation in humans. SIGNOR-261122 0.8 azelastine chemical CHEBI:2950 ChEBI HRH3 protein Q9Y5N1 UNIPROT down-regulates activity chemical inhibition 10030 BTO:0000246 21381763 t Luana Azelastine was used as a standard, with affinities (pKi) for H1 and H3 8.9 and 6.8, respectively.  SIGNOR-257895 0.8 OFD1 protein O75665 UNIPROT ATG13 protein O75143 UNIPROT down-regulates quantity by destabilization binding 9606 34027042 t miannu The OFD1 protein inhibits autophagosome biogenesis by selective autophagy-mediated degradation of Autophagy Related 13 (ATG13), a component of the unc-51-like kinase (ULK1) autophagy initiation complex. SIGNOR-269107 0.2 HPS4 protein Q9NQG7 UNIPROT BLOC-3 complex SIGNOR-C253 SIGNOR form complex binding 9606 20048159 t lperfetto Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. SIGNOR-260692 0.748 SGK1 protein O00141 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates activity phosphorylation Ser211 PGKETNEsPWRSDLL 9606 23650397 t gcesareni SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation|Having demonstrated that SGK1 mediates the cortisol-induced increase in GR phosphorylation at the S203 and S211 phospho-sites, which enhance GR nuclear translocation, but not at the S226 site, which inhibits nuclear translocation SIGNOR-251670 0.469 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates activity phosphorylation Ser438 TPTLTNQsPTLTLQS 9606 BTO:0000801 14592977 t lperfetto Tab1, a subunit of the kinase tak1, was phosphorylated by sapk2a/p38alpha at ser423, thr431 and ser438 in vitro. the results presented here also show that sapk2a/p38? Suppresses the activity of tak1 in cells, because the activation of tak1 by proinflammatory cytokines and lps is enhanced if cells are first pre?incubated With sb 203580 or in cells that do not express sapk2a/p38?. SIGNOR-118922 0.82 STK11 protein Q15831 UNIPROT SNRK protein Q9NRH2 UNIPROT up-regulates activity phosphorylation Thr173 QPGKKLTtSCGSLAY 9606 15733851 t Manara We demonstrate that LKB1 activates SNRK by phosphorylating the T‐loop residue (Thr173) SIGNOR-260824 0.372 isoleucine smallmolecule CHEBI:24898 ChEBI Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270426 0.8 P2RY4 protein P51582 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256727 0.368 NRBF2 protein Q96F24 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 24785657 t miannu We have now identified NRBF2 (nuclear receptor-binding factor 2) as a new member of Vps34 Complex I. NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L, but not the Vps34 Complex II component UVRAG (UV radiation resistance-associated gene). NRBF2 directly interacts with Vps15 via the Vps15 WD40 domain as well as other regions of Vps15. Thus NRBF2 plays a critical role in the induction of starvation-induced autophagy as a specific member of Vps34 Complex I. SIGNOR-265880 0.709 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259809 0.8 PALB2 protein Q86YC2 UNIPROT POLH protein Q9Y253 UNIPROT up-regulates binding 9606 24485656 t miannu Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates SIGNOR-204541 0.525 NPEPPS protein P55786 UNIPROT peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity chemical modification 9606 11062501 t The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. SIGNOR-272468 0.8 MMP2 protein P08253 UNIPROT LRP2 protein P98164 UNIPROT up-regulates quantity binding 10116 28659595 t miannu We show that megalin/LRP-2 acts as an endocytic receptor for proMMP-2:TIMP-2 complex. We found that RAP, an antagonist of the LDL receptor family18, competed with binding of proMMP-2:TIMP-2 complex onto rat BN16 epithelial cells. SIGNOR-265255 0.347 CARS1 protein P49589 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270472 0.8 ZBTB47 protein Q9UFB7 UNIPROT CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR form complex binding 9606 BTO:0000007 20116376 t Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. SIGNOR-253957 0.462 EGFR protein P00533 UNIPROT HGS protein O14964 UNIPROT up-regulates activity phosphorylation Tyr334 ARYLNRNyWEKKQEE 9606 12953068 t lperfetto We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation SIGNOR-100246 0.628 BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates activity binding 9606 BTO:0000007 15694340 t lperfetto Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2 SIGNOR-133759 0.844 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 9335504 t llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 SIGNOR-52687 0.597 SRC protein P12931 UNIPROT FERMT2 protein Q96AC1 UNIPROT up-regulates activity phosphorylation Tyr193 SKTMTPTyDAHDGSP 9606 BTO:0000007 26037143 t miannu Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. SIGNOR-266100 0.376 MARK2 protein Q7KZI7 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 9606 16980613 t lperfetto We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function SIGNOR-149583 0.347 BTG2 protein P78543 UNIPROT SOD1 protein P00441 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254650 0.2 nitric oxide smallmolecule CHEBI:16480 ChEBI Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 9606 BTO:0001176 24078390 f VEGF pathway Gianni After a period of controversial reports, evidence based on eNOS knockout mice and on eNOS-depleted EC established that microvascular hyperpermeability in response to an inflammatory challenge is regulated mainly by endothelial cells through eNOS-derived NO SIGNOR-261947 0.7 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4D protein Q08499 UNIPROT up-regulates activity phosphorylation Ser125 CRAMDRTsYAVETGH 9534 12023945 t miannu Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.These were Ser89Ala-PDE4A8, Ser133Ala-PDE4B1, Ser13Ala-PDE4C2 and Ser126Ala-PDE4D5. SIGNOR-273939 0.2 POLR2D protein O15514 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266164 0.836 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates phosphorylation 9606 BTO:0000782;BTO:0001271 18174237 t gcesareni Constitutive activation of the c-jun n-terminal kinase (jnk) pathway in sup-t1 cells promoted phosphorylation and degradation of bimel via the proteosome. SIGNOR-160326 0.754 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPP2R5C protein Q13362 UNIPROT down-regulates phosphorylation 9606 16456541 t inferred from 70% family members gcesareni Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit. SIGNOR-270196 0.2 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr45 PGGTLFStTPGGTRI 9606 BTO:0000007;BTO:0000443 SIGNOR-C3 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-154814 0.925 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252485 0.758 5-amino-1-(5-phosphonato-D-ribosyl)imidazolium-4-carboxylate(2-) smallmolecule CHEBI:77657 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-268109 0.8 CELF4 protein Q9BZC1 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000227 23209433 f miannu CELF4 (CUGBP, ELAV-like family member 4) is one of six mammalian CELF proteins that function in mRNA metabolism. CELF4 is expressed predominantly in excitatory neurons, with highest expression in pyramidal neurons of the hippocampus and the cerebral cortex. we suggest that CELF4 deficiency leads to abnormal neuronal function by combining a specific effect on neuronal excitation with a general impairment of synaptic transmission. SIGNOR-264257 0.7 PRKDC protein P78527 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates phosphorylation Thr68 SSLETVStQELYSIP 9606 15668230 t gcesareni We have found that dna-pk is the major constituent of an activity present in extracts of mammalian cells that phosphorylates chk2. Our results suggest that hypophosphorylated chk2 can be phosphorylated at thr68 by dna-pk in vitro. SIGNOR-133384 0.602 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation His118 QVGRNIIhGSDSVES 9606 BTO:0000763 22869372 t llicata Ndpk catalytic function requires autophosphorylation at the catalytic his-118 residue. the simplest interpretation of these data is that ampk does not directly phosphorylate ndpk-a at ser-120 or ser-122 (or at any other site) but rather enhances ndpk-a autophosphorylation at his-118. SIGNOR-198667 0.2 TFPT protein P0C1Z6 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270857 0.447 PRKD1 protein Q15139 UNIPROT KAT7 protein O95251 UNIPROT up-regulates quantity by stabilization phosphorylation Thr97 KKYPLRQtRSSGSET 9606 BTO:0002181 33014433 t miannu We show that PKD1 directly interacts and phosphorylates KAT7 at Thr97 and Thr331 in vitro and in vivo. PKD1-mediated phosphorylation of KAT7 enhances its expression levels and stability by reducing its ubiquitination-mediated degradation.  SIGNOR-277829 0.2 EPHA2 protein P29317 UNIPROT CLDN4 protein O14493 UNIPROT down-regulates activity phosphorylation Tyr208 RSAAASNyV 9534 16236711 t miannu EphA2 associates with claudin-4 via their extracellular domains. This association, in turn, leads to phosphorylation of the cytoplasmic carboxyl terminus of claudin-4 at Tyr-208. The tyrosine phosphorylation of claudin-4 attenuates association of claudin-4 with ZO-1, decreasing integration of claudin-4 into sites of cell-cell contact and enhancing paracellular permeability. These results indicate that EphA2 moderates the function of tight junctions via phosphorylation of claudin-4. SIGNOR-262859 0.486 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258304 0.8 DAMPS stimulus SIGNOR-ST18 SIGNOR NLRP1 protein Q9C000 UNIPROT up-regulates activity 16037825 f lperfetto Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-256421 0.7 G6PD protein P11413 UNIPROT 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity chemical modification 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267051 0.8 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Thr179 LGSKGQKtTQNRYSF -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273489 0.269 CWC27 protein Q6UX04 UNIPROT Spliceosomal_snRNP_assembly phenotype SIGNOR-PH79 SIGNOR up-regulates 9606 11991638 f Purification and characterization of native pliceosomes suitable for three-dimensional structural analysis SIGNOR-261148 0.7 PDIA6 protein Q15084 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT down-regulates activity 10116 BTO:0003318 26487694 t Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling. SIGNOR-256537 0.2 DDX17 protein Q92841 UNIPROT Microprocessor complex complex SIGNOR-C356 SIGNOR up-regulates activity binding 9606 26045258 t miannu In addition, nuclear YAP has also been found to regulate miRNA processing. Nuclear YAP/TAZ bind and sequester DEAD box helicase 17 (DDX17) (also known as p72) to repress its association with Microprocessor, a complex that regulates miRNA processing (Figure 3B). SIGNOR-277660 0.565 MAP1LC3B protein Q9GZQ8 UNIPROT Autophagosome_formation phenotype SIGNOR-PH36 SIGNOR up-regulates 9606 20921139 f lperfetto We assessed both conversion of LC3-I to its cleaved and lipidated form LC3-II and its translocation to autophagic structures, two steps in autophagosome formation SIGNOR-219403 0.7 DAPK3 protein O43293 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH -1 15001356 t llicata ZIP kinase phosphorylates p21(WAF1) at Thr145 and alanine-substituted mutations in the p21(WAF1) phosphorylation site alter its ability to be phosphorylated by ZIP kinase. | Transfected ZIPK can promote the phosphorylation of p21(WAF1) at Thr145 in vivo and can increase the half-life of p21(WAF1) SIGNOR-251085 0.319 PRKCA protein P17252 UNIPROT NOX5 protein Q96PH1 UNIPROT up-regulates phosphorylation Ser536 GRGSKRLsRSVTMRK 9606 24505490 t llicata A constitutively active form of pkc? Robustly increased basal and pma-stimulated nox5 activity and promoted the phosphorylation of nox5 on ser490, thr494, and ser498. SIGNOR-204546 0.2 IC-87114 chemical CHEBI:90686 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206193 0.8 KDM1A protein O60341 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264501 0.799 EPO protein P01588 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000574 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251786 0.323 ABL2 protein P42684 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 33622779 f miannu Here, using cultured hippocampal neurons pooled from both sexes of mice, we provide evidence that binding to cortactin tethers Abl2 in spines, where Abl2 and cortactin maintain the small pool of stable actin required for dendritic spine stability. SIGNOR-266594 0.7 MAPK3 protein P27361 UNIPROT ABI1 protein Q8IZP0 UNIPROT up-regulates phosphorylation Ser225 ARLGSQHsPGRTASL 9606 21419341 t gcesareni We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1. SIGNOR-172881 0.44 VEGFD protein O43915 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252278 0.7 AKT3 protein Q9Y243 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity phosphorylation Tyr47 KTGQAPGySYTAANK -1 32781572 t miannu Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. SIGNOR-277235 0.267 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Thr213 SASFPHTtPSMCLNP 9606 BTO:0000664 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262913 0.322 GPR84 protein Q9NQS5 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256847 0.279 EFNA2 protein O43921 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52203 0.922 melatonin smallmolecule CHEBI:16796 ChEBI MTNR1A protein P48039 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257545 0.8 IRF9 protein Q00978 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity binding 9606 BTO:0000007 17923090 t lperfetto By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. SIGNOR-217779 0.721 PCDH15 protein Q96QU1 UNIPROT TIP-LINK complex complex SIGNOR-C291 SIGNOR form complex binding 10090 BTO:0000630 23217710 t lperfetto The adaptor proteins harmonin and SANS, and the motor protein myosin 7a (Myo7a) bind in vitro to each other and to CDH23 (Adato et al., 2005; Bahloul et al., 2010; Boeda et al., 2002; Siemens et al., 2002) and co-localize at the upper insertion site of tip links (Grati and Kachar, 2011; Grillet et al., 2009b), suggesting that they form a protein complex important for transduction. SIGNOR-262575 0.56 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 9275162 t gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-50614 0.742 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 20083114 t lperfetto A recent study revealed that ampk can inhibit mtorc1 independently of tsc2 by phosphorylating raptor at ser863. SIGNOR-216422 0.456 ELOVL2 protein Q9NXB9 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267897 0.8 HBEGF protein Q99075 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 9135143 t gcesareni It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response. SIGNOR-47881 0.744 SREBF2 protein Q12772 UNIPROT SQLE protein Q14534 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000759 31848472 t miannu The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription SIGNOR-265162 0.586 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000562 23457334 t lperfetto Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (pfkfb2) isoenzyme by amino acids. SIGNOR-252528 0.647 PRKACA protein P17612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 BTO:0000887 20151718 t miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-163764 0.277 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16446360 t gcesareni In the present study, we report the identification of cdc7/dbf4 phosphorylation sites on mcm2 and determine the functional role of cdc7/dbf4 phosphorylation of mcm2 in the initiation of dna replication in human cells. SIGNOR-143992 0.961 PLK1 protein P53350 UNIPROT STAG2 protein Q8N3U4 UNIPROT down-regulates activity dephosphorylation Ser1224 PASIMDEsVLGVSMF 9606 BTO:0000567 15737063 t lperfetto Two phosphorylation sites in Scc1 (Thr144 and Thr312) match the consensus proposed by Nakajima et al. [24]. These two sites, in addition to one in Scc1 (Ser454) and three in SA2 (Thr1109, Ser1137, and Ser1224) conform with the consensus proposed by Barr et al. [25]. These findings are consistent with the possibility that at least some of the sites in Scc1 and SA2 are directly phosphorylated by Plk1.|Phosphorylation of SA2 Is Essential for the Dissociation of Cohesin from Chromosomes during Prophase and Prometaphase SIGNOR-275532 0.731 GNG12 protein Q9UBI6 UNIPROT PRKACA protein P17612 UNIPROT down-regulates binding 9606 17251915 t gcesareni As pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp. SIGNOR-152615 0.391 vitamin K epoxide smallmolecule CHEBI:28371 ChEBI vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity precursor of 9606 31226734 t lperfetto This series of oxidation-reduction reactions begins with conversion of vitamin K from a stable oxidized form (quinone form) to a hydroquinone form by vitamin K epoxide reductase (VKOR) SIGNOR-265907 0.8 ROCK1 protein Q13464 UNIPROT PPP1R12B protein O60237 UNIPROT down-regulates phosphorylation Thr646 ARQTRRStQGVTLTD 9606 22937917 t lperfetto Phosphorylation of ppp1r12b on threonine 646 by rho kinase inhibits the activity of the pp1c-ppp1r12b complex. SIGNOR-198812 0.576 CHEK1 protein O14757 UNIPROT CLSPN protein Q9HAW4 UNIPROT up-regulates phosphorylation Thr916 DELLDLCtGKFTSQA 9606 16963448 t gcesareni We found that thr-916 on claspin is phosphorylated by chk1, suggesting that chk1 regulates claspin during checkpoint response. SIGNOR-149411 0.79 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD40 protein P25942 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 f miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. SIGNOR-254785 0.562 DUSP9 protein Q99956 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates binding 9606 21908610 t gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-176583 0.691 SMURF1 protein Q9HCE7 UNIPROT TGFBR2 protein P37173 UNIPROT down-regulates activity ubiquitination 9606 22298955 t lperfetto Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps. SIGNOR-195672 0.605 PK proteinfamily SIGNOR-PF80 SIGNOR pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266540 0.8 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT up-regulates quantity by stabilization phosphorylation Ser43 RNPEAALsPTFRSDS 9606 BTO:0000007 33217317 t miannu Mass spectrometry analysis showed that ERK phosphorylates METTL3 at three highly conserved residues: S43, S50, and S525 (Figures 2D and 2E). Mutational analysis further confirmed these three sites as main ERK phosphorylation sites (Figure 2F). Phosphorylation of METTL3 increases interaction with USP5, decreasing ubiquitination to stabilize the m6 A methyltransferase complex. SIGNOR-265949 0.273 NEK1 protein Q96PY6 UNIPROT ME1 protein P48163 UNIPROT down-regulates activity phosphorylation Ser336 KKIWLVDsKGLIVKG 31735643 t lperfetto PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. SIGNOR-275570 0.2 ID1 protein P41134 UNIPROT TCF3 protein P15923 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C127 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241107 0.646 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS1 protein Q8WY41 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268346 0.353 HEY1 protein Q9Y5J3 UNIPROT MEF2C protein Q06413 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19917614 f lperfetto Our results indicate instead that hey1 is recruited to the promoter regions of myogenin and mef2c, two genes whose induction is critical for myogenesis. SIGNOR-235819 0.311 PRKACA protein P17612 UNIPROT ASIC1 protein P78348 UNIPROT unknown phosphorylation Ser479 QKEAKRSsADKGVAL 9606 BTO:0000142 12578970 t llicata We found that protein kinase a phosphorylation of ser-479 in the asic1 c terminus interfered with pick1 binding. SIGNOR-98196 0.329 CSNK1D protein P48730 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates activity phosphorylation Ser159 GIPVRCYsAEVVTLW -1 10500146 t llicata We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro. SIGNOR-250798 0.543 TFE3 protein P19532 UNIPROT CTSS protein P25774 UNIPROT up-regulates quantity by expression transcriptional regulation 24448649 f lperfetto Overexpression of TFE3 in ARPE-19 cells increased the mRNA abundance of 16 of the 17 genes tested, including those encoding several subunits of the v-ATPase (ATP6V0B1, ATP6V0D1, ATP6V0D2, and ATP6V1C1), lysosomal transmembrane proteins (CD63, CLCN7, CLCN3, LAMP1, and MCOLN1), and lysosomal hydrolases (GAA, GBA, GLA, CTSA, CTSD, CTSF, CTSS, and HEXA) (Fig. 5A). Western blotting confirmed the increase in several lysosomal proteins including LAMP1, RagC (encoded by RRAGC), cathepsin D (encoded by CTSD), and ATP6V1C1 in TFE3-overexpressing cells (fig. S5A). SIGNOR-276818 0.272 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr4 yHAANQSY 9606 23454549 t lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin SIGNOR-192199 0.548 NPC complex SIGNOR-C263 SIGNOR Nuclear_pore_function phenotype SIGNOR-PH130 SIGNOR up-regulates 9606 BTO:0000007 9660920 f miannu Exportin-t Is Predominantly Nuclear, Binds NPCs, and Shuttles Rapidly between Nucleus and Cytoplasm. RanGTP appears to have at least two functions in this complex. First, it stabilizes the tRNA/exportin-t interaction (see Figure 4B). Second, exportin-t apparently has to bind RanGTP for rapid exit from the nucleus . RanGTP causing a conformational change in exportin-t, which increases the affinity for export sites at the NPC. Exportin-t probably makes a direct contact to the NPC and accounts for the interactions that drive translocation of the tRNA/exportin-t/RanGTP complex out of the nucleus. SIGNOR-261395 0.7 IRF3 protein Q14653 UNIPROT Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 10090 BTO:0002572 20610653 f lperfetto Type 1 IFNs are induced in a cell type-specific manner through Toll-like receptor and RIG-I-like receptor pathways, both of which activate interferon regulatory factors (IRFs) and nuclear factor _B (NF-_B) transcription factors. SIGNOR-126962 0.7 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NR3C1 protein P04150 UNIPROT down-regulates phosphorylation -1 9199329 t inferred from 70% family members lperfetto Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action. SIGNOR-270098 0.2 PTK2 protein Q05397 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 15688067 t miannu Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade. SIGNOR-257733 0.699 TRIB3 protein Q96RU7 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates activity binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271602 0.2 FLI1 protein Q01543 UNIPROT GP9 protein P14770 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002581 15466856 f miannu Both Fli-1 and GATA-1 are required for formation of an active transcriptional complex on the C-MPL and GPIX promoters in vivo. SIGNOR-254160 0.249 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser272 RPRSKSQsSSNCSNP -1 12351658 t IRS-1 is a novel direct substrate for IKK and that phosphorylation of IRS-1 at Ser(312) (and other sites) by IKK may contribute to the insulin resistance mediated by activation of inflammatory pathways. SIGNOR-251290 0.648 KDM5D protein Q9BY66 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity demethylation 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‚Äê and di‚Äê methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-265336 0.2 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Thr179 SSPDKRLtLSQIYEW -1 17711846 t done miannu Here, we find that AMPK directly regulates mammalian FOXO3, a member of the FOXO family of Forkhead transcription factors known to promote resistance to oxidative stress, tumor suppression, and longevity. We show that AMPK phosphorylates human FOXO3 at six previously unidentified regulatory sites.Phosphorylation by AMPK leads to the activation of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization.Taken together, these results indicate that AMPK phosphorylates at least six residues of FOXO3 in vitro (Thr179, Ser399, Ser413, Ser555, Ser588, and Ser626). SIGNOR-274094 0.403 ELOVL4 protein Q9GZR5 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267899 0.8 MAPK8IP2 protein Q13387 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 10490659 t gcesareni Deletion analysis demonstrated that the cooh-terminal regions of jip1 and jip2 were sufficient for the formation of hetero-oligomeric complexes SIGNOR-70863 0.648 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LCK protein P06239 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000567 8618896 t inferred from 70% family members lperfetto Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation. SIGNOR-270074 0.2 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation 10090 BTO:0001516 14981546 t These data confirm previous findings that FLT3 receptors with ITD mutations efficiently trigger the activation of ERK, STAT5 and Akt in the absence of FL stimulation. SIGNOR-261522 0.439 RRN3 protein Q9NYV6 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR up-regulates activity relocalization 9606 BTO:0000567 11250903 t lperfetto HRRN3 is essential in the SL1-mediated recruitment of RNA Polymerase I to rRNA gene promoters|We conclude that hRRN3 functions to recruit initiation-competent Pol I to rRNA gene promoters. The essential role for hRRN3 in linking Pol I to SL1 suggests a mechanism for growth control of Pol I transcription. SIGNOR-269647 0.654 vismodegib chemical CHEBI:66903 ChEBI SMO protein Q99835 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21041712 t gcesareni Cyclopamine with improved solubility (ipi-926), smo inhibitors that considerably differ in structure from cyclopamine (gdc-0499, lde225, bms-833923, xl-139, pf-0449913), inhibitors of the transformation of inactive smo into active smo (sant 74-75), and inhibitors of the transport of cytoplasmic inactive smo to cilia (sant 1-4) have been developed to date. SIGNOR-169194 0.8 NSL histone acetyltransferase complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys17 GLGKGGAkRHRKVLR 9606 20018852 t miannu Here we report an analysis of the subunit composition and substrate specificity of the NSL complex. Proteomic analyses of complexes purified through multiple candidate subunits reveal that NSL is composed of nine subunits. by comparing the substrate specificities of the MSL and NSL complexes, we obtain evidence that MOF HAT activity is differentially regulated by assembly into the MSL complex, where it acetylates nucleosomal histone H4 on lysine 16, and the NSL complex, where it also acetylates nucleosomal histone H4 on lysines 5 and 8. SIGNOR-267166 0.2 ULK1 protein O75385 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser472 THRRMVVsMPNLQDI 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264730 0.42 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT down-regulates binding 9606 9311920 t gcesareni Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,. SIGNOR-51104 0.77 ASIP protein P42127 UNIPROT MC1R protein Q01726 UNIPROT down-regulates activity binding 9606 BTO:0000847 14500544 t miannu The antagonist agouti signal protein (ASP) interacts with the Mc1r and blocks its stimulation by MSH. SIGNOR-252378 0.736 8-[4,4-bis(4-fluorophenyl)butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one chemical CHEBI:93369 ChEBI HTR1D protein P28221 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000529 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258539 0.8 PIK3CG protein P48736 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates chemical modification 9606 21779497 t gcesareni The activation of pi3k results in the generation of the second messenger, phosphatidylinositol 3,4,5-triphosphate (pip3) from phosphatidylinositol 4,5-bisphosphate (pip2). In vivo, class i pi3ks primarily generate phosphatidylinositol-3,4,5-trisphosphate (pip3) from phosphatidylinositol- 4,5-bisphosphate (pi-4,5-p2) SIGNOR-175244 0.8 STAT3 protein P40763 UNIPROT CD46 protein P15529 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17699108 f miannu The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. SIGNOR-255238 0.27 NAALAD2 protein Q9Y3Q0 UNIPROT Ac-Asp-Glu(3-) smallmolecule CHEBI:76931 ChEBI down-regulates quantity chemical modification 9606 10085079 t miannu The neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG)1 is expressed both in the central nervous system and in the periphery. Hydrolysis of the neuropeptide N-acetyl-L-aspartyl-L-glutamate (NAAG) by N-acetylated alpha-linked acidic dipeptidase (NAALADase) to release glutamate may be important in a number of neurodegenerative disorders in which excitotoxic mechanisms are implicated. SIGNOR-267541 0.8 HTR6 protein P50406 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257186 0.253 TBK1 protein Q9UHD2 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser473 RPHFPQFsYSASGTA 9606 21329883 t lperfetto Upon mitogen stimulation, triggering of the innate immune response, re-exposure to glucose, or oncogene activation, tbk1 is recruited to the exocyst, where it activates akt. Akt is a direct tbk1 substrate that connects tbk1 to prosurvival signaling. SIGNOR-172132 0.413 MECP2 protein P51608 UNIPROT OPRK1 protein P41145 UNIPROT up-regulates quantity by expression post transcriptional regulation 10090 BTO:0000614 18511691 t Luana MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1. SIGNOR-264677 0.275 PSMA7 protein O14818 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263365 0.824 asparagine smallmolecule CHEBI:22653 ChEBI Asn-tRNA(Asn) smallmolecule CHEBI:29265 ChEBI up-regulates quantity precursor of 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270460 0.8 FNTB protein P49356 UNIPROT KRAS protein P01116 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242556 0.425 CSNK2A2 protein P19784 UNIPROT UBE2R2 protein Q712K3 UNIPROT up-regulates activity phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t llicata UBC3B is specifically phosphorylated by CK2 in vitro and in vivo. We mapped by deletions and site directed mutagenesis the phosphorylation site to a serine residue within the C-terminal domain in position 233 of UBC3B and in the corresponding serine residue of UBC3. | Following CK2-dependent phosphorylation both UBC3B and UBC3 bind to the F-box protein beta-TrCP, the substrate recognition subunit of an SCF (Skp1, Cul1, F-box) ubiquitin ligase. Furthermore, we observed that co-transfection of CK2alpha' together with UBC3B, but not with UBC3DeltaC, enhances the degradation of beta-catenin. SIGNOR-251047 0.456 ARHGAP40 protein Q5TG30 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260496 0.416 TCF12 protein Q99081 UNIPROT MYOD/HEB complex SIGNOR-C128 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241119 0.665 seliciclib chemical CHEBI:45307 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206571 0.8 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176821 0.778 4,4'-sulfonyldiphenol chemical CHEBI:34372 ChEBI AHR protein P35869 UNIPROT up-regulates activity chemical activation -1 31995776 t miannu This study investigated the endocrine-disrupting activity of BPA, BPF, and BPS alone or as a mixture and the agonistic and antagonistic activity of the BPs using an in vitro bioassay to detect ER-, AR-, and AhR-mediated activity.In our study, BPs showed AhR agonist activity only at the highest concentrations, and the mixture did not differ from the single BPs. SIGNOR-268736 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR MTSS1 protein O43312 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 24318128 t miannu Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation.  SIGNOR-276610 0.321 PRTN3 protein P24158 UNIPROT Pr3-ANCA complex SIGNOR-C475 SIGNOR up-regulates activity binding 9606 BTO:0000133 15972951 t lperfetto ANCAs comprise a group of autoantibodies directed against proteins contained in the lysosomal compartments of neutrophils and monocytes. The primary target antigens have been identified as proteinase 3 (Pr3), a 29-kd neutral serine proteinase, and myeloperoxidase (MPO), a 140-kd protein involved in the generation of reactive oxygen species.2 To date, detection of ANCAs has proven to be a helpful diagnostic tool and many clinical studies have confirmed that Pr3-ANCA and MPO-ANCA are highly specific for Wegener's granulomatosis and microscopic polyangiitis, respectively SIGNOR-270581 0.2 KSR2 protein Q6VAB6 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273877 0.606 Oxytocin protein P01178-PRO_0000020495 UNIPROT GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates 9606 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268581 0.2 NR0B2 protein Q15466 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 17909097 f inferred from family member gcesareni As shown in fig. 3a, metformin (0.5 to 2 mmol/l) induced shp gene expression and repressed the camp/dex-induced expression of pepck and g6pase in a dose-dependent manner in h4iie cells SIGNOR-270256 0.2 RUNX2 protein Q13950 UNIPROT VEGFC protein P49767 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255081 0.2 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser2 sDNDDIEV 9606 8018564 t gcesareni Here, we have mapped the nh2-terminal in vivo phosphorylation sites of max to ser2 and ser11[...] SIGNOR-35772 0.365 REN protein P00797 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage 9606 16816138 t Angiotensinogen, an _-glycoprotein, is released from the liver (152, 250, 444) and is cleaved in the circulation by the enzyme renin that is secreted from the juxtaglomerular apparatus of the kidney (245, 250, 540, 631) to form the decapeptide angiotensin (ANG) I SIGNOR-252297 0.927 PRKDC protein P78527 UNIPROT XRCC4 protein Q13426 UNIPROT up-regulates activity phosphorylation Ser328 LETLRNSsPEDLFDE 9606 BTO:0002137 26774286 t miannu In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.  SIGNOR-277199 0.906 D-ribulose 5-phosphate smallmolecule CHEBI:17363 ChEBI D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu The reversible nonoxidative phase starts with Ru5P that is transformed into ribose-5-phosphate (R5P) by ribulose-5-phosphate isomerase. R5P is an essential component of purine and pyrimidine nucleotides biosynthesis. Ru5P may also be converted into xylulose-5-phosphate by ribulose-5-phosphate-3-epimerase, which was reported to enhance glycolytic flux. SIGNOR-267064 0.8 CD3G protein P09693 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates 9606 BTO:0000782 17668895 f gcesareni Tcr stimulation also activates the mitogen- and stress-activated kinases (msk) downstream of erk1/2. SIGNOR-157148 0.2 AR protein P10275 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 15861399 f miannu AR homodimers recruit a panoply of factors including coactivators and mediator proteins whose enzymatic activities promote chromatin remodeling and transcriptional regulation of target genes leading to cell differentiation, survival, and proliferation SIGNOR-251538 0.7 TUBD1 protein Q9UJT1 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-267177 0.7 Mob1 proteinfamily SIGNOR-PF42 SIGNOR LATS1 protein O95835 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-269958 0.2 WNT1 protein P04628 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t lperfetto Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth SIGNOR-129577 0.702 CSF1 protein P09603 UNIPROT CSF1R protein P07333 UNIPROT up-regulates activity binding 9606 BTO:0000876 BTO:0001103 24890514 t apalma The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34) SIGNOR-255568 0.937 RPS4Y2 protein Q8TD47 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262448 0.2 CUDC-907 chemical CID:54575456 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191209 0.8 CREB1 protein P16220 UNIPROT PCSK1 protein P29120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8999965 f miannu both CREB-1 and ATF-1 transactivate the human PC1 promoter in transient transfection experiments. SIGNOR-253789 0.2 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2V1 protein Q13404 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271355 0.451 CSNK2A1 protein P68400 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser118 EVVGGDDsDGLRAED 9606 23226345 t lperfetto More recently, we identified and mapped multiple phosphorylation sites in yy1, including, threonine 39, serine 118, serine 247, threonine 348 and threonine 378. The first kinase proven to phosphorylate yy1 in vivo was plk1, which phosphorylates threonine 39 during g2/m stage of the cell cycle [25]. Ck2_ is another kinase identified as constitutively phosphorylating yy1 at serine 118. This modification protects yy1 cleavage by caspase 7 during apoptosis SIGNOR-200083 0.289 PARP1 protein P09874 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002423 21489980 f miannu Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. SIGNOR-254892 0.2 PRKD2 protein Q9BZL6 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity phosphorylation Ser358 WPLSRTRsEPLPPSA 18692497 t Conserved Phosphorylated residue Ser259 and Ser498 refer to HDAC5 sequence. Phospho-residues in HDAC7 were derived by aligning HDAC5 and HDAC7 lperfetto Histone deacetylase (HDAC) 5 and 7, two members of the class II of classical HDAC [62], are in vivo substrates of PKD3 and PKD [63]. In response to a variety of signals, including phorbol esters, T cell receptor engagement, vascular endothelial growth factor and angiotensin stimulation, the activity of HDAC5 and 7 are regulated by a mechanism that involves PKD3 and PKD-mediated phosphorylation of the highly conserved Ser259 and Ser498 residues that are located in N-terminus of class II HDACs [63–67]. SIGNOR-275935 0.444 BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates phosphorylation 9606 18756288 t lperfetto Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1. SIGNOR-217029 0.573 STK3 protein Q13188 UNIPROT MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-175817 0.812 DNMT3A protein Q9Y6K1 UNIPROT CDKN2D protein P55273 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 26350239 f miannu Quantitative real-time PCR (qPCR) was used to investigate the effect of DNMT3A on p18INK4C expression, along with the other INK4 members, including p15INK4B, p16INK4A and p19INK4D. The results showed that the depletion of DNMT3A increased the transcriptional levels of the four members of the INK4 family SIGNOR-261510 0.2 SIRT1 protein Q96EB6 UNIPROT nicotinamide smallmolecule CHEBI:17154 ChEBI up-regulates quantity chemical modification 9606 18662546 t miannu The SIRT1 catalytic reaction involves the breakdown of one NAD+ molecule for each deacetylated acetyl lysine and the generation of nicotinamide and O-acetyl-ADP-ribose. SIGNOR-267964 0.8 FASN protein P49327 UNIPROT long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267208 0.8 KHK protein P50053 UNIPROT PRPS1 protein P60891 UNIPROT up-regulates activity phosphorylation Thr225 LVDDMADtCGTICHA 29074724 t lperfetto Ketohexokinase-A (KHK-A; also known as fructokinase-A) phosphorylates PRPS1 T225 and activates PRPS1 by blocking the binding of ADP, AMP, and GDP, which is required for hepatocellular carcinoma development SIGNOR-265735 0.352 RPS6KA1 protein Q15418 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15994958 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-138467 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276084 0.281 CHFR protein Q96EP1 UNIPROT SMARCD1 protein Q96GM5 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 t miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. SIGNOR-271459 0.31 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide chemical CHEBI:49868 ChEBI PLK1 protein P53350 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258078 0.8 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-34653 0.589 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-142153 0.2 TSC2 protein P49815 UNIPROT RHEB protein Q15382 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000142 15340059 t lperfetto Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb. SIGNOR-128432 0.921 SOHLH1 protein Q5JUK2 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0002181 22328502 t Luana Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression. SIGNOR-266205 0.352 SMAD2 protein Q15796 UNIPROT CREB1 protein P16220 UNIPROT up-regulates binding 9606 SIGNOR-C8 9689110 t gcesareni We demonstrate that human smad2 and smad4, two essential smad proteins involved in mediating tgf-beta transcriptional responses in endothelial and other cell types, can functionally interact with the transcriptional coactivator creb binding protein (cbp). This interaction is specific in that it requires ligand (tgf-beta) activation and is mediated by the transcriptional activation domains of the smad proteins. SIGNOR-59462 0.33 UBE2S protein Q16763 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000567 19822757 t lperfetto Here, we identify the highly conserved Ube2S as a regulator of human and Drosophila APC/C. Ube2S functions as a K11-specific chain elongating E2 of APC/C, which depends on chain initiation by UbcH10. Together, UbcH10 and Ube2S are required for the degradation of all APC/C substrates tested so far, spindle formation, and progression of cells through mitosis. SIGNOR-265080 0.661 FBXW11 protein Q9UKB1 UNIPROT CHUK protein O15111 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 10321728 t miannu We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.  SIGNOR-272545 0.425 PRKDC protein P78527 UNIPROT USF1 protein P22415 UNIPROT up-regulates phosphorylation 9606 19303849 t miannu Feeding induces the recruitment of dna-pk to usf-1 and its phosphorylation, which then allows recruitment of p/caf, resulting in usf-1 acetylation and fas promoter activation. SIGNOR-184849 0.295 NRAS protein P01111 UNIPROT BRAF protein P15056 UNIPROT up-regulates activity binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175219 0.851 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr534 SRTPSLPtPPTREPK 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-251595 0.699 PRPS1 protein P60891 UNIPROT Nucleotide_synthesis phenotype SIGNOR-PH179 SIGNOR up-regulates 9606 BTO:0006038 29074724 f lperfetto We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. SIGNOR-265733 0.7 TAF1B protein Q53T94 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 t lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. SIGNOR-269565 0.841 CBL protein P22681 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 20332299 t lperfetto Ligand binding to EGFR also leads to rapid internalization and proteosomal/lysosomal degradation of the receptors. This process results in a dramatic downregulation of both total and cell surface receptors. EGF-induced degradation of EGFR is thought to be initiated by phosphorylation of tyrosine 1045 of the receptor followed by binding of Cbl adaptor proteins and ubiquitination of the receptor. Internalized EGFR is transported to early endosomes where receptor-ligand complexes are sorted for either degradation or recycling to the cell surface. SIGNOR-65642 0.884 MGLL protein Q99685 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26997225 f irozzo Overexpression of MGLL inhibits proliferation and delays cell cycle progression in QGY-7703 cells. Forced overexpression of MGLL in human HCC cells resulted in marked inhibition in cell proliferation with a significant delay in cell cycle progression [.] SIGNOR-259139 0.7 HNF4A protein P41235 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni Pgc1alfa is thought to mediate transcription downstream of the nuclear receptor hepatocyte nuclear factor 4alfa (hnf4alfa) and the transcription factor foxo1 in the promoters of key gluconeogenic enzymes, including glucose-6-phosphatase (g6pase) and phosphoenolpyruvate carboxylase (pepck) SIGNOR-142204 0.354 JAK2 protein O60674 UNIPROT GTF2I protein P78347 UNIPROT up-regulates activity phosphorylation Tyr248 EESEDPDyYQYNIQA 10090 BTO:0000944 11313464 t lperfetto Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248 SIGNOR-235313 0.331 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 21440011 t lperfetto Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation.The PI3K/Akt signaling regulates cell proliferation and survival in part by phosphorylating FoxOs to promote their interaction with 14-3-3 protein that results in nuclear exclusion and eventual ubiquitin proteasome pathway (UPP)-dependent degradation of FoxOs SIGNOR-252858 0.909 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44866 0.657 GSK3B protein P49841 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser133 LPYSPVSsPQSSPRL 9606 22778263 t lperfetto Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity. SIGNOR-198138 0.274 TNF protein P01375 UNIPROT REL protein Q04864 UNIPROT up-regulates 9606 BTO:0000782 10823840 f miannu C-rel emerges as the main nf-kb family member stimulated by tnf_ in the context of physiologic activation of resting t cells. SIGNOR-77547 0.42 SENP1 protein Q9P0U3 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates activity desumoylation 9606 BTO:0000007 21791615 t miannu We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. SIGNOR-262681 0.476 CPSF complex complex SIGNOR-C53 SIGNOR PAPOLB protein Q9NRJ5 UNIPROT up-regulates activity relocalization 9606 14749727 t lperfetto Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-268324 0.559 FHIT protein P49789 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159870 0.272 POLR2K protein P53803 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266168 0.827 GABRA4 protein P48169 UNIPROT GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263748 0.512 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Ser295 LSDTPYDsSASYEKE 9606 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo SIGNOR-174848 0.2 LMO2 protein P25791 UNIPROT ERG protein P11308 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001106 21536859 f miannu We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. SIGNOR-253922 0.387 FZD2 protein Q14332 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258962 0.632 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr157 GIRKRPAtDDSSTQN 9606 18570873 t gcesareni Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna. SIGNOR-179117 0.477 CALM2 protein P0DP24 UNIPROT KIF1A protein Q12756 UNIPROT up-regulates activity binding 10116 BTO:0003102 30021165 t miannu To better understand how KIF1A-driven dense core vesicle (DCV) transport is regulated, we identified the KIF1A interactome and focused on three binding partners, the calcium binding protein calmodulin (CaM) and two synaptic scaffolding proteins: liprin-α and TANC2. We showed that calcium, acting via CaM, enhances KIF1A binding to DCVs and increases vesicle motility. In contrast, liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines SIGNOR-266889 0.262 F2RL2 protein O00254 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257360 0.398 SRC protein P12931 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates phosphorylation 9606 24841372 t inferred from family member lperfetto The present finding suggested that the tyrosine residue at position 44 in chicken alpha-enolase is the phosphorylation site by the tyrosine kinase. Our data suggest that eno1 was upregulated by caga protein through activating the src and mek/erk signal pathways SIGNOR-270248 0.417 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15677482 t gcesareni Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of enac. Sgk1 catalyzed phosphorylation of hnedd4-2 at ser-468 maintaining hnedd4-2 in an inactive phosphorylated state. SIGNOR-133438 0.783 BMPR1A protein P36894 UNIPROT FAM83G protein A6ND36 UNIPROT up-regulates activity phosphorylation Ser614 RRPSVASsVSEEYFE -1 24554596 t lperfetto These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. SIGNOR-264766 0.38 AKT1 protein P31749 UNIPROT FAS protein P25445 UNIPROT down-regulates 9606 15004527 f gcesareni Akt may serve to stimulate certain proteins (e.g., Ikk) involved in the prevention of apoptosis such as nf-kb as well as repress other proteins normally involved in the induction of apoptosis such as the forkhead transcription factors (fkhr, now know as foxo3), creb, glycogen synthetase-3 kinase-beta (gsk-3beta), fas, caspase-9 and cell cycle inhibitors such as p27 SIGNOR-252473 0.391 CDK1 protein P06493 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 SIGNOR-C17 17389604 t gcesareni Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 SIGNOR-154047 0.255 PRKD2 protein Q9BZL6 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates phosphorylation Ser294 SNLKRTAsNPKVENE 9606 16912074 t The effect has been demonstrated using Q9UBF8-2 gcesareni Binding of 14-3-3 proteins to pi4kiiibeta involved the pkd phosphorylation site ser294, evident from reduced 14-3-3 binding to a s294a pi4kiiibeta mutant. Phospho-specific binding of 14-3-3 proteins to phosphatidylinositol 4-kinase iii beta protects from dephosphorylation and stabilizes lipid kinase activity. SIGNOR-148880 0.2 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1197 KAYSPRYsISDRTSI 9534 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-235929 0.707 FOXQ1 protein Q9C009 UNIPROT MYLK protein Q15746 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 10896677 t Luana Results from this analysis revealed that the inhibitory activity of HFH-1 was contained within the forkhead DNA-binding domain. Truncated HFH-1 proteins that lack the entire forkhead domain were unable to repress telokin promoter activity, in contrast expression of the forkhead domain alone was able to repress promoter activity SIGNOR-261609 0.2 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT down-regulates activity phosphorylation Tyr570 VRREVGDyGQLHETE 9606 21841788 t lperfetto The jak2 jh2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of jak2 remains unknown. Here we show that jh2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in jak2: ser523 and tyr570. SIGNOR-176058 0.2 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1738 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248744 0.731 PABPC4 protein Q13310 UNIPROT NFX1 protein Q12986 UNIPROT up-regulates activity binding 9606 BTO:0000008 17267499 t Simone We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123. SIGNOR-261051 0.247 CDK9 protein P50750 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Thr217 PSEYQNMtVDILCND 9606 23603988 t lperfetto We showed that cdk9 phosphorylates pirh2 on ser-211 and thr-217 residues through their physical interaction. Phosphorylation of pirh2 renders it inactive and may contribute to p53-inhibition of transcriptional elongation of the hiv-1 ltr. SIGNOR-201927 0.468 KDM6A protein O15550 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 24561908 t This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. SIGNOR-265360 0.2 histidine smallmolecule CHEBI:27570 ChEBI His-tRNA(His) smallmolecule CHEBI:29155 ChEBI up-regulates quantity precursor of 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270492 0.8 ERMP1 protein Q7Z2K6 UNIPROT UPR phenotype SIGNOR-PH131 SIGNOR up-regulates activity 9606 BTO:0000093 27566589 f Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. SIGNOR-261295 0.7 CDK1 protein P06493 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates activity phosphorylation 9606 12202491 t lperfetto Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. SIGNOR-264648 0.564 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118031 0.711 PRKDC protein P78527 UNIPROT PNPT1 protein Q8TCS8 UNIPROT up-regulates activity phosphorylation Ser776 IVMGEPIsQSSSNSQ 9606 22815474 t miannu We also demonstrated that DNAPK phosphorylates PNPase at Ser-776, which is critical for its ribonuclease activity. SIGNOR-263182 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR PRPH protein P41219 UNIPROT up-regulates activity phosphorylation Ser59 SSSVRLGsFRSPRAG 9606 BTO:0000007 17569669 t miannu Here we demonstrate that peripherin, which is a peripheral nervous system neuron-specific intermediate filament protein, is a novel Akt substrate, and that Ser66 of peripherin is the phosphorylation site. Peripherin phosphorylation is apparently induced in motor neurons after nerve injury, suggesting that the Akt-mediated peripherin phosphorylation may play a role in motor nerve regeneration. SIGNOR-262627 0.2 HRAS protein P01112 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t lperfetto The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175183 0.834 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CASP8 protein Q14790 UNIPROT down-regulates phosphorylation Ser387 YLEMDLSsPQTRYIP 9606 BTO:0000149 24342355 t lperfetto We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity SIGNOR-244509 0.2 glycerone phosphate(2-) smallmolecule CHEBI:57642 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 16051738 t miannu Triosephosphate isomerase (TPI) is the glycolytic enzyme with the highest activity in vitro. TPI catalyzes the interconversion of glyceraldehyde-3-phosphate and DHAP (Figure 1). It consists of a dimer with 2 identical subunits of 248 amino acids (27 kDa). SIGNOR-268136 0.8 IRX1 protein P78414 UNIPROT SPON1 protein Q9HCB6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261669 0.2 EIF5B protein O60841 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR down-regulates activity binding 9606 30211544 t lperfetto eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC. SIGNOR-269120 0.667 CSNK2A1 protein P68400 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser10 LNRTLSMsSLPGLED -1 2117608 t llicata With all four peptides, prior phosphorylation significantly stimulated phosphorylation by casein kinase I. From these results, we propose that there are substrates for casein kinase I for which prior phosphorylation is a critical determinant of protein kinase action. | From analysis of 32P release during Edman degradation, no radioactively labeled phosphate was associated with Thr3 or Ser7, but could be accounted for by phosphorylation at Ser10 SIGNOR-250878 0.332 TFIID complex SIGNOR-C343 SIGNOR GTF2B protein Q00403 UNIPROT up-regulates activity relocalization 9606 8990153 t lperfetto Early in PIC assembly, TFIIA can associate with and stabilize the TFIID–DNA or the TFIIB–TFIID–DNA complexes, allowing them to ward off the deleterious effects of inhibitory negative cofactors and enhance the stimulatory effects of transcriptional activators SIGNOR-269308 0.644 DLGAP1 protein O14490 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264586 0.853 IGF1R protein P08069 UNIPROT PIK3C2A protein O00443 UNIPROT up-regulates phosphorylation 9606 7692086 t gcesareni Analysis of the ability of the full-length igfr and its mutant receptors described above to associate with phosphatidylinositol 3 kinase indicated that the association required ptk activity and tyrosine [?] Phosphorylation of the receptors and correlated well with their transforming activities SIGNOR-32076 0.277 FAF1 protein Q9UNN5 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates activity binding 9606 BTO:0002181 30472208 t miannu We find that the scaffold protein FAF1 forms aggregates that negatively regulate MAVS.FAF1 antagonizes the poly-ubiquitination and aggregation of MAVS by competing with TRIM31 for MAVS association. SIGNOR-277619 0.2 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000782 10702316 t lperfetto We report here the identification of a FRAP autophosphorylation site. This site, Ser-2481, is located in a hydrophobic region near the conserved carboxyl-terminal FRAP tail. We demonstrate that the COOH-terminal tail is required for FRAP kinase activity and for signaling to the translational regulator p70(s6k) (ribosomal subunit S6 kinase). SIGNOR-217000 0.68 tandutinib chemical CHEBI:90237 ChEBI KIT protein P10721 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207212 0.8 PRKACA protein P17612 UNIPROT CACNA1H protein O95180 UNIPROT down-regulates activity phosphorylation Ser1107 LPDSRRGsSSSGDPP 9606 19131331 t miannu Here, we identify protein kinase A (PKA) as a molecular switch that allows Gbeta(2)gammax dimers to effect voltage-independent inhibition of Ca(v)3.2 channels. Inhibition requires phosphorylation of Ser(1107), a critical serine residue on the II-III loop of the channel pore protein. S1107A prevents inhibition of unitary currents by recombinant Gbeta(2)gamma(2) dimers but does not disrupt dimer binding nor change its specificity. SIGNOR-263110 0.2 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser100 DEDSGKGsQPPSPPS 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129398 0.568 EDNRB protein P24530 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256924 0.269 PRKDC protein P78527 UNIPROT TOP1 protein P11387 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 GDHLHNDsQIEADFR 9606 BTO:0002201 28415827 t miannu Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.  SIGNOR-277352 0.455 SRC protein P12931 UNIPROT RPS6KA3 protein P51812 UNIPROT unknown phosphorylation Tyr488 DVYDDGKyVYVVTEL 9606 BTO:0000007 18156174 t llicata The results showed that tyr-488 is a major site of src but mutations at tyr-529 or tyr-707 did not significantly decrease src-dependent tyrosine phosphorylation of rsk2 (fig. 4c). However, we have previously characterized the tyr-488 site that is also phosphorylated by fgfr3 (14), and substitution of tyr-488 did not affect rsk2 activation. SIGNOR-160056 0.36 ERBB3 protein P21860 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 16729043 t gcesareni Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4. SIGNOR-252673 0.713 EMSY protein Q7Z589 UNIPROT CBX1 protein P83916 UNIPROT up-regulates activity binding 9606 BTO:0000567 14651845 t miannu The binding sites for HP1β and BS69 with EMSY abut each other, and are found directly adjacent to the ENT domain of EMSY. This demonstrates that EMSY has the capacity to contact directly at least two proteins which contain a Royal Family domain. Since this domain is found in proteins with a chromatin connection, we assume that EMSY functions, at least partly, in the regulation of chromatin. SIGNOR-263917 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SIRT3 protein Q9NTG7 UNIPROT up-regulates activity phosphorylation Ser159 SGIPDFRsPGSGLYS 9606 BTO:0001109 26141949 t miannu  Posttranscriptionally, SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by cyclin B1-CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3.  SIGNOR-276921 0.293 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-267525 0.8 RPL13 protein P26373 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262486 0.788 SMO protein Q99835 UNIPROT MAL protein P21145 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 f Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. SIGNOR-269224 0.2 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT up-regulates activity phosphorylation Ser49 HKAELQGsDEDEHVR -1 9461343 t llicata Here, we report that Myf-5 protein constitutes a substrate for phosphorylation in vitro by protein kinase CK2. We identified two potential phosphorylation sites at serine49 and serine133, both of which seem to be necessary for Myf-5 activity.  SIGNOR-251017 0.309 RBM10 protein P98175 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0001938 30403180 f irozzo Osteosarcoma is the most common malignant bone tumor with high incidence in adolescence and poor prognosis. RBM10, a member of RBPs, was reported to be a tumor suppressor in many kinds of cancers. The results showed that U2OS cell growth was significantly inhibited when RBM10 is overexpressed as compared with negative control cells. SIGNOR-259149 0.7 PPARGC1A protein Q9UBK2 UNIPROT Gluconeogenesis phenotype SIGNOR-PH35 SIGNOR up-regulates 9606 20640476 f Gianni However, in contrast to the role of AMPK, most reports to date indicate that PGC-1a induces gluconeogenesis SIGNOR-209932 0.7 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser380 ATLARRDsLQKPGLE 9606 21822051 t lperfetto In the present study, aurora a was demonstrated to phosphorylate lats2 on serine 380 (s380) during mitosistogether, the results suggest that the aurora a-lats1/2-aurora b axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of lats2. SIGNOR-175939 0.385 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 9606 15379552 t lperfetto Erk phosphorylation enhances hgf-dependent gab1/pi3k but inhibits egf-dependent gab1/pi3k association and activation implicates that mapk activation provides another specific regulatory mechanism which can result in divergent effects for distinct rtks.we identified four serine and two threonine residues that are phosphorylated by erk in vitro. Five of these phosphorylation sites (t312, s454, t476, s581, s597) SIGNOR-129200 0.2 mTORC1 complex SIGNOR-C3 SIGNOR TFEB protein P19484 UNIPROT down-regulates activity phosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 22343943 t Here, we have used an mTORC1 in-vitro kinase assay and a phosphoantibody to demonstrate that serine S142, which we previously found to be phosphorylated by ERK2, is also phosphorylated by mTOR and that this phosphorylation has a crucial role in controlling TFEB subcellular localization and activity. SIGNOR-255309 0.368 LRFN5 protein Q96NI6 UNIPROT PTPRD protein P23468 UNIPROT up-regulates activity binding 9606 BTO:0000938 27225731 t miannu SALM5 trans-synaptically interacts with LAR-RPTPs in a splicing-dependent manner to regulate synapse development. we identified LAR-RPTPs as novel ligands of SALM5 that mediates SALM5-dependent presynaptic differentiation in a splicing-dependent manner. Our data indicate that SALM5 interacts with all three known LAR-RPTPs—LAR, PTPδ, and PTPσ (Fig. 1). SIGNOR-264086 0.279 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr594 TYVDPHTyEDPNQAV -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246039 0.652 NFYA protein P23511 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 f miannu Our results further confirm the important transactivating role for NF-Y for the CBS-1b promoter, via its synergism with Sp1. While differential phosphorylation of Sp1 likely contributes to binding to multiple GC-/GT-boxes in the CBS-1b and promoter activation [16], NF-Y is clearly necessary for a maximal activation response. SIGNOR-254815 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1951 SPGYSPTsPTYSLTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269372 0.721 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage -1 10978167 t lperfetto Thrombin selectively cleaves PAR1, PAR3, and PAR4 to induce activation of platelets and vascular cells, SIGNOR-263608 0.885 BMS-554417 chemical CID:54754526 PUBCHEM IGF1R protein P08069 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190455 0.8 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser405 QARAHGLsLIPSTGL 9606 BTO:0005451 25605940 t miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. SIGNOR-276477 0.442 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1917 SPTSPTYsPTSPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203592 0.773 BLOC-1 complex SIGNOR-C381 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f lperfetto BLOC-1, a novel complex containing the pallidin and muted proteins involved in the biogenesis of melanosomes and platelet-dense granules|Interestingly, immunofluorescence and in vitro binding experiments demonstrated that pallidin/BLOC-1 is able to associate with actin filaments. We propose that BLOC-1 mediates the biogenesis of lysosome-related organelles by a mechanism that may involve self-assembly and interaction with the actin cytoskeleton. SIGNOR-265940 0.7 MICU1 protein Q9BPX6 UNIPROT MCU_MICU2_variant complex SIGNOR-C502 SIGNOR form complex binding 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270876 0.684 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT up-regulates activity phosphorylation Tyr99 RGRYRSPySGPKFNS 9606 BTO:0000007 27018250 t miannu In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. SIGNOR-262610 0.326 ATF6 protein P18850 UNIPROT NUCB1 protein Q02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17686766 f miannu we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6. SIGNOR-253753 0.358 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser100 QPQDKVIsGIAREKL 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262713 0.738 IL1A protein P01583 UNIPROT SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254807 0.2 PRKCA protein P17252 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Ser139 EEWTRHGsFVNKPTR 10090 12052829 t lperfetto Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms. SIGNOR-249150 0.407 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169522 0.527 MAPK1 protein P28482 UNIPROT THRB protein P10828 UNIPROT down-regulates activity phosphorylation Ser142 IQKNLHPsYSCKYEG 9606 12809513 t llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-102216 0.398 SCN1A protein P35498 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 27262167 t miannu Voltage-gated Na1 channels (NaV channels) drive the rapid upstroke of action potentials in cardiac and skeletal muscle and in most neurons, thereby serving as initiators of electrical activity in excitable tissue. Nine genes encode a family of homologous of NaV channel pore-forming a subunits. While channels are open, Na1 ions flux through the central pore down an electrochemical gradient, further depolarizing the membrane and triggering an action potential. SIGNOR-253402 0.8 CEBPA protein P49715 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 17139329 f fferrentino C/EBPα induces many adipocyte genes directly, and in vivo studies indicate an important role for this factor in the development of adipose tissue. SIGNOR-132946 0.7 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. Runx1 is also upregulated in the NUP98‐HOXA9 transcriptosome and is a critical regulator of hematopoietic development and a frequent target for chromosomal translocation in leukemia SIGNOR-261499 0.2 PPP1CA protein P62136 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity dephosphorylation Ser311 PYHSREQsTDSGLGL 9606 21189257 t miannu PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. SIGNOR-277115 0.532 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270404 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates activity phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni Evidence that the inhibition of glycogen synthase kinase-3_ by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 SIGNOR-242578 0.2 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr647 RDVHNLDyYKKTTNG 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3 the two tyrosine residues in the YYKK Motif of the activation loop of fgfrs are required for kinase activity of fgfr1 and fgfr3. SIGNOR-106730 0.2 TAB1 protein Q15750 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205440 0.824 P2RY4 protein P51582 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256870 0.368 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR DBP protein Q10586 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 30100984 t miannu The albumin D-box binding protein (DBP) is a member of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family and functions as important regulator of circadian core and output gene expression. Gene expression of DBP itself is under the control of E-box-dependent binding by the Bmal1-Clock heterodimer and CRE-dependent binding by the cAMP responsive element binding protein (CREB). SIGNOR-268029 0.705 CRY1 protein Q16526 UNIPROT BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267971 0.893 MTNR1B protein P49286 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256707 0.457 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263607 0.379 SCHEMBL14517914 chemical CID:10016910 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Xl844 (exelixis) a potent atp-competitive inhibitor of chk1 (ki, 2.2nm) and chk2 (ki, 0.07nm). SIGNOR-163231 0.8 APC-c complex SIGNOR-C150 SIGNOR IRS2 protein Q9Y4H2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 32554797 t miannu We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1 Consistent with the APC/C's role in degrading cell cycle regulators. Consistent with this observation, we found that APC/C inhibition decreased the polyubiquitylation of HA-tagged IRS2 in HeLa cells treated with MG132 (Fig. 2G). SIGNOR-272196 0.2 Elongator complex complex SIGNOR-C466 SIGNOR TUBA4A protein P68366 UNIPROT up-regulates activity acetylation 9606 BTO:0000007 19185337 t miannu Elongator Subunits Interact with the Microtubules and Are Required for Proper Acetylation of α-Tubulin. SIGNOR-269722 0.253 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates activity phosphorylation Ser397 SMVGGERsPPRILPP 9606 BTO:0000007 21059642 t The effect has been demonstrated using Q01196-8 gcesareni Phosphorylation of runx1 on ser-303 by cdks leads its ubiquitin-mediated degradation during g2/m (19). We developed additional evidence that cdks phosphorylate ser-303 and found that ser-48 and ser-424 are also substrates of cdk1/cyclin b and cdk6/cyclin d3. Moreover, we demonstrated that phosphorylation of ser-48, ser-303, and ser-424 strengthens the ability of runx1 to activate transcription and to stimulate proliferation of the ba/f3 hematopoietic cell line (20). SIGNOR-273030 0.569 IL23R protein Q5VWK5 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12. SIGNOR-87808 0.694 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp SIGNOR-148592 0.2 EGFR protein P00533 UNIPROT CALM1 protein P0DP23 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 7925415 t lperfetto Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-34691 0.41 BCORL1 protein Q5H9F3 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates activity binding 9606 BTO:0000567 17379597 t irozzo BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor. SIGNOR-259112 0.434 GRK2 protein P25098 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1278 EPGFREVsFYYSEEN -1 22509025 t miannu GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation SIGNOR-276413 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 t gcesareni The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. SIGNOR-148675 0.2 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr397 SVSETDDyAEIIDEE 9606 16782899 t llicata Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain SIGNOR-147183 0.484 NOD1 protein Q9Y239 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 BTO:0000567 19898471 f miannu Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. SIGNOR-252404 0.7 JAG1 protein P78504 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 7227 18660822 t Binding Ca-dependent lperfetto We identify functional fragments of human notch-1 (n-1) and jagged-1 (j-1) which interact in a calcium-dependent manner. SIGNOR-219253 0.632 ELAVL2 protein Q12926 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266863 0.2 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 9606 20802513 t gcesareni In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain (band 4.1 and ezrin/radixin/moesin homology domain). SIGNOR-167654 0.484 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 9606 BTO:0003736 6777394 t inferred from family member miannu The high levels of circulating D-T4 and presumably of circulating D-T3 originating from the peripheral conversion of D-T4 achieved after the chronic administration of D-T4 (Choloxin) may be responsible for a high degree of saturation of the human pituitary nuclear T3 receptors, thus resulting in the suppression of the TRH-induced TSH response. SIGNOR-270294 0.8 MAPK9 protein P45984 UNIPROT MFN2 protein O95140 UNIPROT down-regulates phosphorylation Ser27 HMAEVNAsPLKHFVT 9606 22748923 t lperfetto Jnk phosphorylation of mitofusin 2 in response to cellular stress leads to recruitment of the ubiquitin ligase (e3) huwe1/mule/arf-bp1/hecth9/e3histone/lasu1 to mitofusin 2, with the bh3 domain of huwe1 implicated in this interaction. This results in ubiquitin-mediated proteasomal degradation of mitofusin 2these data establish that mfn2 is phosphorylated on ser27 in response to a variety of cellular stresses and implicate jnk in this process SIGNOR-198054 0.355 KIF2B protein Q8N4N8 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 22535524 f lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. SIGNOR-252051 0.7 LAMC2 protein Q13753 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR form complex binding 9211848 t lperfetto Like the other laminins (3), Ln-5 comprises three disul- fide-bonded subunits: a3, b3, and g2. SIGNOR-253237 0.574 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 10090 BTO:0000944 12150915 t lperfetto We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. SIGNOR-235511 0.813 PCDH19 protein Q8TAB3 UNIPROT GABRA1 protein P14867 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C330 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267217 0.369 SKP1 protein P63208 UNIPROT SCF-FBW7 complex SIGNOR-C135 SIGNOR form complex binding 9606 15340381 t gcesareni The F-box family of proteins €” which are the substrate-recognition components of the Skp1€“Cul1€“F-box-protein (SCF) ubiquitin ligase €” are important players in many mammalian functions. SIGNOR-243760 0.936 BRMS1 protein Q9HCU9 UNIPROT KDM1A protein O60341 UNIPROT up-regulates activity binding 9606 BTO:0000093 30416854 t miannu Our results have showed that BRMS1 together with LSD1 are required for inhibition of breast cancer cell migration and invasion. Collectively, these findings demonstrate that BRMS1 executes transcriptional suppression of breast cancer metastasis by associating with the LSD1 and thus can be targeted for breast cancer therapy. SIGNOR-266409 0.259 TARDBP protein Q13148 UNIPROT GSK3B protein P49841 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 BTO:0004170 PMC7642658 t lperfetto Importantly, we found that TDP-43 protein could interact with GSK3β mRNA and regulate the level of GSK3β protein translation. Taken together, our findings suggest that TDP-43 may activate the Wnt/β-catenin pathway by targeting the inhibition of GSK3β protein translation|TDP-43 activates Wnt/β-catenin pathway probably by inhibiting the GSK3β protein translation. A. Interaction between TDP-43 protein and GSK3β mRNA was analyzed using RIP assay. SIGNOR-262113 0.269 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 22936936 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-198747 0.682 NOTCH1 protein P46531 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000938 16554461 f gcesareni Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes. SIGNOR-145322 0.505 RIPK1 protein Q13546 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 BTO:0000007;BTO:0000661 16603398 t lperfetto Taken together, these results indicate that polyubiquitination of RIP1 mediates the independent re- cruitment of TAB2 and NEMO, which in turn recruits TAK1 and IKK, respectively, to TNF-R1. SIGNOR-145861 0.86 IL1RL1 protein Q01638 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 35238669 t miannu The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes SIGNOR-277716 0.2 ADORA1 protein P30542 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256840 0.446 NRAS protein P01111 UNIPROT ARAF protein P10398 UNIPROT up-regulates binding 9606 21779497 t gcesareni The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases. SIGNOR-175216 0.831 PRKG1 protein Q13976 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates activity phosphorylation Ser101 RRRRGAIsAEVYTEE 9606 BTO:0002181 29378851 t miannu  In this study, we further examined the potential of RIα phosphorylation to regulate physiologically relevant "desensitization" of PKAc activity. First, the serine 101 site of RIα was validated as a target of PKGIα phosphorylation both in vitro and in cells.These findings suggest that RIα phosphorylation may be a novel mechanism to circumvent the requirement of cAMP stimulus to activate type I PKA in cells. SIGNOR-277383 0.235 TRIM27 protein P14373 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 BTO:0000671 12807881 f miannu Rfp expression in hek 293 cells activated jnk1 SIGNOR-102034 0.259 CDK5 protein Q00535 UNIPROT APEX1 protein P27695 UNIPROT up-regulates activity phosphorylation Thr233 NKKNAGFtPQERQGF 9606 21727086 t miannu Apurinic/apyrimidinic endonuclease-1 (APE1) is a multifunctional DNA repair/gene regulatory protein in mammalian cells, and was recently reported to be phosphorylated at Thr233 by CDK5. SIGNOR-276337 0.383 INSR protein P06213 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity phosphorylation Tyr576 RYMEDSTyYKASKGK -1 9507031 t P125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor. p125(Fak) phosphorylation by the receptor results in its activation. SIGNOR-251323 0.357 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT down-regulates activity dephosphorylation Ser671 RKRSTRRsVRGSQAQ 9606 BTO:0000007 24333728 t Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function|P-gp is known to be phosphorylated at Ser667, Ser671, and Ser683 by PKA; at Ser661, Ser667, and Ser671 by PKC; and at Ser683 by Pim-1|simultaneous expression of PP5 and PPP2R3C reduced the phosphorylation detected by the antibodies that specifically recognize serine/threonine phosphorylated by PKA or serine phosphorylated by PKC. These results suggest that the PP5/PPP2R3C complex dephosphorylates PKA- and PKC-phosphorylated serine residues on P-gp SIGNOR-272507 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 t lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva SIGNOR-244214 0.2 ROCK1 protein Q13464 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Ser229 VKIYSSNsGPTRRED 9606 BTO:0000672 15793569 t llicata In addition, active rhoa is able to stimulate the phospholipid phosphatase activity of pten in human embryonic kidney cells and leukocytes, and this regulation seems to require rhoa's downstream effector, rhoa-associated kinase (rock). together with the observation that individual substitution of ser 229 and thr 223 restored some of the rescuing ability (fig. 4b), we conclude that effective regulation of pten by sdf-1 may require more than one of these residues. SIGNOR-134851 0.649 GTF2F1 protein P35269 UNIPROT GTF2F1 protein P35269 UNIPROT down-regulates phosphorylation Ser385 GGSSRGNsRPGTPSA 9606 10428810 t gcesareni We show that tfiifalpha possesses a serine/threonine kinase activity, allowing an autophosphorylation of the two residues at position serine 385 and threonine 389. Mutation analysis strongly suggests that autophosphorylation of both sites regulates the transcription elongation process. SIGNOR-69767 0.2 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni Receptor internalization, altered;intracellular localization SIGNOR-97554 0.558 SAGA complex complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269635 0.2 TSC22D1 protein Q15714 UNIPROT NPPC protein P23582 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 9022669 t Luana TSC-22 significantly enhanced CNP promoter activity in GH3 cells. SIGNOR-266226 0.259 BUB1B protein O60566 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR up-regulates 9606 20888775 f gcesareni The multidomain protein kinases bub1 and bubr1 (mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (sac) SIGNOR-168195 0.7 NME1 protein P15531 UNIPROT SMO protein Q99835 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255168 0.2 ZWINT protein O95229 UNIPROT RZZ complex complex SIGNOR-C357 SIGNOR form complex binding 9606 BTO:0000567 20462495 t lperfetto The RZZ complex recruits dynein to kinetochores. We investigated structure, topology, and interactions of the RZZ subunits (ROD, ZWILCH, and ZW10) in vitro, in vivo, and in silico. SIGNOR-265013 0.645 EIF2B1 protein Q14232 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269134 0.686 PKA proteinfamily SIGNOR-PF17 SIGNOR TENT2 protein Q6PIY7 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 31057087 t inferred from 70% family members miannu We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition. SIGNOR-270130 0.2 VCP protein P55072 UNIPROT AURKA protein O14965 UNIPROT down-regulates activity binding 6239 23649807 t lperfetto The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts SIGNOR-265044 0.317 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 15864272 t gcesareni The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2 SIGNOR-135955 0.707 APOE protein P02649 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni Several ligands for the vldl receptor have been identified in addition to tfpi. These include apolipoprotein e (apoe) SIGNOR-106221 0.635 PRKD1 protein Q15139 UNIPROT RIN1 protein Q13671 UNIPROT unknown phosphorylation Ser351 RPLLRSMsAAFCSLL 9606 11784866 t llicata Serine 351 is a substrate for protein kinase d (pkd [also known as pkcmu]) in vitro and in vivo. These data suggest that the normal localization and function of rin1, as well as its ability to compete with raf, are regulated in part by 14-3-3 binding, which in turn is controlled by pkd phosphorylation. SIGNOR-113964 0.409 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Ser974 EESLAEMsIMTTELQ 9606 18055457 t lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta SIGNOR-159574 0.273 PTEN protein P60484 UNIPROT CFL1 protein P23528 UNIPROT up-regulates activity dephosphorylation 9606 22317922 t lperfetto Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN. SIGNOR-276980 0.449 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t miannu In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus. SIGNOR-256188 0.2 AURKB protein Q96GD4 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-98297 0.2 PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex II complex SIGNOR-C241 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260320 0.893 FGF13 protein Q92913 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253443 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 10464286 t gcesareni Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun. SIGNOR-265345 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1910 TPTSPKYsPTSPTYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273106 0.749 AKAP12 protein Q02952 UNIPROT PKC proteinfamily SIGNOR-PF53 SIGNOR up-regulates activity relocalization 14657015 t lperfetto A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. SIGNOR-271838 0.467 propionyl-CoA(4-) smallmolecule CHEBI:57392 ChEBI (S)-methylmalonyl-CoA(5-) smallmolecule CHEBI:57327 ChEBI up-regulates quantity precursor of 9606 15890657 t miannu Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC consists of two heterologous subunits, alpha PCC and beta PCC, which are encoded by the nuclear PCCA and PCCB genes, respectively. SIGNOR-267185 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271339 0.591 PAK2 protein Q13177 UNIPROT SORT1 protein Q99523 UNIPROT down-regulates activity phosphorylation Ser793 RFLVHRYsVLQQHAE 9606 BTO:0000007 31767632 t miannu PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction. SIGNOR-273717 0.2 MTOR protein P42345 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates activity phosphorylation Ser183 PTQQYAKsLPVSVPV -1 SIGNOR-C3 SIGNOR-C3 18372248 t lperfetto Pras40 functions as a negative regulator when bound to mtorc1, and it dissociates from mtorc1 in response to insulin. Pras40 has been demonstrated to be a substrate of mtorc1, and one phosphorylation site, ser-183, has been identified. SIGNOR-178120 0.903 PIM proteinfamily SIGNOR-PF34 SIGNOR MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0002552 19749799 t lperfetto Pim1 phosphorylates and negatively regulates ask1-mediated apoptosispim1 phosphorylation of ask1 on ser83 inhibited ask1-mediated c-jun n-terminal kinase phosphorylation SIGNOR-259410 0.2 CAMK2A protein Q9UQM7 UNIPROT HOMER3 protein Q9NSC5 UNIPROT down-regulates activity phosphorylation Ser159 EKLFRSQsADAPGPT -1 18480293 t miannu Homer3 is phosphorylated at Ser120, Ser159, and Ser176 by CaMKII in vitro. Homer3 phosphorylation reduces its affinity for target molecules and modulates the Ca2+ signaling patterns induced by mGluR1α activation SIGNOR-262685 0.2 PTPRG protein P23470 UNIPROT ITGB1 protein P05556 UNIPROT down-regulates activity dephosphorylation Tyr783 DTGENPIyKSAVTTV -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254706 0.267 HMGB2 protein P26583 UNIPROT POU3F1 protein Q03052 UNIPROT up-regulates activity binding 10090 BTO:0002910 7720710 t 2 miannu HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins SIGNOR-240148 0.309 RET protein P07949 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates activity phosphorylation Tyr9 ARTTSQLyDAVPIQS 10029 12738763 t lperfetto Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1. SIGNOR-235863 0.2 PRKN protein O60260 UNIPROT EPS15 protein P42566 UNIPROT up-regulates ubiquitination 9606 BTO:0000938 BTO:0000142 16862145 t gcesareni Treatment of cells with egf stimulates parkin binding to both eps15 and the egfr and promotes parkin-mediated ubiquitination of eps15 SIGNOR-148218 0.2 PRKACA protein P17612 UNIPROT AICDA protein Q9GZX7 UNIPROT unknown phosphorylation Ser38 YVVKRRDsATSFSLD 9606 BTO:0000776 18417471 t llicata We have found using sf9 insect cells to overexpress human gst-aid that a small fraction of the enzyme is phosphorylated at ser38 and thr27 and at two residues not reported previously, ser41 and ser43 SIGNOR-178244 0.327 MMP15 protein P51511 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272360 0.7 MAVS protein Q7Z434 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22588174 f Giorgia ECSIT enhances IPS-1-mediated IFN-Beta promoter activation SIGNOR-260372 0.498 UBE2D1 protein P51668 UNIPROT MGRN1 protein O60291 UNIPROT up-regulates activity binding 9606 BTO:0000567 17229889 t miannu Our in vivo and in vitro ubiquitylation studies demonstrate that the binding of TSG101 to Mahogunin targets the substrate TSG101 for ubiquitylation by Mahogunin E3 ligase in cooperation with its cognate E2 enzyme Ubc5a SIGNOR-271637 0.482 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser746 RRSVRIGsYIERDVT 9606 7539802 t miannu Phosphorylation of kit/scfr by pkc-_ in vitro: identification of ser-741 and ser-746 as the major phosphorylation sites for pkc / pkc, which acts in an scf-stimulated feedback loop, that negatively controls kit/scfr kinase activity SIGNOR-28605 0.518 NEDD4 protein P46934 UNIPROT SYK protein P43405 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 11046148 t miannu The latent membrane protein (LMP) 2A of Epstein-Barr virus (EBV) is implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling. LMP2A enhances Lyn and Syk ubiquitination in vivo in a fashion that depends on the activity of Nedd4 family members and correlates with destabilization of the Lyn tyrosine kinase. These results suggest that LMP2A serves as a molecular scaffold to recruit both B-cell tyrosine kinases and C2/WW/Hect domain E3 protein-ubiquitin ligases.  SIGNOR-272581 0.294 TYK2 protein P29597 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates activity phosphorylation 9606 15120645 t miannu Despite signaling through distinct receptor complexes, type I IFNs and IFN-lambda activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (Fig. 6). In both cases, receptor engagement leads via the activation of the Jak kinases Jak1 and Tyk2 to the activation of the IFN-stimulated gene factor 3 (ISGF3) transcription complex, composed of latent transcriptional factors of the Signal Transducers and Activators of Transcription (STAT) family, Stat1 and Stat2, and of the interferon regulatory factor (IRF) IRF9 (ISGF3g or p48). SIGNOR-260148 0.724 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 18394876 t lperfetto The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity SIGNOR-252859 0.909 FOXO1 protein Q12778 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260090 0.26 TRIO protein O75962 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260579 0.683 FZD1 protein Q9UP38 UNIPROT DVL2 protein O14641 UNIPROT up-regulates activity binding 9606 23151663 t areggio Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.  SIGNOR-258952 0.67 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TP53 protein P04637 UNIPROT unknown phosphorylation Ser392 FKTEGPDsD -1 10884347 t llicata Our previous data has shown that cyclin A-cdk2 is the major enzyme responsible for modifying p53 at Ser315 in vivo after irradiation damage and in this report we dissect the mechanism of cyclinA-cdk2 binding to and phosphorylation of p53. SIGNOR-250751 0.806 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PARP1 protein P09874 UNIPROT up-regulates phosphorylation Ser372 VAATPPPsTASAPAA 9606 BTO:0000938 BTO:0000142 16627622 t lperfetto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-244669 0.2 SLC19A1 protein P41440 UNIPROT (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity relocalization 9606 10787414 t lperfetto The differential polarized distribution of the reduced-folate transporter (RFT-1) and folate receptor alpha (FRalpha), the two proteins involved in the transport of folate, has been characterized in normal mouse retinal pigment epithelium (RPE) and in cultured human RPE cells. SIGNOR-268266 0.8 SLC44A2 protein Q8IWA5 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 12761501 f Giorgia Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways SIGNOR-260390 0.2 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser160 NLLFKDNsLDAPVKL 9606 BTO:0000007 35064619 t miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. SIGNOR-276745 0.2 SMAD7 protein O15105 UNIPROT SMURF1 protein Q9HCE7 UNIPROT up-regulates activity binding 9534 BTO:0000298 11278251 t miannu Here we show that Smurf1, an E3 ubiquitin ligase for bone morphogenetic protein-specific Smads, also interacts with Smad7 and induces Smad7 ubiquitination and translocation into the cytoplasm. In addition, Smurf1 associates with TbetaR-I via Smad7, with subsequent enhancement of turnover of TbetaR-I and Smad7.  SIGNOR-272942 0.879 calcitriol smallmolecule CHEBI:17823 ChEBI calcitetrol smallmolecule CHEBI:47799 ChEBI up-regulates quantity precursor of 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270570 0.8 MAPK1 protein P28482 UNIPROT MYC protein P01106 UNIPROT up-regulates activity phosphorylation Ser62 LLPTPPLsPSRRSGL 9534 BTO:0004055 8386367 t lperfetto Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62. SIGNOR-235700 0.729 ACE protein P12821 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage 9606 11076943 t gcesareni Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide. SIGNOR-253326 0.778 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000876 BTO:0001103 11602185 f apalma The GM-CSF promoted cell survival and proliferation correlated with MEK-1 dependent ERK1/2, Elk-1 and CREB phosphorylation and Egr-1, c-Fos expression as well as with increased STAT-5, AP-1, c-Myb and NF-kappaB DNA-binding. SIGNOR-255580 0.7 CIB2 protein O75838 UNIPROT a7/b1 integrin complex SIGNOR-C126 SIGNOR up-regulates activity binding 9606 35408910 t miannu So far, two integrins have been found to interact with CIB2: αIIbβ3 is expressed by platelets and megakaryocytes and, apparently, a common target for all CIB family members, at odds with α7Bβ1D, which seems to be CIB2-specific and is expressed in skeletal muscles. SIGNOR-269668 0.2 NDUFA10 protein O95299 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262151 0.821 IRF2BP1 protein Q8IU81 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 BTO:0000567 12799427 t miannu We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation. SIGNOR-224045 0.706 AKT1 protein P31749 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser143 RTPRRSKsDGEAKPE 9606 21151116 t gcesareni Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1. SIGNOR-170530 0.537 SMARCD1 protein Q96GM5 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270694 0.79 HSPA9 protein P38646 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267693 0.681 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203564 0.773 GW 791343 HYDROCHLORIDE chemical CID:9848159 PUBCHEM P2RX7 protein Q99572 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193116 0.8 ANXA3 protein P12429 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR up-regulates activity 9606 26095609 f miannu ANXA3 Induces a Feed-Forward Loop that Is Mediated by the MKK4/JNK Signaling Cascade. To substantiate the importance of the JNK/AP-1 pathway in ANXA3-driven HCC, we performed rescue experiments using the JNK-specific inhibitor (JNKi) SP600125. JNKi suppressed the oncogenic properties conferred by ANXA3 overexpression, as evidenced by the diminished abilities of HCC cells to form colonies, migrate, invade, induce angiogenesis, form hepatospheres, and resist apoptosis and chemotherapy (Figures 6F–6J). Interestingly, treatment of parental HCC cells or HCC cells overexpressing ANXA3 with JNKi resulted in not only a reduction in JNK activity and modulation of downstream target genes (c-MYC and p21) but also a marked decrease in ANXA3 expression, suggesting that ANXA3 induces a feed-forward loop that is mediated by MKK4/JNK signaling (Figures 6K–6L). SIGNOR-262214 0.28 CSNK2A1 protein P68400 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Thr714 EESDSSEtEKEDDEG -1 21296876 t miannu CK2 phosphorylation of an acidic Ser/Thr di-isoleucine motif in the Na+/H+ exchanger NHE5 isoform promotes association with beta-arrestin2 and endocytosis SIGNOR-276250 0.2 SUPT20H protein Q8NEM7 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269575 0.743 TNF protein P01375 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity 10090 10485710 f lperfetto Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-252733 0.321 ATM protein Q13315 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates activity phosphorylation Ser395 SQESEDYsQPSTSSS -1 12383858 t gcesareni Dephosphorylation stabilizes mdm2 and increases its affinity for p53, inducing p53 degredation. ;phosphorylated s260 and s395 ands260d and s395d mutant peptides inhibited binding of binding of a specific monoclonal antibody raised to mdm2. Phosphorylation of mdm2 regulates p53 degradation. SIGNOR-94268 0.751 EPHB1 protein P54762 UNIPROT CASKIN1 protein Q8WXD9 UNIPROT up-regulates activity phosphorylation Tyr336 TGNDRVGyFPSSLGE 9534 23181695 t miannu EphB1 phosphorylates Caskin1 on tyrosine 296 and 336. Tyrosine phosphorylated Caskin1 then likely promotes reorganization of the actin cytoskeleton leading to spine formation. SIGNOR-262861 0.286 CREBBP protein Q92793 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity acetylation Lys288 CAHPGCGkSYTKSSH 9606 11259590 t Regulation miannu EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain. SIGNOR-251826 0.499 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function SIGNOR-252850 0.909 MACC1 protein Q6ZN28 UNIPROT MET protein P08581 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000038 19098908 t Luana Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level SIGNOR-266058 0.401 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 ChEBI 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI up-regulates quantity precursor of 9606 21498505 t miannu Plasma-derived fatty acids are esterified to acyl-CoA by acyl-CoA synthetases and transferred to lysophospholipids by acyl-CoA:lysophospholipid acyltransferases. We report the characterization of three lysophosphatidylcholine (lysoPC) acyltransferases (LPCATs), products of the AYTL1, -2, and -3 genes.  SIGNOR-272768 0.8 CASP8 protein Q14790 UNIPROT Caspase 8 complex complex SIGNOR-C231 SIGNOR form complex binding cleavage:Asp216 SDSPREQdSESQTLD 10508785 t lperfetto Activated caspase-8 (an alpha2beta2 heterotetramer) activates other downstream caspases that are incapable of autocatalytic processing and activation. |The alphabeta dimeric protein associates further to form an alpha2beta2 heterotetramer that appears to be required for catalytic activity. SIGNOR-256395 0.2 SYP protein P08247 UNIPROT Synaptic_vesicle_recycling phenotype SIGNOR-PH161 SIGNOR up-regulates 9606 BTO:0000938 33769286 f miannu This study reveals that Syp has a single physiological role in SV recycling, the accurate trafficking, and retrieval of SybII. SIGNOR-264111 0.7 TFEB protein P19484 UNIPROT GALNS protein P34059 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276538 0.292 TGFB2 protein P61812 UNIPROT Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 BTO:0000988 38540204 t miannu Resident fibroblasts, especially PSC, have the ability to transdifferentiate from a “quiescent” retinoid/lipid storing phenotype in the normal pancreas to an “activated” α-smooth muscle-actin-producing myofibroblastic phenotype through tumor-derived stimuli such as cytokines (interleukin(IL)-1, IL-6, and IL-8 and tumor necrosis factor (TNF)-α), growth factors (platelet-derived growth factor (PDGF) and tumor growth factor (TGF)-β), and reactive oxygen species [33]. Activated PSCs can, in turn, produce autocrine factors such as PDGF, TGF-β, and cytokines, which may contribute to a looping mechanism promoting a desmoplastic reaction SIGNOR-277680 0.7 NFATC1 protein O95644 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates transcriptional regulation 9606 BTO:0001103 14729474 f apalma To summarize, these two studies have generated important insights into the control of skeletal muscle hypertrophy by the calcineurin/NFATc1 signaling pathway SIGNOR-256215 0.7 sorafenib tosylate chemical CHEBI:50928 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib, Nexavar), which has recently been approved by the FDA for advanced renal cell carcinoma in phase III clinical trials. Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). SIGNOR-259220 0.8 CDK1 protein P06493 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 18337751 t gcesareni Phosphorylation at ser359 inhibits eef2k activity even at high calcium concentrations. we demonstrate that cdc2 contributes to controlling eef2 phosphorylation in cells. inactivation of eef2k by cdc2 may serve to keep eef2 active during mitosis SIGNOR-177982 0.372 MRPL9 protein Q9BYD2 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262343 0.737 PRKCA protein P17252 UNIPROT LRRK1 protein Q38SD2 UNIPROT up-regulates activity phosphorylation Thr1075 NQRNRCStFRVKRNQ -1 36040231 t miannu PKCα unexpectedly does not activate LRRK1 by phosphorylating the kinase domain, but instead phosphorylates a cluster of conserved residues (Ser1064, Ser1074 and Thr1075) located within a region of the CORB domain of the GTPase domain. we postulate that phosphorylation of Ser1064, Ser1074 and Thr1075 activates LRRK1 by promoting interaction and stabilization of the αC-helix on the kinase domain. SIGNOR-276865 0.2 RCAN1 protein P53805 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR down-regulates activity binding 9606 12554096 t MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure SIGNOR-252341 0.616 PHKA2 protein P46019 UNIPROT PHKG2 protein P15735 UNIPROT down-regulates activity binding 9606 10487978 t Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit. SIGNOR-267406 0.915 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates chemical activation 9606 16794003 t gcesareni The evidence suggests that s1p acting on s1p receptors coupled to gq SIGNOR-147233 0.8 ROR2 protein Q01974 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates binding 9606 23151663 t gcesareni Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase SIGNOR-199588 0.2 methoxamine chemical CHEBI:6839 ChEBI ADRA1D protein P25100 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258448 0.8 SGK1 protein O00141 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates activity phosphorylation Thr383 PSVAYVHtTPGLPSG -1 12911626 t miannu Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1. SIGNOR-263076 0.783 CTCFL protein Q8NI51 UNIPROT BAG1 protein Q99933 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003293 18413740 t lperfetto DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation SIGNOR-254107 0.283 KLF11 protein O14901 UNIPROT HBG2 protein P69892 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 10207080 f Regulation miannu Transfection of K562 cells with FKLF cDNA enhanced the expression of the endogenous epsilon- and gamma-globin genes, suggesting an in vivo role of FKLF in fetal and embryonic globin gene expression. SIGNOR-251827 0.2 CSNK1A1 protein P48729 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates quantity by destabilization phosphorylation Ser268 SSNASSVsTRLSPLR 9606 BTO:0001109 28945225 t miannu Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268.  SIGNOR-277326 0.2 CYLD protein Q9NQC7 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity deubiquitination 9606 12917691 t lperfetto Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract) SIGNOR-117860 0.669 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 10581361 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-72712 0.516 SOCS3 protein O14543 UNIPROT IL6ST protein P40189 UNIPROT down-regulates activity binding 9606 BTO:0000887;BTO:0001103 19620279 t miannu We now show that SOCS1, SOCS3, and PIAS1 promote myogenic differentiation by specifically inhibiting the LIF-induced JAK1/STAT1/STAT3 pathway via distinct targets; whereas SOCS1 and SOCS3 selectively bind and inhibit JAK1 and gp130, respectively, PIAS1 targets mainly the activated STAT1 and prevents its binding to DNA. SIGNOR-202045 0.643 FHIT protein P49789 UNIPROT MMP14 protein P50281 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159876 0.28 ZBED1 protein O96006 UNIPROT RPS6 protein P62753 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 17220279 t Luana HDRE-like sequences act as positive regulatory elements for RP gene promoter activities in vivo. | Cotransfection of a plasmid expressing hDREF increased luciferase expression directed by each RP gene promoter more than 30% compared with the values obtained without the hDREF-expressing plasmid. SIGNOR-266082 0.2 GDNF protein P39905 UNIPROT CLU protein P10909 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252187 0.263 H3-3A protein P84243 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263876 0.2 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser323 HCSAEAGsPAMAVLD 9606 16286470 t lperfetto The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain SIGNOR-141609 0.781 KCNJ11 protein Q14654 UNIPROT KATP channel complex SIGNOR-C274 SIGNOR form complex binding 9606 28842488 t lperfetto ATP-sensitive K+ (KATP) channels, found throughout the body, are generated as octameric complexes consisting of four pore-forming Kir6.1 or Kir6.2 subunits with four regulatory sulfonylurea receptor (SUR1 or SUR2) subunits. SIGNOR-262055 0.656 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 27660409 t diabetic macular edema gcesareni They differ according to their glucocorticoid-receptor binding affinities (dexamethasone > triamcinolone > fluocinolone) and their lipophilicity (triamcinolone > fluocinolone > dexamethasone), characteristics that may partially explain their relative potencies SIGNOR-251694 0.8 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 21883093 t miannu In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. SIGNOR-269194 0.581 HAP1 protein P54257 UNIPROT AHI1 protein Q8N157 UNIPROT up-regulates activity binding 9606 BTO:0000452 23532844 t miannu Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knock-out mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis. SIGNOR-269081 0.559 IFNG protein P01579 UNIPROT S100A10 protein P60903 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567;BTO:0002923 12645529 f miannu The effect of interferon (IFN)-gamma on p11 expression was studied in two human epithelial cell lines (BEAS-2B and HeLa). Treatment with IFN-gamma resulted in increased steady-state levels of p11 mRNA and protein expression, with a time-dependent and dose-dependent effect. SIGNOR-255236 0.269 A5/b1 integrin complex SIGNOR-C163 SIGNOR Activated PSC phenotype SIGNOR-PH224 SIGNOR up-regulates 9606 32928643 t miannu CTGF is highly expressed in PDAC tissues, especially in tumor stroma (as shown by immunohistochemistry, CTGF: brown stain). The tumor cell-secreted CTGF promotes pancreatic stellate cell (PSC) proliferation, adhesion, and migration via integrin α5β1, leading to extracellular matrix (ECM) deposition.Pancreatic cancer cells secrete high levels of CTGF that binds to integrin α5β1, promoting PSC proliferation, adhesion, and migration SIGNOR-277688 0.7 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000007 19478061 t Transfection of wild-type PTPRD resulted in the specific dephosphorylation of STAT3 at tyrosine 705, a residue that must be phosphorylated for STAT3 to be active SIGNOR-248442 0.527 EIF4E protein P06730 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 11408474 t miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. SIGNOR-108515 0.842 MED4 protein Q9NPJ6 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266675 0.814 N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide chemical CHEBI:91418 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 BTO:0001271 21697284 t gcesareni Exel-2880 (xl880, gsk1363089) is a small-molecule kinase inhibitor that targets members of the hgf and vegf receptor tyrosine kinase families, with additional inhibitory activity toward kit, flt-3, platelet-derived growth factor receptor _, and tie-2. SIGNOR-174552 0.8 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser739 GSIDMVDsPQLATLA 9606 BTO:0000938 16923168 t The effect has been demonstrated using P10636-8 lperfetto Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation. SIGNOR-148978 0.459 PTPRB protein P23467 UNIPROT ALK protein Q9UM73 UNIPROT down-regulates dephosphorylation 9606 BTO:0000785 17681947 t gcesareni Rptpbeta/zeta dephosphorylates alk at the site(s) in alk that is undergoing autophosphorylation through autoactivation. SIGNOR-157175 0.338 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr741 NLYSGDYyRIQGRAV 9606 16186108 t gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. SIGNOR-140767 0.385 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Ser344 QDDDAPLsPMLYSSS 9606 19282669 t lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-252962 0.588 (2S)-2-[[2-(2,3-dihydro-1H-inden-5-yloxy)-9-[(4-phenylphenyl)methyl]-6-purinyl]amino]-3-phenyl-1-propanol chemical CHEBI:94469 ChEBI ARFGAP1 protein Q8N6T3 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 17460038 t Through affinity chromatography and subsequent functional assays, we showed that QS11 binds and inhibits the GTPase activating protein of ADP-ribosylation factor 1 (ARFGAP1), suggesting that QS11 modulates Wnt/beta-catenin signaling through an effect on protein trafficking. Consistent with its function as an ARFGAP inhibitor, QS11 inhibits migration of ARFGAP overexpressing breast cancer cells SIGNOR-261914 0.8 CKM complex complex SIGNOR-C406 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 15546612 t gcesareni Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo. SIGNOR-273153 0.381 FASN protein P49327 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization 9606 BTO:0001130 18838960 f lperfetto Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer SIGNOR-242878 0.271 Obatoclax mesylate chemical CID:46930996 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates activity chemical inhibition -1 23515850 t lperfetto Obatoclax and its predecessor analogs bind to BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 in vitro SIGNOR-262024 0.8 EID1 protein Q9Y6B2 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates activity binding 11073989 t lperfetto Here, we show that EID-1 is a potent inhibitor of differentiation and link this activity to its ability to inhibit p300 (and the highly related molecule, CREB-binding protein, or CBP) histone acetylation activity. SIGNOR-253380 0.412 MAPK8IP3 protein Q9UPT6 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 15767678 t gcesareni The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk. SIGNOR-134558 0.718 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258305 0.8 PTPN2 protein P17706 UNIPROT SRC protein P12931 UNIPROT down-regulates dephosphorylation 9606 22080863 t gcesareni We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._ SIGNOR-177116 0.714 POU5F1 protein Q01860 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22795133 t lperfetto Oct4 and Nanog upregulate Dnmt1 through direct binding to its promoter, thereby leading to the repressed expression of p16 and p21 and genes associated with development and lineage differentiation SIGNOR-253158 0.445 PRMT1 protein Q99873 UNIPROT TAF15 protein Q92804 UNIPROT up-regulates methylation 9606 19124016 t miannu The methylation of taf15 by prmt1 is required for the ability of taf15 to positively regulate the expression of the studied endogenous taf15-target genes. SIGNOR-183137 0.437 MYBBP1A protein Q9BQG0 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268821 0.474 MTMR3 protein Q13615 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269811 0.8 CAMK2D protein Q13557 UNIPROT ANKRD28 protein O15084 UNIPROT down-regulates activity phosphorylation Ser1011 TNTSKTVsFEALPIM -1 17023142 t lperfetto We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K SIGNOR-264793 0.2 CDK2 protein P24941 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C16 21902831 t gcesareni Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation. SIGNOR-176512 0.881 Gbeta proteinfamily SIGNOR-PF4 SIGNOR IL16 protein Q14005 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 14768064 t inferred from 70% family members lperfetto The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 in antigen receptor-, sdf1alpha- and il-2-activated t cells. Genetic and pharmacological-inhibitor experiments showed that the phosphorylation of proil-16 is dependent on activation of the kinases erk1/2. Il-16 is secreted by mitogen-activated t cells, and the biochemical link between proil-16 and erk1/2, revealed by studies with pap-1, prompted analysis of the role of map kinases in this response. SIGNOR-270056 0.2 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr445 ANDVPSPyEVRGFPT -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262894 0.2 KDM1A protein O60341 UNIPROT CoREST-HDAC complex complex SIGNOR-C105 SIGNOR form complex binding 9606 BTO:0000567 11171972 t miannu Here we describe the components of a histone deacetylase (HDAC) complex that we term the CoREST-HDAC complex. CoREST Is a Component of an HDAC1/2 Complex. p40 is a Sox-like protein, p110b contains homology to polyamine oxidases, p110a is ZNF217, an eight-zinc finger protein, and p80 is a hypothetical protein of unknown function. SIGNOR-222121 0.74 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT down-regulates activity phosphorylation Thr354 RKPANDItSQLEINF 9606 BTO:0004974 14699138 t lperfetto We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation SIGNOR-249246 0.292 TIMELESS protein Q9UNS1 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity binding 9534 23418588 t miannu We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization. SIGNOR-268054 0.791 TGFBR2 protein P37173 UNIPROT PIK3R2 protein O00459 UNIPROT up-regulates binding 9606 9435577 t lperfetto These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells. SIGNOR-227528 0.439 GSK3A protein P49840 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159432 0.2 NR3C1 protein P04150 UNIPROT NR4A2 protein P43354 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15591535 f gcesareni We now show that the other nur factors, nurr1 and nor-1, are also subject to antagonism by gr and that this transrepression appears to involve direct protein-protein interactions between the dbds of gr and nur factors. SIGNOR-132254 0.309 GCC1 protein Q96CN9 UNIPROT ITSN1 protein Q15811 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 30540523 t Giulio GFP-GCC88 was immunoprecipitated by both the short and long form of ITSN-1 but not with FLAG-Rheb (Figure 4A). These data demonstrate that both GCC88 and ITSN-1 are part of a complex. We propose that GCC88 recruits ITSN-1-L to the TGN, which in turn activates Cdc42 at the trans-face of the Golgi (Figure 9A). SIGNOR-260600 0.2 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 9724739 t amattioni Activated jnk phosphorylates p53 SIGNOR-59812 0.793 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser197 TKSIYTRsVIDPVPA -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250226 0.2 motesanib chemical CHEBI:51098 ChEBI FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194560 0.8 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser7 sSSSYRRM -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248886 0.287 NFIB protein O00712 UNIPROT NFIX protein Q14938 UNIPROT down-regulates activity binding 9606 BTO:0000567 9099724 t 2 miannu Coexpression of NFI-B3 with other isoforms of the NFI-B, -C, and -X family, however, led to a strong reduction of transcriptional activation compared with the expression of these factors alone. NFI-B3 apparently forms heterodimers with other NFI proteins thereby interfering with their function. SIGNOR-240915 0.425 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT down-regulates activity phosphorylation Thr194 FPKTSSAtPQETLIS -1 12361598 t miannu GST-tagged recombinant CP110 (GST-wt) was robustly phosphorylated by cyclin E/CDK2 (Figure 2A). Expression of a mutant derivative of CP110 refractory to CDK phosphorylation provokes marked polyploidy. We localized the majority (nine of ten) of potential CDK2 phosphorylation sites in CP110 to an amino-terminal fragment (GST-ΔN1; Figure 1B) SIGNOR-265961 0.525 RTKs proteinfamily SIGNOR-PF38 SIGNOR ITGB4 protein P16144 UNIPROT up-regulates activity phosphorylation 9606 30889378 t miannu The RTKs in turn induce phosphorylation of focal adhesion kinase (FAK) or the signaling domain of the b4 integrin. These elements recruit distinct subsets of signaling enzymes and adaptors, refining the specificity of individual partner RTKs. SIGNOR-259031 0.2 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates chemical activation 9606 16014605 t gcesareni Lpa exerts its downstream signaling by binding to the lpa(1), lpa(2), and lpa(3) (formerly edg-2, -4, and -7) family of seven-transmembrane, segmented, heterotrimeric guanine nucleotide-binding protein (g protein)-coupled receptors. SIGNOR-138582 0.8 ABCA7 protein Q8IZY2 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 10090 14570867 f miannu Transfected ABCA7-GFP induced apolipoprotein-mediated assembly of cholesterol-containing HDL also in L929 cells, which otherwise generate only cholesterol-deficient HDL with their endogenous ABCA1. SIGNOR-265177 0.7 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270368 0.8 APH1B protein Q8WW43 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 t gcesareni Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. SIGNOR-97110 0.941 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity phosphorylation Ser282 NSLQRVPsYDSFDSE BTO:0003637 12475968 t llicata Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1  SIGNOR-250686 0.311 SRC protein P12931 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Tyr374 PLPPAPAyLSSPLAL 9606 BTO:0000007 23131831 t miannu Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.  SIGNOR-276370 0.423 CSNK2A1 protein P68400 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity phosphorylation Thr531 NTTGSDNtDTEGS 9606 BTO:0000567 17936701 t PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2 SIGNOR-262290 0.349 TSH complex SIGNOR-C412 SIGNOR TSHR protein P16473 UNIPROT up-regulates activity binding 9606 BTO:0001379 25905363 t scontino The thyroid-stimulating hormone (TSH) receptor (TSHR) is a member of the glycoprotein hormone receptors (GPHRs), a sub-group of class A G protein-coupled receptors (GPCRs). TSHR and its ligand thyrotropin are of essential importance for growth and function of the thyroid gland. SIGNOR-267048 0.567 MAML1 protein Q92585 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 16510869 t gcesareni Unexpectedly, however, emerging evidence implicate maml proteins as exciting key transcriptional co-activators in other signal transduction pathways including: muscle differentiation and myopathies (mef2c), tumor suppressor pathway (p53) and colon carcinoma survival (beta-catenin). SIGNOR-144913 0.4 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT down-regulates activity phosphorylation Tyr658 GEMDTTSyDVSVLNS 10029 BTO:0000246 16027153 t lperfetto cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity. SIGNOR-246462 0.578 GSK3B protein P49841 UNIPROT UNG protein P13051 UNIPROT down-regulates quantity by destabilization phosphorylation Thr60 AGQEEPGtPPSSPLS 9606 BTO:0000812 phosphorylation:Ser64 EPGTPPSsPLSAEQL 27875297 t lperfetto Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation SIGNOR-264885 0.2 PIAS1 protein O75925 UNIPROT DDX5 protein P17844 UNIPROT up-regulates sumoylation Lys53 WNLDELPkFEKNFYQ 9606 17369852 t miannu We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53. SIGNOR-153719 0.534 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD6 protein O43541 UNIPROT down-regulates activity relocalization 9606 22298955 t lperfetto Smurf1, with its WW domain, specifically binds to the PY motif of Smad6 and transports Smad6 into the cytoplasm. SIGNOR-253261 0.2 SOSTDC1 protein Q6X4U4 UNIPROT WNT1 protein P04628 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242704 0.279 PFKFB2 protein O60825 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR up-regulates 9606 20640476 f lperfetto The decreased glycogen synthesis rates upon acute AMPK activation are generally coupled to an increase in the glycolytic flux, thanks to the activation of 6-phosphofructo-2-kinase (PFK-2) through direct phosphorylation on Ser466 [35]. PFK-2 catalyzes the synthesis of fructose 2,6-bisphosphate, a potent stimulator of glycolysis. Therefore, activation of AMPK rapidly mobilizes glucose into ATP-generating processes. SIGNOR-209950 0.7 S1PR2 protein O95136 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 10488065 t gcesareni Edg-3 and edg-5 couple not only to gibut also to gqand g13. SIGNOR-70664 0.46 SMO protein Q99835 UNIPROT GNG2 protein P59768 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199183 0.368 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 16880739 t lperfetto Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis. SIGNOR-216821 0.279 FASTKD5 protein Q7L8L6 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25683715 f miannu DHX30, DDX28, FASTKD2, and FASTKD5 Are Bona Fide RNA Granule Proteins. FASTKD5 siRNA treatment caused a reduction of all RNA granule proteins, along with MRPS18B, a protein of the mt-SSU. SIGNOR-261226 0.7 RUNX2 protein Q13950 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001610 22641097 f miannu Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. SIGNOR-255085 0.456 SAGA complex complex SIGNOR-C465 SIGNOR Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR up-regulates 9606 15970593 f lperfetto Transcription initiation is a major regulatory step in eukaryotic gene expression. Co-activators establish transcriptionally competent promoter architectures and chromatin signatures to allow the formation of the pre-initiation complex (PIC), comprising RNA polymerase II (Pol II) and general transcription factors (GTFs).|this observation appears remarkably prevalent for chromatin-modifying and remodeling complexes. Here, we use the modular organization of the evolutionary conserved Spt-Ada-Gcn5 acetyltransferase (SAGA) complex as a paradigm to illustrate how co-activators share and combine a relatively limited set of functional tools. SIGNOR-269570 0.7 HSPB1 protein P04792 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 12855565 f gcesareni These data demonstrate that hsp27 inhibits the release of smac SIGNOR-103539 0.332 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT down-regulates activity phosphorylation Tyr770 LSAPFEQySPGGQDT 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3these results suggest that y770 may negatively regulate the activation of pi 3-kinase by constitutively activated fgfr3 SIGNOR-106746 0.2 Guanabenz chemical CHEBI:5553 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258910 0.8 PRKCB protein P05771 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 BTO:0000661 11123317 t lperfetto Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5.  SIGNOR-249075 0.361 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206313 0.8 PPP2CA protein P67775 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t inferred from 70% of family members gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). SIGNOR-269896 0.2 SYN1 protein P17600 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269187 0.7 lofexidine chemical CHEBI:51368 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 10030 BTO:0000246 22341244 t Luana Lofexidine was selected because its scaffold is similar to that of the imidazolines of the present study and, as emerged from our functional study (Table 2), it displayed significant α2A- and α2C-AR agonism.  SIGNOR-258332 0.8 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser214 TVLTAQEsFSGSLGH -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276216 0.386 FZD6 protein O60353 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-198828 0.671 COL4A2 protein P08572 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254666 0.7 LSM7 protein Q9UK45 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270647 0.8 DNMT1 protein P26358 UNIPROT DNMT1/DNMT3A complex SIGNOR-C42 SIGNOR form complex binding 9606 12145218 t miannu We show that the human de novo enzymes hdnmt3a and hdnmt3b form complexes with the major maintenance enzyme hdnmt1 /in vivo co-expression of hdnmt1 and hdnmt3a or hdnmt3b leads to methylation spreading in the genome, suggesting co-operation between de novo and maintenance enzymes during dna methylation SIGNOR-90836 0.779 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates chemical activation 9606 16293724 t gcesareni Pge2 receptors are coupled to the G protein Gs, which causes accumulation of cyclic adenosine monophosphate (cAMP) and activates protein kinase a (PKA), we confirmed that PGE2 treatment or transfection of cells with the active catalytic subunit of PKA also stimulated the activity of a cAMP-responsive-element driven reporter gene (CRE-luc). SIGNOR-141786 0.8 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219349 0.71 FBXO11 protein Q86XK2 UNIPROT TP53 protein P04637 UNIPROT down-regulates neddylation Lys321 SSPQPKKkPLDGEYF 9606 17098746 t miannu Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321 SIGNOR-150673 0.663 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser38 QVSSLSEsEESQDSS 9606 20730097 t lperfetto These data suggested that atf1 is always hyperphosphorylated on the ck sites in vivo. Also, the antibody reactivity suggested that in addition to ser-36 and ser-41, ser-38 and ser-44 were phosphorylated in vivo. To accommodate these findings, we propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. SIGNOR-167548 0.298 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile chemical CHEBI:77397 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 18487050 t Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  SIGNOR-257794 0.8 CTDSP2 protein O14595 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16882717 t lpetrilli In human cells, rnai-mediated depletion of scp1 and scp2 increases the extent and duration of smad1 phosphorylation in response to bmp, the transcriptional action of smad1, and the strength of endogenous bmp gene responses. The present identification of the scp family as smad c-terminal phosphatases sheds light on the events that attenuate smad signaling and reveals unexpected links to the essential phosphatases that control rna polymerase ii in eukaryotes. SIGNOR-148434 0.486 TFDP1 protein Q14186 UNIPROT PCNA protein P12004 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253858 0.47 MAPK1 protein P28482 UNIPROT PARP1 protein P09874 UNIPROT up-regulates phosphorylation Thr373 AATPPPStASAPAAV 9606 BTO:0000938 BTO:0000142 16627622 t esanto Parp1 phosphorylation by erk1/2 is required for maximal parp-1 activation after dna damage. S372a and t373a mutations impaired parp-1 activation. SIGNOR-146224 0.528 DOCK6 protein Q96HP0 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 23462102 t lperfetto Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton. SIGNOR-275670 0.515 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-106481 0.8 GH1 protein P01241 UNIPROT PRLR protein P16471 UNIPROT up-regulates binding 9606 7984244 t gcesareni Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap. SIGNOR-35575 0.77 MAPK11 protein Q15759 UNIPROT TCF3 protein P15923 UNIPROT up-regulates phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 t p38 MAPK in particular phosphorylates Ser140 of E47. Its been observed that phosphorylation of E47 improves its ability to form heterodimers with Myod transcription factor gcesareni Here we show that p38 mapk, whose activity is essential for myogenesis, regulates myod/e47 heterodimerization. Phosphorylation of e47 at ser140 by p38 induces myod/e47 association and activation of muscle-specific transcription, while the nonphosphorylatable e47 mutant ser140ala fails to heterodimerize with myod and displays impaired myogenic potentia SIGNOR-134190 0.421 IL10 protein P22301 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0000938 BTO:0001264 23357618 f miannu Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Consistent with the electrophysiological results, real-time PCR and western blot revealed that IL-10 (200 pg/ml) down-regulated VGSCs in both mRNA and protein levels and reversed the up-regulation of VGSCs by TNF-α. SIGNOR-253496 0.2 HDAC4 protein P56524 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275663 0.29 PRKG1 protein Q13976 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser660 FSAERRNsILTETLH 9606 1377674 t lperfetto Direct amino acid sequencing and peptide mapping of cf-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by pka and pkgcftr possesses a large cluster of strict dibasic consensus sites for phosphorylation by protein kinase a (pka) in the r-domain and an obligatory dependence on phosphorylation is a hallmark of cftr cl(-) channel function SIGNOR-18237 0.516 RAB21 protein Q9UL25 UNIPROT Early macropinosomes phenotype SIGNOR-PH228 SIGNOR up-regulates binding 9606 19693279 f miannu It was demonstrated that wild-type Rab21 was transiently associated with macropinosomes. Rab21 was recruited to the macropinosomes after a decrease in PI(4,5)P(2) and PI(3,4,5)P(3) levels. Although Rab21 was largely colocalized with Rab5, the recruitment of Rab21 to the macropinosomes lagged a minute behind that of Rab5, and preceded that of Rab7. SIGNOR-277782 0.7 LYN protein P07948 UNIPROT PDIA3 protein P30101 UNIPROT unknown phosphorylation Tyr467 KKLNPKKyEGGRELS -1 8631326 t miannu Lyn phosphorylates tyrosine residues Y444, Y453 and Y466 which are located in a highly acidic region of the protein at the C-terminus. Upon phosphorylation, p57 forms a complex with Lyn which can be immunoprecipitated with anti-Lyn IgG. The association which occurs between the phosphorylated substrate and the SH2 domain of the kinase is consistent with the suggested 'processive phosphorylation' model, which implies that a primary phosphorylation site of the substrate binds to the SH2 domain of the enzyme and triggers the phosphorylation at secondary site(s). SIGNOR-262896 0.2 MAPK8 protein P45983 UNIPROT HNRNPK protein P61978 UNIPROT up-regulates activity phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto The current studies demonstrate the identification of hnrnp-k as a jnk and erk substrate. The phosphoacceptor sites for jnk and erk on the k protein are different, and indeed, erk phosphorylation results in biological consequences different from those of phosphorylation by jnk (49). Whereas erk phosphorylation on aa 284 and 353 contributes to k protein nuclear export and concomitant inhibition of rna translation (49), phosphorylation by k protein on aa 216 and 353 increases the transcriptional effects of the k protein. SIGNOR-105247 0.378 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1069 EDSFLQRySSDPTGA 9606 10635327 t llicata Initially, an autophosphorylation reaction creates docking sites for several signaling proteins, including a Cbl binding site at tyrosine 1045 of EGFR. SIGNOR-251093 0.2 PRKCA protein P17252 UNIPROT ADRA1B protein P35368 UNIPROT down-regulates activity phosphorylation Ser406 RSQSRKDsLDDSGSC 9534 BTO:0000298 9353340 t lperfetto  Phorbol ester-induced phosphorylation of the Ser394 and Ser400 as well as GRK2-mediated phosphorylation of the Ser404, Ser408, and Ser410, resulted in the desensitization of alpha1BAR-mediated inositol phosphate response.  SIGNOR-248987 0.395 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1672 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273046 0.55 WNT5B protein Q9H1J7 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131888 0.624 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 22575959 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wnt by promoting the turnover of frizzled and lrp6. Frizzled receptors are regu__lated by cycles of ubiquitylation and deubiquitylation, and znrf3 and rnf43 act as frizzled ubiquitin ligases, removing frizzled and possibly lrp6 from the plasma membrane. SIGNOR-197420 0.648 ATF4 protein P18848 UNIPROT DDIT4 protein Q9NX09 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19439225 f lperfetto We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress. SIGNOR-253726 0.421 AP-1 complex complex SIGNOR-C248 SIGNOR AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260674 0.564 PRKCE protein Q02156 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Ser779 PLDQYSPsFPDTRSS 9606 BTO:0000938 23564461 t lperfetto Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiationour findings show that in addition to fgfr tyrosine phosphorylation, the phosphorylation of a conserved serine residue, ser(779), can quantitatively control ras/mapk signaling to promote specific cellular responses. SIGNOR-201671 0.2 PRDM16 protein Q9HAZ2 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887;BTO:0001103 18719582 f fspada Loss of prdm16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of prdm16 in myoblasts induces their differentiation into brown fat cells. SIGNOR-180295 0.7 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-162 SIGNOR-250012 0.35 PCGF2 protein P35227 UNIPROT HSF2 protein Q03933 UNIPROT down-regulates activity sumoylation 9606 BTO:0000007 18211895 t miannu MEL-18, in contrast to the polycomb protein PC2/CBX4, in which SUMO E3 activity stimulates sumoylation of certain proteins, actually functions like an anti-SUMO E3 protein, interacting with both HSF2 and the SUMO E2 UBC9 but acting to inhibit UBC9 activity and thereby decreasing sumoylation of a target protein, in this case that of HSF2. sumoylation of HSF2 is up-regulated during mitosis and is important for the interaction of this factor with a subunit of the condensin complex during the bookmarking process SIGNOR-226245 0.328 EGLN3 protein Q9H6Z9 UNIPROT BCL2L11 protein O43521-1 UNIPROT up-regulates quantity by stabilization hydroxylation Pro70 PLAPPASpGPFATRS 9606 31375625 t lperfetto EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues SIGNOR-262004 0.255 HCFC1 protein P51610 UNIPROT CREB3 protein O43889 UNIPROT up-regulates activity binding -1 9658067 t 2 miannu We also show that while interaction with HCF is not required for the ability of Luman to activate transcription when tethered to the GAL4 promoter, it appears to be essential for Luman to activate transcription through CRE sites. SIGNOR-241372 0.577 MLH1 protein P40692 UNIPROT MLH1/PMS1 complex SIGNOR-C58 SIGNOR form complex binding 9606 10542278 t miannu We now show that hpms1 is expressed in human cells and that it interacts with hmlh1 with high affinity to form the heterodimer hmutl_. SIGNOR-71768 0.694 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser531 GSRSRTPsLPTPPTR -1 9614189 t miannu S214 can be rapidly and selectively phosphorylated in vitro by PKA, and this single site strongly affects tau's ability to bind and stabilize microtubules. SIGNOR-250006 0.438 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination Lys62 CAVPIAQkSEPHSLS 9606 BTO:0002552 31732561 t lperfetto AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. SIGNOR-267673 0.382 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr972 EYLGTKRyIHRDLAT 9606 BTO:0000007 20304997 t lperfetto Tyrosines 868, 966, and 972 in the kinase domain of jak2 are autophosphorylated and required for maximal jak2 kinase activity SIGNOR-236294 0.2 FOXA1 protein P55317 UNIPROT NFIB protein O00712 UNIPROT up-regulates binding 9606 24801505 t miannu Androgen receptor (ar) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between ar and forkhead box (fox) transcription factors, particularly foxa1./ Foxa1 is capable of bringing ar and nfix into proximity, indicating that foxa1 facilitates the ar and nfi interaction by bridging the complex. SIGNOR-205027 0.317 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1081 TGALTEDsIDDTFLP 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250622 0.375 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 16729043 t gcesareni We identified stat5 as a direct binding partner to egfr and erbb4 and discovered new recognition motifs for shc and stat5.Egf stimulation and subsequent phosphorylation of egfr at tyrosine y978, y998 and y869 would then subsequently lead to recruitment and activation of stat5. SIGNOR-146852 0.819 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000887 11940578 t gcesareni Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth. SIGNOR-116485 0.606 IRF3 protein Q14653 UNIPROT IFNB1 protein P01574 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 16699525 t lperfetto Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants SIGNOR-252257 0.658 MAGOH protein P61326 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265243 0.95 CDK1 protein P06493 UNIPROT INCENP protein Q9NQS7 UNIPROT up-regulates phosphorylation Thr412 DTEIANStPNPKPAA 9606 16378098 t gcesareni Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase. SIGNOR-143387 0.754 PPP2R2A protein P63151 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity binding 10090 18042541 t gcesareni Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt.|Phosphorylation of Akt at regulatory residues Thr-308 and Ser-473 leads to its full activation. The protein phosphatase 2A (PP2A) has long been known to negatively regulate Akt activity. The PP2A holoenzyme consists of the structural |Here we report the identification of the specific B regulatory subunit that targets the PP2A holoenzyme to Akt. We found endogenous association of PP2A AB55C holoenzymes with Akt by co-immunoprecipitation analyses in pro-lymphoid FL5.12 cells.subunit (A), catalytic subunit (C), and a variable regulatory subunit (B). SIGNOR-252637 0.478 CRABP2 protein P29373 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000551 30696915 f Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. SIGNOR-259371 0.7 AHCYL1 protein O43865 UNIPROT PAPOLA protein P51003 UNIPROT down-regulates activity binding 9606 BTO:0000007 19224921 t lperfetto Inositol 1,4,5-triphosphate receptor-binding protein released with inositol 1,4,5-triphosphate (IRBIT) associates with components of the mRNA 3' processing machinery in a phosphorylation-dependent manner and inhibits polyadenylation|In addition to CPSF, IRBIT interacted in vitro with poly(A) polymerase (PAP), which is the enzyme recruited by CPSF to elongate the poly(A) tail, and inhibited PAP activity in a phosphorylation-dependent manner. SIGNOR-268329 0.247 alpha-aminoacyl-tRNA smallmolecule CHEBI:2651 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270808 0.8 F2RL1 protein P55085 UNIPROT CORO1C protein Q9ULV4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu Both PAR2 and PAR1 activation resulted in up-regulated expression of several genes (CD44, FOSL1, TNFRSF12A, RAB3A, COPEB, CORO1C, THBS1, SDC4) known to be important in cancer. SIGNOR-254838 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AMPH protein P49418 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 15262992 t inferred from 70% family members lperfetto Thus, we propose that mapk phosphorylation of amphiphysin1 controls ngf receptor/trka-mediated endocytosis by terminating the amphiphysin1-ap-2 interaction.Our results indicate that phosphorylation of amphiphysin 1 at ser-285 and/or ser-293 affects the function of amphiphysin1.Mapk phosphorylation of ser-285 and ser-293 could modulate the interaction between prd and ap-2, resulting in the dissociation of amphiphysin1 from ap-2. SIGNOR-270197 0.2 SRC protein P12931 UNIPROT AP2B1 protein P63010 UNIPROT down-regulates phosphorylation Tyr737 THRQGHIyMEMNFTN 9606 18938240 t gcesareni The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin. SIGNOR-181743 0.274 N-(6-Chloro-7-methoxy-9H-pyrido[3,4-b]indol-8-yl)-2-methylnicotinamide chemical CID:9929127 PUBCHEM IKBKB protein O14920 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258249 0.8 DAB2IP protein Q5VWQ8 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity binding 9606 BTO:0001033 26512963 t miannu DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. SIGNOR-254761 0.351 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT down-regulates activity relocalization 9606 18596912 t lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform SIGNOR-179407 0.405 AP3S2 protein P59780 UNIPROT Neuronal AP-3 complex SIGNOR-C445 SIGNOR form complex binding 9606 BTO:0000938 19497727 t miannu Mammals contain more than one AP-3 complex owing to the existence of pairs of genes encoding β3, μ3, and σ3 subunits (A and B isoforms). While both σ3A and σ3B are expressed ubiquitously and seem to be functionally equivalent, the B isoforms of β3 and μ3 display rather restricted expression patterns, mostly in cells of neuronal origin. This has led to the notion of the existence of two types of mammalian AP-3 complexes: a ubiquitous AP-3 comprising δ, β3A, μ3A, and σ3(A or B) subunits, and a brain-specific AP-3 complex containing δ, β3B, μ3B, and σ3(A or B) SIGNOR-268518 0.704 OXSR1 protein O95747 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity phosphorylation Thr84 LPSDFEHtIHVGFDA 9606 BTO:0000567 14707132 t miannu OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity. SIGNOR-250210 0.387 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr293 PAPSGRAyTSPLIDM -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263040 0.396 WWP1 protein Q9H0M0 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates ubiquitination 9606 15221015 t gcesareni Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7 SIGNOR-126581 0.521 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 9649584 t gcesareni This study investigated the molecular physiology of the nh2-terminal phosphorylation sites that regulate inactivation gating of an a-type k+ channel. The main results show that: (a) pkc acts on four phosphate acceptors (s8, s9, s15, and s21) within the inactivation domain because mutation of these residues to alanine is necessary and sufficient to remove the action of pkc on channel inactivation. SIGNOR-58502 0.2 CSRP3 protein P50461 UNIPROT MYF6 protein P23409 UNIPROT up-regulates activity binding 10090 BTO:0004058 9234731 t 2 miannu we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements. SIGNOR-241096 0.453 GLI2 protein P10070 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates quantity transcriptional regulation 9606 NBK6142 f SimoneGraziosi Therefore, Gli2 activity regulates the late phase of Olig2 gene expression in the ventral neuroepithelium and its subsequent production of OPC cells. SIGNOR-269219 0.36 CBFbeta-MYH11 fusion protein SIGNOR-FP3 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates activity binding 9606 29958106 t miannu The genes encoding CBFβ and RUNX1 are frequent targets of mutations in hematologic malignancies. The chromosome inversion inv(16)(p13;q22), found in 8% of acute myeloid leukemia (AML) cases, fuses the CBFB and MYH11 genes to produce the leukemic oncoprotein CBFβ-SMMHC. This fusion protein has higher affinity and altered stoichiometry for RUNX1 relative to the native CBFβ (Cao et al., 1997; Lukasik et al., 2002). During development, CBFβ-SMMHC expression blocks definitive hematopoiesis and embryos die at mid-gestation (Castilla et al., 1996), a similar phenotype to that of Runx1- and Cbfb-knock out embryos (Wang et al., 1996a; Wang et al., 1996b), indicating that CBFβ-SMMHC has a dominant negative effect on RUNX function. SIGNOR-255743 0.2 GSK3A protein P49840 UNIPROT EIF2B5 protein Q13144 UNIPROT down-regulates activity phosphorylation Ser540 MDSEEPDsRGGSPQM 9606 BTO:0000007 11500362 t We identify multiple phosphorylation sites in the largest, catalytic, subunit (epsilon) of mammalian eIF2B. Glycogen synthase kinase 3 (GSK3) is responsible for phosphorylating Ser535. This regulatory phosphorylation event requires both the fourth site (Ser539) and a distal region, which acts to recruit GSK3 to eIF2Bepsilon in vivo. eIF2Bϵ from mammals or insects is a substrate for glycogen synthase kinase 3 (GSK3), and this inhibits the activity of eIF2B SIGNOR-251215 0.372 tolazoline chemical CHEBI:28502 ChEBI ADRA2A protein P08913 UNIPROT down-regulates activity chemical inhibition 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258912 0.8 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr118 AGPLIVPyNLPLPGG 9606 20600357 t llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. SIGNOR-166497 0.361 A5/b1 integrin complex SIGNOR-C163 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257705 0.601 OPHN1 protein O60890 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 t miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro SIGNOR-268399 0.58 AMHR2 protein Q16671 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 14746809 t gcesareni See table2 SIGNOR-121593 0.541 RPS6KA3 protein P51812 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates quantity by destabilization phosphorylation Thr263 SIRDRNGtHLDAGAL 21183680 t lperfetto The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle, and cell transformation. Here, we report that RSK2 phosphorylates caspase-8, and Thr-263 was identified as a novel caspase-8 phosphorylation site. In addition, we showed that EGF induces caspase-8 ubiquitination and degradation through the proteasome pathway, and phosphorylation of Thr-263 is associated with caspase-8 stability. SIGNOR-272997 0.375 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser295 FKLGGRDsRSGSPMA -1 2413024 t miannu Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-164 SIGNOR-250014 0.35 CTNNB1 protein P35222 UNIPROT FOXA2 protein Q9Y261 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22945641 f gcesareni Our study indicates that beta-catenin regulates foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation SIGNOR-198929 0.452 SOS1 protein Q07889 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 25624485 t Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. gcesareni Because the KRAS-GDP to KRAS-GTP transition catalyzed by the GEF, son of sevenless 1 (SOS1), represents the rate-limiting step for nucleotide exchange, disrupting the activating SOS1/KRAS protein interaction has also been the focus of drug development efforts SIGNOR-201703 0.824 JAKMIP1 protein Q96N16 UNIPROT TUBB protein P07437 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000661 15277531 t SARA In Jamip1, the N-terminal region mediates the association with microtubules, when highly expressed, N-ter drastically affects the organization of microtubules that appear to be bundled, stabilized against the depolymerizing effect of nocodazole, and enriched in acetylated tubulin. SIGNOR-260987 0.2 TFEB protein P19484 UNIPROT NDUFA8 protein P51970 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276702 0.2 CREB5 protein Q02930 UNIPROT MAPKAPK3 protein Q16644 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002814 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253807 0.252 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 17634129 t lperfetto The activity of Cdc2 is regulated by the phosphatase Cdc25C. Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis.|Cdc2 is activated by Cdc25C that removes phosphate groups from tyrosine 15 and threonine 14 .|Dephosphorylation of Cdc2 at threonine 14 and tyrosine 15 by Cdc25C results in activation of Cdc2 and initiation of an autoactivation loop between Cdc25C and Cdc2 that efficiently drives cells into mitosis. SIGNOR-276945 0.855 MAPK3 protein P27361 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser380 HQLFRGFsFVATGLM 9534 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219341 0.71 QOCYWLABLBUJOR-UHFFFAOYSA-N chemical CID:53299324 PUBCHEM SLC6A3 protein Q01959 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 18487050 t Luana For [3H]paroxetine, [3H]citalopram, [3H]nisoxetine, and [3H]WIN35,428 the following KD values were obtained on the human monoamine transporters hSERT, hNET, and hDAT by homologous competition experiments: 0.69 nM [3H]paroxetine, 4.46 nM [3H]citalopram, 6.77 nM [3H]nisoxetine, and 24.1 [3H]WIN35,428.  SIGNOR-257796 0.8 IL1A protein P01583 UNIPROT IL1R1 protein P14778 UNIPROT up-regulates activity binding 9606 BTO:0000876 7964161 t lperfetto Interleukin-1 receptor (il-1r) is a cytokine receptor which binds interleukin 1. SIGNOR-35077 0.762 BTG2 protein P78543 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 21172304 f Androgen-induced promoter activation and expression of prostate-specific antigen (PSA) are significantly attenuated by BTG2. SIGNOR-253658 0.2 MAPK1 protein P28482 UNIPROT TNFRSF1A protein P19438 UNIPROT down-regulates activity phosphorylation Thr280 FSPTPGFtPTLGFSP -1 11606045 t lperfetto Phosphorylation of murine CD120a by p42(mapk/erk2) has been shown to inhibit its ability to initiate apoptosis while preserving signaling events such as NF-kappaB activation.|Additionally, we demonstrated that (i) the p42(mapk/erk2)-dependent phosphorylation of CD120a and DR3 occurred on Ser and Thr residues, (ii) p42(mapk/erk2) phosphorylated residues located in the membrane proximal regions but not the death domains of CD120a and DR3, (iii) Ser 253 is a preferred site of phosphorylation on CD120a SIGNOR-249453 0.509 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr30 NQSSGYRyGTDPTPQ -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251165 0.2 PPP1CA protein P62136 UNIPROT MECOM protein Q03112 UNIPROT down-regulates activity dephosphorylation Ser1037 IGNSNHGsQSPRNVE 23858473 t phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. SIGNOR-273429 0.2 A11/b1 integrin complex SIGNOR-C168 SIGNOR Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 10090 BTO:0000165 11518510 f lperfetto In addition, alpha11beta1 mediated contraction of fibrillar collagen gels in a manner similar to alpha2beta1, and supported migration on collagen I in response to chemotactic stimuli. Our data support a role for alpha11beta1 as a receptor for interstitial collagens on mesenchymally derived cells and suggest a multifunctional role of alpha11beta1 in the recognition and organization of interstitial collagen matrices during development. SIGNOR-253349 0.7 serotonin smallmolecule CHEBI:28790 ChEBI AANAT protein Q16613 UNIPROT up-regulates activity chemical activation -1 22775292 t miannu Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. Melatonin synthesis requires serotonin, which is first acetylated by the arylalkylamine N-acetyltransferase (AA-NAT) to produce N-acetyl serotonin (NAS) (Fig. 1A). Then, acetyl serotonin methyltransferase (ASMT, also known as hydroxyindole O-methyltransferase or HIOMT) produces melatonin by transferring a methyl group from the cofactor S-adenosyl-L-methionine (SAM) to NAS. SIGNOR-265477 0.8 F9 protein P00740 UNIPROT Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR form complex binding 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263552 0.761 PPP2R5B protein Q15173 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Thr308 KDGATMKtFCGTPEY 9606 16495456 t gcesareni Activation of pp2a is the intermediate step between the abeta-ceramide cascade and the subsequent inactivation of akt. SIGNOR-252615 0.652 PRKD1 protein Q15139 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates activity phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 20940406 t lperfetto Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba. SIGNOR-168537 0.474 YAP/TAZ proteinfamily SIGNOR-PF120 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23075495 f miannu YAP and TAZ are two main downstream effectors of the Hippo pathway, and they function as transcription co-activators to promote cell proliferation and inhibit apoptosis. SIGNOR-277640 0.7 PML protein P29590 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15093545 f gcesareni The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor SIGNOR-124320 0.7 NR2F1 protein P10589 UNIPROT RXRA protein P19793 UNIPROT up-regulates binding 9606 10900149 t lperfetto Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site SIGNOR-79440 0.536 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr36 LPPGDYStTPGGTLF 9606 SIGNOR-C3 17510057 t lperfetto In response to insulin and nutrients, mTORC1, consisting of mTOR, raptor (regulatory-associated protein of mTOR), and mLST8, is activated and phosphorylates eukaryotic initiation factor 4E-binding protein (4EBP) and p70 S6 kinase to promote protein synthesis and cell size. SIGNOR-154810 0.925 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109551 0.789 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264954 0.7 JUN protein P05412 UNIPROT Brown_adipogenesis phenotype SIGNOR-PH27 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni Other g protein-mediated pathways are the planar cell polarity (pcp) pathway (shown in blue) leading to the activation of rac/rho, c-jun n-terminal kinase (jnk), and/or rho-associated kinase (rock). Jnk can induce jun, which, together with fos, forms the ap-1 early response transcription factor. Both pcp pathways have been implicated in cytoskeletal rearrangements SIGNOR-198834 0.7 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser114 EETRTPEsQPDTPPG 9606 21824916 t lperfetto We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro. SIGNOR-176016 0.641 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273060 0.635 SRC protein P12931 UNIPROT MUC1 protein P15941 UNIPROT up-regulates phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 11152665 t lperfetto The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin SIGNOR-85938 0.451 CTBP2 protein P56545 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002181 21315774 t Luana Overexpression of the CtBP2 protein enhanced the repression activity of the E-cadherin promoter in a dose-dependent manner, whereas overexpression of ataxin-1 increased the activity of the E-cadherin promoter in a dose-dependent manner  SIGNOR-261578 0.388 HARS1 protein P12081 UNIPROT tRNA(His) smallmolecule CHEBI:29178 ChEBI down-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270485 0.8 CDK4 protein P11802 UNIPROT RBL1 protein P28749 UNIPROT up-regulates activity phosphorylation Ser650 SVHERYSsPTAGSAK 9606 12006580 t llicata Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.  SIGNOR-250763 0.803 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCB protein P05771 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190347 0.8 ADRA1D protein P25100 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256808 0.293 PRKCD protein Q05655 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates phosphorylation Thr312 TNGEFKMtDPDEVAR 9606 21321929 t lperfetto We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter. SIGNOR-172113 0.35 MLF1 protein P58340 UNIPROT COP1 protein Q8NHY2 UNIPROT up-regulates 9606 15861129 f miannu As downstream elements of mlf1 leading to cell growth arrest due to p53 accumulation, we identified two factors, csn3, the third component of the cop9 signalosome (csn), and cop1, a recently characterized e3 ubiquitin ligase for p53 SIGNOR-135940 0.2 MAPK8 protein P45983 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr278 SVSAATLtPSSQAVT 9606 19245816 t gcesareni In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed. SIGNOR-184190 0.699 FIG4 protein Q92562 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 t miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. SIGNOR-253528 0.93 POM121 protein Q96HA1 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262071 0.472 CBL protein P22681 UNIPROT FRS2 protein Q8WU20 UNIPROT down-regulates ubiquitination 9606 11997436 t lperfetto The experiments presented in this report illustrate that in response to fgf stimulation, cbl is recruited by grb2 binding to the frs2_ multiprotein complex, resulting in ubiquitination of frs2_ and fgfr. grb2 functions as a link between frs2_ and cbl;grb2 is bound to tyrosine-phosphorylated frs2_ by means of its sh2 domain and to a proline-rich region in the c terminus of cbl by means of its sh3 domains. SIGNOR-87166 0.565 CTNNB1 protein P35222 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates activity binding 10090 BTO:0001086 21295277 t flangone We provide evidence suggesting that Beta-catenin’s interaction with the pluripotency regulator Oct-4 at least partially underlies its effects on sustaining pluripotency. SIGNOR-241981 0.586 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258098 0.8 MAP3K1 protein Q13233 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation Ser271 ISGRLVDsKAKTRSA 9606 9312068 t lperfetto Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1 SIGNOR-51207 0.715 GRK6 protein P43250 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser375 GTLRTSIsVERQIHK 9606 BTO:0000007 11517230 t Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration. SIGNOR-251206 0.29 ARPC5 protein O15511 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251518 0.959 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation 9606 9748228 t fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 SIGNOR-60174 0.695 MAPK1 protein P28482 UNIPROT PARVA protein Q9NVD7 UNIPROT up-regulates activity phosphorylation Ser8 MATSPQKsPSVPKSP 9606 BTO:0001938 22955285 t lperfetto Actopaxin (alpha-parvin) is a paxillin, integrin-linked kinase, and F-actin binding focal adhesion protein with several serine phosphorylation sites in the amino terminus that contribute to the regulation of cell spreading and migration.|Actopaxin phosphorylation of Ser4/8 enhances cell migration whereas a nonphosphorylatable (Quint) mutant suppresses migration in U2OS osteosarcoma cells (7). SIGNOR-265759 0.261 MARK3 protein P27448 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates activity phosphorylation Ser151 LSLAKSVsTTNIAGH 9606 BTO:0002181 29089450 t miannu Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules. SIGNOR-277368 0.388 HSPH1 protein Q92598 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255243 0.463 RXRB protein P28702 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 10976919 t inferred from family member gcesareni Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr SIGNOR-270297 0.645 quinpirole chemical CHEBI:75401 ChEBI DRD3 protein P35462 UNIPROT up-regulates activity chemical activation -1 7576010 t miannu D3 receptors have been reported, however, to have affinities nearly 100-fold higher than those of D2 receptors for some agonists, including (+/-)-7-hydroxy-n,n-dipropyl-aminotetralin (7-OH-DPAT) and quinpirole. SIGNOR-258440 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25A protein P30304 UNIPROT up-regulates phosphorylation Ser116 PQKLLGCsPALKRSH 9606 12411508 t lperfetto Mitotic stabilization of cdc25a reflects its phosphorylation on ser17 and ser115 by cyclin b-cdk1, modifications required to uncouple cdc25a from its ubiquitin-proteasome-mediated turnover. SIGNOR-216761 0.845 NCOA6 protein Q14686 UNIPROT GREB1 protein Q4ZG55 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003041 31744881 t miannu Herein, using growth-regulating estrogen receptor binding 1 (GREB1) as an ERα target gene in Ishikawa cells, we demonstrate that nuclear receptor co-activator 6 (NCOA6) is essential for estradiol (E2)/ERα-activated GREB1 transcription. We found that NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner and that NCOA6 knockout reduces chromatin looping, enhancer-promoter interactions, and basal GREB1 expression in the absence of E2. SIGNOR-265883 0.2 CUL9 protein Q8IWT3 UNIPROT FERMT2 protein Q96AC1 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 35469017 t miannu M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2. SIGNOR-276717 0.2 DDX3X protein O00571 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 21883093 t miannu In the present study, we indentified the SG marker PABP1 [poly(A)-binding protein 1] as another direct interaction partner of DDX3. Interestingly, down-regulation of DDX3 interfered with SG assembly, led to nuclear accumulation of PABP1 and reduced cell viability following stress. Conversely, supplementation with a shRNA (short hairpin RNA)-resistant DDX3 restored SG formation, the translocation of PABP1 into SGs and cell survival. SIGNOR-269201 0.581 HOXA9 protein P31269 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding -1 9343407 t 2 miannu We now show that the Hoxa-9 protein physically interacts with Meis1 proteins. Hox proteins from the other AbdB-like paralogs, Hoxa-10, Hoxa-11, Hoxd-12, and Hoxb-13, also form DNA binding complexes with Meis1b. DNA binding complexes formed by Meis1 with Hox proteins dissociate much more slowly than DNA complexes with Meis1 alone, suggesting that Hox proteins stabilize the interactions of Meis1 proteins with their DNA targets. SIGNOR-241162 0.633 ABL2 protein P42684 UNIPROT CRK protein P46108 UNIPROT down-regulates phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 15886098 t gcesareni Rin1 binds to the abl sh3 and sh2 domains, and these interactions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl, inhibiting these cytoskeletal regulators by promoting intramolecular over intermolecular associations. the ability of crk to function as an adaptor protein is negatively regulated and terminated by phosphorylation on y221, which results in an intramolecular sh2-ptyr clamp, thereby resulting in the disassembly of crk-mediated signaling complexes SIGNOR-136955 0.688 Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270834 0.759 RPL35A protein P18077 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262465 0.851 ADNP protein Q9H2P0 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000007 32533114 t miannu Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. SIGNOR-266756 0.251 SOX6 protein P35712 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 SIGNOR-251760 0.426 KLF3 protein P57682 UNIPROT KLF8 protein O95600 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000759 18687676 t Luana Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.  SIGNOR-266049 0.257 RRAGC protein Q9HB90 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates binding 9606 20006481 t lperfetto Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor. SIGNOR-217547 0.692 SREBF1 protein P36956 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 t gcesareni Well-described targets of srebp-1 and the carbohydrate response element binding protein (chrebp), which include the following: fatty acid synthase (fas), acetyl coa carboxylase (acc1), and liver pyruvate kinase (l-pk) SIGNOR-142297 0.293 UBE2C protein O00762 UNIPROT Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 9606 19632176 f miannu The evolution of prostate cancer from an androgen-dependent state (ADPCa) to one that is androgen-independent (AIPCa) marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in AIPCa is poorly understood. We have defined the direct AR-dependent target genes in both AIPCa and ADPCa by generating AR-dependent gene expression profiles and AR cistromes. In contrast to ADPCa, AR selectively up-regulates M-phase cell cycle genes in AIPCa including UBE2C, a gene that inactivates the M-phase checkpoint. SIGNOR-251544 0.7 MAPK8 protein P45983 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10116 BTO:0003324 16306447 t gcesareni We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase. SIGNOR-252426 0.434 HIPK2 protein Q9H2X6 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Ser882 IVIPDTPsPTVSVIT 9606 BTO:0002181 24145406 t miannu  Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. SIGNOR-276600 0.2 UBA52 protein P62987 UNIPROT PRKN protein O60260 UNIPROT up-regulates activity binding 10090 BTO:0002572 phosphorylation: ser65 DYNIQKEsTLHLVLR 24784582 t The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. SIGNOR-270344 0.2 FGF9 protein P31371 UNIPROT TGFB1 protein P01137 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22298955 f FGF-2 and FGF-9 increased expression of other??osteogenic??factors??BMP-2??and TGFbeta-1 gcesareni Fgf-2 and fgf-9 increased expression of other osteogenic factors bmp-2 and tgf-beta1, and endogenous fgf/fgfr signaling is a positive upstream regulator of the bmp-2 gene in calvarial osteoblasts SIGNOR-195594 0.311 oligopeptide smallmolecule CHEBI:25676 ChEBI peptide antigen smallmolecule CHEBI:166824 ChEBI up-regulates quantity precursor of 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267863 0.8 PTPN13 protein Q12923 UNIPROT ABL1 protein P00519 UNIPROT down-regulates activity dephosphorylation Tyr226 KRNKPTVyGVSPNYD 9606 28924170 t lperfetto We also found that PTPN13 dephosphorylates and inhibits c-Abl.|While the above results indicated that calpain-2 could cleave PTPN13 and that PTPN13 could dephosphorylate c-Abl at tyrosine 245, they did not determine whether calpain-2-mediated cleavage of PTPN13 resulted in its inactivation and increased tyrosine phosphorylation of c-Abl at tyrosine 245. SIGNOR-277012 0.396 PTPN11 protein Q06124 UNIPROT SPRY1 protein O43609 UNIPROT down-regulates dephosphorylation 9606 16481357 t gcesareni These results identify sprouty proteins as in vivo targets of corkscrew/shp-2 tyrosine phosphatases and show how corkscrew/shp-2 proteins can promote rtk signaling by inactivating a feedback inhibitor. SIGNOR-144547 0.415 ESCRT-III complex SIGNOR-C379 SIGNOR Viral_budding phenotype SIGNOR-PH125 SIGNOR up-regulates 9606 26775243 f miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. SIGNOR-265534 0.7 CSNK1E protein P49674 UNIPROT PER2 protein O15055 UNIPROT down-regulates quantity by destabilization phosphorylation Ser480 PVPHSGSsGYGSLGS -1 30425162 t miannu Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2 SIGNOR-277419 0.9 PPP2CA protein P67775 UNIPROT RBL2 protein Q08999 UNIPROT up-regulates dephosphorylation 9606 15467457 t miannu Pocket protein family consists of the retinoblastoma tumor suppressor protein (prb) and the functionally and structurally related proteins p107 and p130./dephosphorylation of p130 and p107 in cell extracts is inhibited by concentrations of okadaic acid known to inhibit pp2a, but not pp1. Finally, the pp2a catalytic subunit pp2a/c) specifically interacts with both p130 and p107 / the cell cycle repressor activity of pocket proteins is inactivated by cdk mediated phosphorylation. SIGNOR-129752 0.569 PIK3CA protein P42336 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 BTO:0000150 19573809 f lperfetto However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth SIGNOR-236436 0.814 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT up-regulates activity binding 9606 15907471 t lperfetto Cytochrome c (Cyt c) is then released from the intermembrane space of the mitochondrion into the cytosol, where it binds to apoptotic protease-activating factor 1 (Apaf-1) in the presence of ATP/dATP to form the apoptosome. SIGNOR-137295 0.789 ARPC3 protein O15145 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR form complex binding 9606 12479800 t The subunits in mammalian cells are named Arp3, Arp2, p41-Arc, p34-Arc, p21-Arc, p20-Arc and p16-Arc SIGNOR-251516 0.963 CHEK1 protein O14757 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates activity phosphorylation Ser296 GFSKHIQsNLDFSPV 8355 15707391 t lperfetto This suggests that Ser296 is probably one of the sites autophosphorylated when Chk1 is fully activated [21], despite the sequence surrounding Ser296 (FSKHIQS296NL) being only weakly related to the optimal Chk1-recognition motif (M/I/L/V)-X-(R/K)-X-X-(S/T), where (S/T) is the phosphorylated residue SIGNOR-219240 0.2 SLC12A2 protein P55011 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264634 0.8 ITGB2 protein P05107 UNIPROT AL/b2 integrin complex SIGNOR-C169 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253190 0.913 RNF7 protein Q9UBF6 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271449 0.302 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Thr1047 SSSSELStPEKPPHQ 9606 BTO:0000680;BTO:0001573;BTO:0001286 14551205 t lperfetto Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex SIGNOR-216949 0.422 PTPN1 protein P18031 UNIPROT KRT8 protein P05787 UNIPROT down-regulates activity dephosphorylation Tyr267 IAEVKAQyEDIANRS 9606 BTO:0000182 24003221 t lperfetto Keratin 8 phospho-Tyr-267 is dephosphorylated by PTP1B and promotes insolubility and filament organization, as does the paralogous GFAP tyrosine. SIGNOR-265495 0.2 MAPK15 protein Q8TD08 UNIPROT MAPK15 protein Q8TD08 UNIPROT up-regulates phosphorylation Thr175 GPEDQAVtEYVATRW 9606 16336213 t lperfetto Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif.Our results suggest that the activity of erk8 in transfected hek-293 cells depends on the relative rates of erk8 autophosphorylation SIGNOR-142969 0.2 KIRREL3 protein Q8IZU9 UNIPROT CASK protein O14936 UNIPROT up-regulates activity binding 9606 BTO:0000232 33853164 t miannu A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia. KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene.  SIGNOR-269078 0.466 FOXO1 protein Q12778 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 30519351 t miannu To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter. SIGNOR-277739 0.619 MDM2 protein Q00987 UNIPROT TP53 protein P04637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 10935507 t lperfetto Many posttranslational modifications of p53, such as phosphorylation, dephosphorylation, acetylation and ribosylation, have been shown to occur following cellular stress. Some of these modifications may activate the p53 protein, interfere with MDM2 binding and/or dictate cellular localization of p53. SIGNOR-80528 0.968 PRKCA protein P17252 UNIPROT TRPV5 protein Q9NQA5 UNIPROT up-regulates activity phosphorylation Ser654 YVEVFKNsDKEDDQE 9606 17006539 t gcesareni A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. SIGNOR-149952 0.2 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7318 RPGSRAGsRAGSRAS 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264432 0.442 XCL1 protein P47992 UNIPROT XCR1 protein P46094 UNIPROT up-regulates binding 9606 BTO:0000763 10518929 t gcesareni Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells. SIGNOR-71164 0.783 C3AR1 protein Q16581 UNIPROT Vascular_Permeability phenotype SIGNOR-PH140 SIGNOR up-regulates 10984054 f lperfetto The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability SIGNOR-263458 0.7 CXCL10 protein P02778 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 t miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. SIGNOR-260969 0.782 MIB1 protein Q86YT6 UNIPROT DLL1 protein O00548 UNIPROT up-regulates activity ubiquitination 9606 16140393 t lperfetto Mib physically interacts with Delta and promotes its ubiquitination and internalization [66], which have been shown to up-regulate Notch activity. SIGNOR-209750 0.736 FGF14 protein Q92915 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253437 0.26 EGFR protein P00533 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 11602604 t lperfetto Rgs16 contains two conserved tyrosine residues in the rgs box, tyr(168) and tyr(177), which are predicted sites of phosphorylation. Rgs16 underwent phosphorylation in response to m2 muscarinic receptor or egfr stimulation in hek 293t or cos-7 cells, which required egfr kinase activity. Mutational analysis suggested that rgs16 was phosphorylated on both tyrosine residues (tyr(168) tyr(177)) after egf stimulation.Phosphorylated rgs16 demonstrated enhanced gtpase accelerating (gap) activity on galpha(i). Mutation of tyr(168) to phenylalanine resulted in a 30% diminution in rgs16 gap activity mutation of tyr(177) to phenylalanine had no effect on rgs16 gap activity but also abolished its regulation of g(i)-mediated signal transduction in these cells. SIGNOR-111024 0.421 entinostat chemical CHEBI:132082 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257905 0.8 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120104 0.314 PRKACB protein P22694 UNIPROT GPKOW protein Q92917 UNIPROT up-regulates activity phosphorylation Thr316 GTASSRKtLWNQELY 21880142 t miannu Using yeast two-hybrid screening with the PKA Cβ2 subunit as bait we identified GPKOW, also known as MOS2 homolog or T54 protein, as an interaction partner for Cβ2.PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites. SIGNOR-266298 0.309 MAPK1 protein P28482 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT 9606 12972619 t lperfetto We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2. SIGNOR-236014 0.787 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2J2 protein Q8N2K1 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271373 0.473 APC-c complex SIGNOR-C150 SIGNOR CCNF protein P41002 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27653696 t miannu We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. SIGNOR-266362 0.445 FLI1 protein Q01543 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates activity 10090 BTO:0000725 23320737 f The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice SIGNOR-259972 0.7 PURA protein Q00577 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12933792 f miannu In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene. SIGNOR-253902 0.2 PRKCB protein P05771 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97283 0.2 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr791 TPMYGSQtPLQDGSR 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143931 0.772 PRKCG protein P05129 UNIPROT APTX protein Q7Z2E3 UNIPROT up-regulates phosphorylation Thr125 AKNPGLEtHRKRKRS 9606 19561170 t llicata We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx. SIGNOR-186409 0.324 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 21154127 t irozzo Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. SIGNOR-255819 0.8 RRM1 protein P23921 UNIPROT Ribonucleotide reductase complex SIGNOR-C233 SIGNOR form complex binding 9606 14583450 t miannu Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair.RR consists of two subunits, hRRM1 and hRRM2. SIGNOR-259363 0.932 BAK1 protein Q16611 UNIPROT HTRA2 protein O43464 UNIPROT up-regulates relocalization 9606 14585074 t Translocation from Mitochondria to Cytosol amattioni Bax and/or bak-mediated release of pro-apoptotic mediators including smac/diablo and omi SIGNOR-118908 0.299 docetaxel anhydrous chemical CHEBI:4672 ChEBI TUBA4A protein P68366 UNIPROT down-regulates activity chemical inhibition 9606 23337758 t miannu Tubulin exists in the cell as dimers of α and β subunits, which complexes with a variety of regulatory proteins. There is a dynamic equilibrium between free and polymerized tubulin causing a state called "dynamic instability," which is a target of anticancer drugs, which inhibit tubulin through polymerization (taxanes, epothilones) or depolymerization (vinca alkaloids). Docetaxel-based therapy was the first such treatment to demonstrate a survival benefit in men with castration-resistant prostate cancer. SIGNOR-259342 0.8 MED24 protein O75448 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266666 0.776 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252773 0.2 HBEGF protein Q99075 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 10209155 t gcesareni It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response. SIGNOR-67009 0.744 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109559 0.672 PELI1 protein Q96FA3 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates quantity by stabilization ubiquitination 9606 BTO:0002552 27248820 t miannu Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity. SIGNOR-259395 0.462 RPS20 protein P60866 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262430 0.875 NEK2 protein P51955 UNIPROT YAP1 protein P46937 UNIPROT up-regulates quantity by stabilization phosphorylation Thr143 AVSPGTLtPTGVVSG 35705994 t lperfetto NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143 SIGNOR-276586 0.2 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263823 0.7 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT up-regulates phosphorylation Tyr199 ELLEQQKyTVTVDYW 9606 SIGNOR-C14 12645577 t gcesareni These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-99318 0.366 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr153 YGPRPEEyEFLTPVE 9606 19321744 t llicata Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes. SIGNOR-184908 0.401 AREL1 protein O15033 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination Lys191 RNHIQLVkLQVEEVH 9606 BTO:0002552 31732561 t lperfetto AREL1 ubiquitinated SMAC, primarily on Lys62 and Lys191 |E701A substitution in the AREL1 HECT domain substantially increased its autopolyubiquitination and SMAC ubiquitination activity, whereas deletion of the last three amino acids at the C terminus completely abrogated AREL1 autoubiquitination and reduced SMAC ubiquitination. SIGNOR-267672 0.382 PLAG1 protein Q6DJT9 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11888928 f miannu Plagl1 has been shown to prevent the proliferation of tumor cells by inducing cell cycle arrest and apoptosis SIGNOR-256658 0.7 CDK2 protein P24941 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates activity phosphorylation Ser251 EVSIRVGsPQPSSSG 9606 BTO:0002181 29229926 t miannu  During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. SIGNOR-277374 0.333 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246281 0.2 HES1 protein Q14469 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 16282371 f Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1 SIGNOR-253058 0.7 morphine chemical CHEBI:17303 ChEBI OPRM1 protein P35372 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258765 0.8 AKT1 protein P31749 UNIPROT GATA1 protein P15976 UNIPROT up-regulates phosphorylation Ser310 QTRNRKAsGKGKKKR 9606 16107690 t llicata We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter. SIGNOR-139782 0.523 KAT6A protein Q92794 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 SIGNOR-C54 11965546 t miannu Moz and morf both interact with runx2 / while morf does not acetylate runx2, its sm domain potentiates runx2-dependent transcriptional activation. SIGNOR-117332 0.311 CAMK2B protein Q13554 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 BTO:0000567 SIGNOR-C15 15980064 t gcesareni These data indicate that the camkks function in intact cells as ampkks, predicting wider roles for these kinases in regulating ampk activity in vivo. SIGNOR-138360 0.2 AX/b2 integrin complex SIGNOR-C171 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257714 0.444 IFNAR complex SIGNOR-C243 SIGNOR PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9606 21631354 t miannu These results indicate that NF-κB activation by IFN via the PI3K pathway is distinct from the ISRE-driven mechanism in regulating gene expression. Activation of PI3K/AKT by IFN has also been described through the insulin receptor substrate 1 (Uddin and others 1997) and through the direct interaction of PI3K with IFNAR1, which also leads to induction of NF-κB activity SIGNOR-260436 0.2 ATR protein Q13535 UNIPROT USP28 protein Q96RU2 UNIPROT up-regulates activity phosphorylation Ser714 ESSTNSSsQDYSTSQ 31938050 t lperfetto Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity.|Representative immunoblots of n = 3. C Immunoblotting of total and phosphorylated USP28 at serine 67 and 714 in A431 cells exposed to indicated concentrations of CPPD for 6 h. SIGNOR-275851 0.2 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-253332 0.636 HMOX1 protein P09601 UNIPROT heme smallmolecule CHEBI:30413 ChEBI down-regulates quantity chemical modification 9606 10490932 t Regulation miannu Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme SIGNOR-251911 0.8 AKT2 protein P31751 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 9606 17277771 t lperfetto Furthermore, pras40 phosphorylation by akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mtor. These findings identify pras40 as an important regulator of insulin sensitivity of the akt-mtor pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes. SIGNOR-235967 0.575 CDK6 protein Q00534 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates activity phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 16508017 t gcesareni Here, we show that p21cip1 is associated with k cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the k cyclin/cdk6 complex, resulting in phosphorylation of p21cip1 on serine 130. This phosphoform of p21cip1 appeared unable to associate with cdk2 in vivo. SIGNOR-144832 0.861 IL2 protein P60568 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 22128144 f miannu We observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. SIGNOR-253895 0.363 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205743 0.8 CSNK2A1 protein P68400 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates phosphorylation Ser226 KEREKEIsDDEAEEE 9606 18591256 t gcesareni Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation. SIGNOR-179260 0.337 IKBKB protein O14920 UNIPROT COPS5 protein Q92905 UNIPROT down-regulates activity phosphorylation Ser201 KPPDEGPsEYQTIPL -1 31950832 t lperfetto Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro. SIGNOR-275518 0.334 PRKAR2B protein P31323 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates activity phosphorylation Ser114 NRFTRRAsVCAEAYN 10090 15822905 t miannu Ser114 (the autophosphorylation site) of human RII beta. Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts. SIGNOR-250076 0.2 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser262 TFRPRSSsNASSVST 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252854 0.909 AKT1 protein P31749 UNIPROT LTB4R2 protein Q9NPC1 UNIPROT unknown phosphorylation Thr324 GGRSREGtMELRTTP 9606 22044535 t llicata Blt2 phosphorylation at thr355 by akt is necessary for blt2-mediated chemotaxis. SIGNOR-252516 0.387 GPHN protein Q9NQX3 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT up-regulates activity binding 9606 BTO:0000938 25882190 t miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264974 0.483 KDM4C protein Q9H3R0 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity demethylation 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-265333 0.2 RNF183 protein Q96D59 UNIPROT TNFRSF10B protein O14763 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 31889078 t miannu RNF183 mediated K63-linked ubiquitination and lysosomal degradation of DR5. SIGNOR-272212 0.2 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser932 DDTPEKDsFRARSTS 9606 BTO:0002181 30684133 t miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. SIGNOR-277426 0.2 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-75906 0.382 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates phosphorylation Ser664 KKTSGPLsPPTGPPG 9606 15851026 t lperfetto Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. s664 is the primary erk phosphorylation site on tsc2 in vitro and in vivo SIGNOR-244765 0.2 CKM complex complex SIGNOR-C406 SIGNOR SMAD3 protein P84022 UNIPROT down-regulates quantity by destabilization phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914168 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-273146 0.426 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT down-regulates activity phosphorylation Ser191 HRFRRQLsEPCNSFP 452646 11551945 t miannu MK2 phosphorylates ER81 in vitro within its central inhibitory domain, and overexpression of MK2 leads to increased in vivo phosphorylation of ER81. Two serine residues, ER81 amino acids 191 and 216, were identified as MK2 phosphorylation sites. MK2 suppresses basal ER81-dependent transcription SIGNOR-250145 0.602 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser706 ARIIGEKsFRRSVVG 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275961 0.2 NRXN2 protein Q9P2S2 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265460 0.264 CCND1 protein P24385 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates activity 9606 15713663 f areggio Collectively, these studies suggest an important role of cyclin D1 in regulation of PPARgamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARgamma function. SIGNOR-258981 0.7 INS protein P01308 UNIPROT TRIP10 protein Q15642 UNIPROT up-regulates 9606 12242347 f gcesareni The specific interaction of active tc10 with cip4 2 suggested thatinsulinmight induce a change in the subcellular localization of cip4 2 SIGNOR-93062 0.268 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT up-regulates activity binding 9606 25335892 t miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. SIGNOR-261815 0.912 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2L3 protein P68036 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271360 0.481 PRKCD protein Q05655 UNIPROT TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser939 SFRARSTsLNERPKS 9606 BTO:0002181 30684133 t miannu In vivo kinase analysis further indicated that both S932 and S939 are phosphorylated in response to translation inhibitors. Finally, phosphorylation defective TSC2 mutants (S932A and S939A single mutants and a S932A/S939A double mutant) failed to upregulate mTORC1 activity in the presence of translation inhibitors, suggesting that activation of mTORC1 by translation inhibitors is mediated by PKC-δ phosphorylation of TSC2 at S932/S939, which inactivates TSC. SIGNOR-277427 0.2 PRKCA protein P17252 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates quantity by stabilization phosphorylation Ser144 TLPSDKLsKIQTLKL 9606 BTO:0002181 30733340 t miannu Because most of these sites were predicted to be phosphorylated by protein kinase C (PKC), we overexpressed PKCα in several cell lines and found that it phosphorylates Twist1 on Ser-144. we observed that PKCα-mediated Twist1 phosphorylation at Ser-144 inhibits Twist1 ubiquitination and consequently stabilizes it. SIGNOR-277429 0.2 WASF1 protein Q92558 UNIPROT WRC complex complex SIGNOR-C191 SIGNOR form complex binding 9606 21107423 t miannu WAVE proteins are constitutively associated with four additional proteins in cells: Sra1/Cyfip1, Nap1/Hem-2, Abi and HSPC300. The components of this ~400 kDa pentamer, termed the WAVE regulatory complex (WRC) have all been implicated in control of Arp2/3 complex-mediated actin assembly in a wide range of systems. SIGNOR-253572 0.894 HDAC5 protein Q9UQL6 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates binding 9606 11062529 t gcesareni The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis. SIGNOR-84029 0.703 PAK5 protein Q9P286 UNIPROT TCF3 protein P15923 UNIPROT up-regulates activity phosphorylation Ser39 NGKGRPAsLAGAQFG 9606 BTO:0000150 26212009 t lperfetto The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation SIGNOR-275653 0.2 MYOD1/SWI/SNF complex complex SIGNOR-C93 SIGNOR TNNI2 protein P48788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 15870273 f miannu Swi/snf enzymes are necessary for myod to activate muscle gene transcription / myod increased the expression of 94 genes and decreased that of 70 genes /these 94 genes (represented by 96 array features) were analyzed for their dependence on a functional brg1-based swi/snf complex. In the presence of dominant-negative brg1, 29 genes did not achieve full activation by myod, as determined by statistical criteria (q 0.05) and a twofold or more decrease in expression level (table 1; see also table s1 in the supplemental material) SIGNOR-136786 0.349 EEF1A2 protein Q05639 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269529 0.8 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257928 0.8 STOML2 protein Q9UJZ1 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 18641330 t Giorgia In these studies, we also found that SLP-2 interacted with Lck, ZAP70, LAT, and PLC-gamma1 during the 30-min period following stimulation in vitro|The SLP-2-associated pool of these molecules became phosphorylated/activated in a sequential manner, a profile compatible with their temporal involvement in early TCR signalling. SIGNOR-260378 0.2 GAPDHS protein O14556 UNIPROT 3-phosphonato-D-glyceroyl phosphate(4-) smallmolecule CHEBI:57604 ChEBI up-regulates quantity chemical modification 9606 11724794 t miannu GAPDH is commonly known as a key enzyme in glycolysis (GAPDH catalyzes the NAD-mediated oxidative phosphorylation of glyceraldehyde 3-phosphate to 1,3-diphosphoglycerate), a number of intriguing intracellular roles have been reported including modulation of the cytoskeleton, kinase activity, and the promotion of vesicle fusion SIGNOR-266497 0.8 HBA1 protein P69905 UNIPROT EDN1 protein P05305 UNIPROT down-regulates activity 9606 8573884 f Regulation of localization miannu Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury. SIGNOR-251767 0.263 JAK3 protein P52333 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Tyr694 LAKAVDGyVKPQIKQ 9606 19088846 t gcesareni For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated. SIGNOR-182817 0.852 MYCT1 protein Q8N699 UNIPROT CCND2 protein P30279 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261731 0.2 MAPK3 protein P27361 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser649 PVLYMQPsPL 9606 12620228 t llicata Erk-dependent phosphorylation of the transcription initiation factor tif-ia is required for rna polymerase i transcription and cell growth. phosphopeptide mapping and mutational analysis reveals two serine residues (s633 and s649) that are phosphorylated by erk and rsk kinases. Replacement of s649 by alanine inactivates tif-ia, inhibits pre-rrna synthesis, and retards cell growth. SIGNOR-98984 0.2 JAK2 protein O60674 UNIPROT SLC6A8 protein P48029 UNIPROT down-regulates activity relocalization 443947 BTO:0000964 22407360 t miannu Janus-activated kinase-2 (JAK2) participates in the regulation of the Na⁺-coupled glucose transporter SGLT1 and the Na⁺-coupled amino acid transporter SLC6A19. JAK2 is a novel regulator of the creatine transporter SLC6A8, which downregulates the carrier, presumably by interference with carrier protein insertion into the cell membrane. SIGNOR-265781 0.2 SB 505124 chemical CHEBI:100922 ChEBI ACVR1C protein Q8NER5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206739 0.8 IC-87114 chemical CHEBI:90686 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252662 0.8 PTK2 protein Q05397 UNIPROT ACTN4 protein O43707 UNIPROT down-regulates phosphorylation Tyr31 GGGSMGDyMAQEDDW 9606 23454549 t lperfetto Phosphorylation at y12 by fak reduces _-actinin1's affinity for actin [25] and [27]. _-actinin4 is phosphorylated at y4, y31, and y265. Phosphorylation at y4 or y31 decreases its binding to actin [28] while phosphorylation of y265 increases its affinity for actin SIGNOR-192195 0.548 TRAC protein P01848 UNIPROT TCR complex SIGNOR-C153 SIGNOR form complex binding 9606 12507424 t miannu The T cell receptor-CD3 complex (TCR-CD3) serves a critical role in the differentiation, survival, and function of T cells, and receptor triggering elicits a complex set of biological responses that serve to protect the organism from infectious agents. The receptor is composed of six different chains that form the TCR heterodimer responsible for ligand recognition, as well as the CD3γε, CD3δε, and ζζ signaling modules.the TCRα-CD3δε and TCRβ-CD3γε interactions are similar since both require a lysine in the TM region of the respective TCR chain and both acidic TM residues in the relevant CD3 heterodimer. Nevertheless, formation of fully assembled αβ TCR-CD3 complexes containing the ζ-chain strictly required both CD3γ and δ SIGNOR-255297 0.2 PRKACA protein P17612 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Ser27 TSPTGRGsMAAPSLH 9606 11162439 t llicata Serine 27, a human retinoid x receptor alpha residue, phosphorylated by protein kinase a is essential for cyclicamp-mediated downregulation of rxralpha function. SIGNOR-104954 0.2 ASCL1 protein P50553 UNIPROT DKK1 protein O94907 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000527 23707066 t gcesareni We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. SIGNOR-245885 0.31 Apelin smallmolecule CID:56841713 PUBCHEM APLNR protein P35414 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257460 0.8 CAMK2A protein Q9UQM7 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Ser325 EQLSRELsTLRNLFK -1 1314426 t llicata These studies implicate Ser276 of CIEBPP as the major in vim phosphorylation site for CaMKII. | Phosphorylation of serine at position 276 within the leucine zipper of C/EBP beta appeared to confer calcium-regulated transcriptional stimulation of a promoter that contained binding sites for C/EBP beta. SIGNOR-250617 0.329 KDM4C protein Q9H3R0 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys37 APATGGVkKPHRYRP 9606 29207681 t miannu As one member of the Jumonji-C histone demethylase family, JMJD2C has the ability to demethylate tri- or di-methylated histone 3 and 2 in either K9 (lysine residue 9) or K36 (lysine residue 36) sites by an oxidative reaction, thereby affecting heterochromatin formation, genomic imprinting, X-chromosome inactivation, and transcriptional regulation of genes.JMJD2C has been proved to be a demethylase for H3K9 methylation, in the manner of catalyzing the demethylation of H3K9me3/me2 (the known repressive markers of gene regulation), a histone mark found in heterochromatin associated with euchromatic transcriptional silencing and heterochromatin formation SIGNOR-263864 0.2 MOB1B protein Q7L9L4 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates binding 9606 21084559 t Lats1 and Lats2 are nuclear Dbf2-related (NDR) family protein kinases. gcesareni Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1. SIGNOR-169798 0.874 PRKACA protein P17612 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t miannu Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII). Incubation of Rad with PKA decreases GTP binding by 60-70%, but this effect seems to be independent of phosphorylation, as it is observed with the Ser273-->Ala mutant of Rad containing a mutation at the site of PKA phosphorylation. SIGNOR-250048 0.343 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser12 TKRTADSsSSEDEEE 9606 21245376 t gcesareni Hp1_ was multiply phosphorylated at n-terminal serine residues (s11-14) in human and mouse cells and that this phosphorylation enhanced hp1_'s affinity for h3k9me. Unphosphorylatable mutant hp1_ exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. SIGNOR-171699 0.359 STAT6 protein P42226 UNIPROT KLF4 protein O43474 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22378047 t lperfetto STAT6 coordinates and synergizes with both PPAR? and KrŸppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function. SIGNOR-249568 0.35 STAT3 protein P40763 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000452 26738736 f miannu Collectively, the activation of IL-6/STAT3 pathway contributed to the PSCs-induced EMT i SIGNOR-277690 0.7 FOXO3 protein O43524 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260100 0.25 RORB protein Q92753 UNIPROT OPN1MW protein P04001 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001175 19381306 t miannu These observations indicate that RORβ is required for the induction of S opsin and support the conclusion that RORβ regulates Opn1sw transcription in a direct manner through ROREs within its proximal promoter region. In addition, they explain the greatly diminished expression of Opn1sw observed in the retina of RORβ-/- mice. SIGNOR-266851 0.2 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 10581258 t gcesareni In mcf-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at ser33 and ser46, a newly identified site. SIGNOR-72691 0.451 PKN1 protein Q16512 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation 9606 17251915 t gcesareni Phosphorylation of mltkalpha by pknalpha enhances its kinase activity SIGNOR-152768 0.2 TFDP1 protein Q14186 UNIPROT CDK1 protein P06493 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 14618416 f miannu To assess transactivating activity of E2F1/DP-1, we also analyzed expression of ten putative transcriptional targets of this complex in HCCs. Expression levels of TFDP1 and E2F1 correlated with those of seven transcriptional targets ( TYMS, DHFR, PCNA, RRM1, CCNE1, CDC2, and MYBL2) that play important roles in the G1/S transition, and down-regulation of TFDP1 inhibited growth of Hep3B cells. SIGNOR-253859 0.572 CAMK2A protein Q9UQM7 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser19 KGFRRAVsELDAKQA 9606 BTO:0000142 1680128 t llicata This increase in ser19 phosphorylation was associated with enhanced th activity and was due, in part, to glutamate-receptor-mediated calcium influx and possibly calcium/calmodulin-dependent protein kinase ii (camkii) activation. SIGNOR-20912 0.258 SETD1B protein Q9UPS6 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 32546568 t miannu SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. SIGNOR-265578 0.2 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT down-regulates activity phosphorylation Ser3 sGVAVSDG 9606 BTO:0001363 11418599 t lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin SIGNOR-246723 0.539 ATR protein Q13535 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser717 KDGGPVTsQESGQKL 9606 16943440 t lperfetto In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents SIGNOR-149305 0.665 MAPK8 protein P45983 UNIPROT GRB7 protein Q14451 UNIPROT down-regulates quantity by destabilization phosphorylation Ser194 KYELFKSsPHSLFPE 9606 BTO:0000017 27658202 t miannu Our data show that phosphorylation of Grb7 protein on the Ser194-Pro motif by c-Jun N-terminal kinase facilitates its binding with the WW domain of Pin1. Subsequently, Grb7 is degraded by the ubiquitin- and proteasome-dependent proteolytic pathway. I SIGNOR-277280 0.264 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT up-regulates activity phosphorylation Ser135 VNNESGEsQRGTDFS -1 18571408 t miannu Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). SIGNOR-262636 0.388 WWTR1 protein Q9GZV5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity binding 9606 21084559 t lperfetto Taz has been shown to interact with smad2 and smad3 through its coiled-coil region, and to be important in maintaining the nuclear localization of smad2 and smad3 as well as the expression of their target genes in response to tgf-b signaling and, thus, in the maintenance of human esc self-renewal. SIGNOR-169838 0.583 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG1-LLGL1_variant complex SIGNOR-C511 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270911 0.584 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser439 EPGTATGsGIKSHNS 9606 15574499 t amattioni Ikkbeta phosphorylates dok1 s(439)s(443) and s(446)s(450) after tnf-alpha, il-1, or gamma-radiation. mutant dok1 a(439), a(443), a(446), and a(450) differed from wild-type dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant dok1 a(439), a(443), a(446), and a(450) also did not promote cell motility whereas wild-type dok1 promoted cell motility. SIGNOR-131447 0.254 FH protein P07954 UNIPROT (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI up-regulates quantity chemical modification 9606 30761759 t miannu Fumarate hydratases (FHs, fumarases) catalyze the reversible conversion of fumarate into l-malate. FHs are distributed over all organisms and play important roles in energy production, DNA repair and as tumor suppressors. SIGNOR-266280 0.8 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Ser408 GPLPRAPsISTVEPK 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259860 0.337 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser696 EKNYALPsPATTEGG 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169514 0.527 Aldolase proteinfamily SIGNOR-PF75 SIGNOR beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266490 0.8 PCSK7 protein Q16549 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates phosphorylation 9606 11259586 t gcesareni This together with the rapid kinetics of pp1-pp2a activation following p38 activation suggests that pp1 and/or pp2a complexes are direct targets for p38-mediated phosphorylation SIGNOR-105783 0.2 PIM1 protein P11309 UNIPROT PSMD2 protein Q13200 UNIPROT up-regulates activity phosphorylation Ser361 ENNRFGGsGSQVDSA -1 31843888 t done miannu Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).  SIGNOR-273895 0.2 CDK1 protein P06493 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser123 EEGFGSSsPVKSPAA 9606 15070733 t gcesareni We have found also that the major M-phase kinases polo-like kinase 1 (Plk1) and Cdc2 are responsible for the phosphorylation of S53 and S123, respectively, and that in each case phosphorylation generates an unconventional phospho-degron (signal for degradation) that can be recognized by beta-TrCP SIGNOR-123824 0.856 DAB2 protein P98082 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT up-regulates activity binding 9606 27858941 t miannu In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation. SIGNOR-254744 0.531 ritanserin chemical CHEBI:64195 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258691 0.8 SYK protein P43405 UNIPROT LCK protein P06239 UNIPROT down-regulates activity phosphorylation Tyr192 NLDNGGFyISPRITF 9606 BTO:0000782 8798764 t lperfetto Our experiments indicate that the TCR-induced activation of Erk2 depends on the function of SH2 domain of Lck and is reduced by phosphorylation of wild type Lck at Tyr192 or by mutation of this site to a negatively charged amino acid. Such dependence on the SH2 domain has also been reported for the bulk of TCR-induced tyrosine phosphorylation and activation of the interleukin 2 gene (26). Thus, phosphorylation of Lck at Tyr192 may represent a negative feedback mechanism in the interplay between Src and Syk family PTKs in TCR signaling SIGNOR-246562 0.58 ITSN1 protein Q15811 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR up-regulates quantity by stabilization binding 24789820 t lperfetto Early recruitment of FCHo1/2, Eps15, epsin, and intersectin to the rims of assembling coated pits is essential for their stability and further growth SIGNOR-260714 0.569 TAF10 protein Q12962 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263926 0.894 phenformin chemical CHEBI:8064 ChEBI KCNJ11 protein Q14654 UNIPROT down-regulates activity chemical inhibition 9606 20188727 t lperfetto Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel |Phenformin but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). SIGNOR-262031 0.8 L-thyroxine smallmolecule CHEBI:18332 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates activity chemical activation 10116 BTO:0000759 2158622 t inferred from family member miannu We determined the affinity for T3 and analog binding characteristics of the translational products of c-erbA a- and /3-probes together with hepatic nuclear extracts. SIGNOR-270300 0.8 EZH2 protein Q15910 UNIPROT ALDH1A1 protein P00352 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004094 22144423 f miannu For three selected genes (ALDH1A1, SSTR1, and DACT3), we validated their upregulation upon EZH2 knockdown and confirmed the binding of EZH2/H3K27Me3 to their genomic loci. SIGNOR-254141 0.397 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000567 12853467 t 14-3-3s bind directly to cardiac PFK-2 phosphorylated by PKB. PFK-2 was phosphorylated on both Ser466 and Ser483 by PKB. the precise mechanism of fru-2,6-P2 regulation by 14-3-3s is still puzzling. SIGNOR-252574 0.647 Av/b3 integrin complex SIGNOR-C177 SIGNOR KRAS protein P01116 UNIPROT up-regulates activity binding 9606 BTO:0000584 32745890 t Oncogenic RAS miannu Oncogenic RAS requires a protein scaffold to induce downstream signaling and macropinocytosis, three separate studies have identified upstream and downstream regulators that help drive this process in cancer cells. Anchorage-independent growth of cancer cells is supported by avb3 integrins which can be clustered by the extracellular lectin, galectin-3 to drive mutant RAS-mediated macropinocytosis for nutrient supplementation and growth of anchorage-independent cells. Secreted galectin-3 was found to bind to the N-glycans on surface avb3 integrins, clustering the integrins on the surface of the nonadherent cells for the recruitment of mutant KRAS as a signaling platform for inducing macropinocytosis. SIGNOR-277742 0.35 PRKCE protein Q02156 UNIPROT ADAP1 protein O75689 UNIPROT unknown phosphorylation Thr276 GFRKRWFtMDDRRLM -1 12893243 t lperfetto The sites of phosphorylation by PKCalpha on centaurin-alpha1‚ were identified as S87 (peptide ARFEK) and T276 (peptide WFMDDRR) (‚ Fig. 5).‚ | The phosphorylation site analysis was carried out twice after phosphorylation of centaurin-alpha1‚ with PKCalpha and once with PKC_. A similar pattern of phosphopeptides was obtained each time. SIGNOR-249226 0.316 TGFB1 protein P01137 UNIPROT SKP2 protein Q13309 UNIPROT down-regulates 9606 21212736 f gcesareni Skp2, a f-box protein that determines the substrate specificity for scf ubiquitin ligase, has recently been demonstrated to be degraded by cdh1/apc in response to tgfbeta signaling. SIGNOR-171013 0.26 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Thr331 CTPVVTCtPSCTAYT phosphorylation:Ser374;Ser362 PSSDSLSsPTLLAL;AAAHRKGsSSNEPSS 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263009 0.2 ITCH protein Q96J02 UNIPROT MAVS protein Q7Z434 UNIPROT down-regulates quantity by destabilization ubiquitination Lys420 GLGSELSkPGVLASQ 9606 BTO:0002181 19881509 t Giorgia These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation SIGNOR-260363 0.636 PPM1F protein P49593 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t inferred from 70% of family members gcesareni Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity. SIGNOR-269882 0.395 PCDH19 protein Q8TAB3 UNIPROT GABRA6 protein Q16445 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C334,SIGNOR-C328,SIGNOR-C329 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267221 0.2 STRN4 protein Q9NRL3 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 t miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms SIGNOR-261699 0.598 FYN protein P06241 UNIPROT TOM1L1 protein O75674 UNIPROT up-regulates activity phosphorylation Tyr460 AVTTEAIyEEIDAHQ -1 11711534 t Tyr-457, located in the presumed Src SH2 binding site, is the predominant tyrosine residue that is phosphorylated by Fyn.Fyn can phosphorylate Srcasm, and association of these molecules relies on cooperative binding between the SH2 and SH3 domains of Fyn and corresponding canonical binding sites in Srcasm. Srcasm is capable of interacting with Grb2 and the regulatory subunit of phosphoinositide 3-kinase, p85, in a phosphorylation-dependent manner. The evidence suggests that Srcasm may help promote Src family kinase signaling in cells. SIGNOR-251185 0.44 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR UBTF protein P17480 UNIPROT down-regulates phosphorylation 9606 11741541 t inferred from 70% family members lperfetto Erk1/2 was found to phosphorylate the architectural transcription factor ubf at amino acids 117 and 201 within hmg boxes 1 and 2, preventing their interaction with dna SIGNOR-270181 0.2 GPS1 protein Q13098 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270774 0.922 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 21880741 t gcesareni Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat. SIGNOR-252311 0.641 STK11 protein Q15831 UNIPROT MARK1 protein Q9P0L2 UNIPROT up-regulates phosphorylation Thr215 TVGNKLDtFCGSPPY 9606 14976552 t lperfetto Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold SIGNOR-122545 0.416 NR3C1 protein P04150 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9590696 t gcesareni Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP. SIGNOR-251682 0.764 CREB1 protein P16220 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16205321 f gcesareni The results showed that the nuclear pkcalpha was significantly decreased in the liver during sepsis, which was accompanied by decreases in phospho-creb content, dna-binding activity of creb, and bcl-xl expression. SIGNOR-140911 0.366 NEUROG3 protein Q9Y4Z2 UNIPROT VSX2 protein P58304 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19028584 f miannu Ngn3 overexpression altered the expression of a number of regulatory genes, including ash1, ath3, ath5, chx10, neuroD, ngn1, ngn2, and NSCL1. Early gene ngn1 was induced, but ash1, ngn2, ath3, and chx10, whose expressions persist through later phases of neurogenesis, were down-regulated. SIGNOR-254635 0.276 RB1 protein P06400 UNIPROT E2F2 protein Q14209 UNIPROT down-regulates binding 9606 22569856 t gcesareni Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins. SIGNOR-197328 0.913 NOTCH1 protein P46531 UNIPROT TCF12 protein Q99081 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22577461 f miannu E2a positively regulates notch1 expression, which induces the expression of hebalt, bcl11b, and il7r. SIGNOR-197514 0.371 tertatolol chemical CHEBI:135244 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258862 0.8 HARS1 protein P12081 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 10430027 t miannu Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. SIGNOR-270489 0.8 PRKDC protein P78527 UNIPROT XRCC6 protein P12956 UNIPROT up-regulates activity phosphorylation Ser33 ASGDYKYsGRDSLIF 9606 BTO:0001546 26337656 t done miannu Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks. SIGNOR-274023 0.94 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation Ser368 QRPSSRAsSRASSRP 10116 10871288 t lperfetto Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication. SIGNOR-144465 0.446 TNPO1 protein Q92973 UNIPROT HNRNPA1 protein P09651 UNIPROT up-regulates activity relocalization 29970603 t lperfetto TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import SIGNOR-262099 0.583 DNA_damage stimulus SIGNOR-ST1 SIGNOR KDM4B protein O94953 UNIPROT up-regulates 9606 30759871 f miannu The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. KDM4 enzymes are generally over-expressed in cancers, making them compelling targets for study and therapeutic inhibition. One of these family members, KDM4B, is especially interesting due to its regulation by multiple cellular stimuli, including DNA damage, steroid hormones, and hypoxia. SIGNOR-263736 0.7 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI guanosine 5'-monophosphate smallmolecule CHEBI:17345 ChEBI up-regulates quantity precursor of 9606 6698284 t miannu The de novo synthesis of guanosine monophosphate (GMP) involves the oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) followed by amination to GMP. This latter reaction is catalyzed by GMP synthetase. (XMP: I.-glutamine amidoligase (AMP) EC 6.3.5.2). SIGNOR-267336 0.8 ADRA1B protein P35368 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256807 0.492 ROS stimulus SIGNOR-ST2 SIGNOR SNCA protein P37840 UNIPROT up-regulates quantity 9606 16000336 f lperfetto The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions. SIGNOR-249699 0.7 LPAR2 protein Q9HBW0 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257324 0.251 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Thr317 EDATLEEtLVKKKKK 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166333 0.367 SAMM50 protein Q9Y512 UNIPROT SAM complex complex SIGNOR-C422 SIGNOR form complex binding 31387448 t lperfetto The SAM complex of the outer membrane mediates insertion of β-barrel proteins into the outer membrane. hSam50 associates with MTX1 and MTX2. SIGNOR-267683 0.803 E2F1 protein Q01094 UNIPROT CDC25A protein P30304 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 11154267 f lperfetto Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen SIGNOR-245468 0.543 JAK2 protein O60674 UNIPROT TET2 protein Q6N021 UNIPROT up-regulates activity phosphorylation Tyr1939 CEKYGPDyVPQKSHG -1 30944118 t miannu Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacts with the erythroid transcription factor KLF1, and this interaction with TET2 is increased upon exposure to erythropoietin.  SIGNOR-277290 0.426 KAT6A protein Q92794 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates binding 9606 SIGNOR-C54 11742995 t miannu The activation domain of aml1 is required for its interaction with moz / moz activates aml1_mediated transcription SIGNOR-113056 0.472 PDGFRB protein P09619 UNIPROT NCK2 protein O43639 UNIPROT up-regulates binding 9606 10026169 t gcesareni The sh2 domains of grb2, nck, and grb4 all precipitated activated pdgf receptor with similar efficiency. SIGNOR-64740 0.604 tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates quantity precursor of 9606 16429158 t miannu YARS (also known as TyrRS) catalyzes the aminoacylation of tRNATyr with tyrosine by a two-step mechanism. Tyrosine is first activated by ATP to form tyrosyl-adenylate and is then transferred to tRNATyr SIGNOR-270523 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 SIGNOR-244576 0.2 RPL22L1 protein Q6P5R6 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262498 0.73 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGC4 protein Q9Y5F7 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265715 0.2 DAB2IP protein Q5VWQ8 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 BTO:0000007 20080667 t miannu DAB2IP activates GSK-3β and antagonizes Wnt-mediated EMT. GSK-3β appears to directly associate with DAB2IP. Because DAB2IP is not a phosphatase, the mechanism of GSK-3β activation by DAB2IP is likely mediated by a separate phosphatase associated within this complex. PP2A is critical for DAB2IP-mediated GSK-3β activation and MET responses. SIGNOR-254752 0.313 FZD3 protein Q9NPG1 UNIPROT CXCL1 protein P09341 UNIPROT up-regulates binding 9606 17251915 t gcesareni In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor gpcrs signal through four relatively small families of galfa proteins (galfas, galfai/o, galfaq, and galfa12/13), and if fzd receptors are classic gpcrs, they should signal through one of these four galfa families. SIGNOR-152597 0.2 DBH protein P09172 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 10090 7961964 t brain lperfetto Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. SIGNOR-264005 0.8 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 9219684 t gcesareni The three-dimensional structure of the complex between human h-ras bound to guanosine diphosphate and the guanosine triphosphatase (gtpase)-activating domain of the human gtpase-activating protein p120gap (gap-334) in the presence of aluminum fluoride was solved at a resolution of 2.5 angstroms. SIGNOR-49477 0.844 EIF4H protein Q15056 UNIPROT EIF4A1 protein P60842 UNIPROT up-regulates activity binding -1 11418588 t Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability SIGNOR-261294 0.798 LRP1B protein Q9NZR2 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000038; BTO:0000675 28408316 f irozzo Forced expression of LRP1B in SW480 and SW620 cells inhibited the growth, migration and anchorage-independent growth of cancer cells. SIGNOR-259091 0.7 CSNK1A1 protein P48729 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276261 0.311 RXRA protein P19793 UNIPROT PPARA protein Q07869 UNIPROT up-regulates binding 9606 11237216 t gcesareni Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105345 0.585 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser243 DKRKDPSsVDIKKVL -1 10480872 t llicata The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. | although CLK1 and CLK2 directly phosphorylate PTP-1B on both Ser50 and Ser242/Ser243, the preferred CLK phosphorylation site is Ser50, as it is preferentially phosphorylated at an approximate ratio of 9:1 over the Ser242/Ser243 site. SIGNOR-250776 0.325 Av/b1 integrin complex SIGNOR-C175 SIGNOR UTF1 protein Q5T230 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253275 0.263 CDK2 protein P24941 UNIPROT RPL12 protein P30050 UNIPROT unknown phosphorylation Ser38 KIGPLGLsPKKVGDD 9606 18847512 t llicata Finally, we selected one novel substrate, the ribosomal protein rl12, for further study: site-directed mutagenesis and phosphopeptide mapping confirmed that cdk2 phosphorylates rl12 in vitro and in vivo on the same site determined by our methods. SIGNOR-181603 0.2 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Thr714 EESDSSEtEKEDDEG 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275502 0.2 SKIL protein P12757 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates activity binding 9606 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-236152 0.883 NANOG protein Q9H9S0 UNIPROT LAMB1 protein P07942 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001086;BTO:0005511 15983365 f miannu Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCG-beta. SIGNOR-254628 0.268 MECP2 protein P51608 UNIPROT IGFBP3 protein P17936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 17278996 f miannu We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. SIGNOR-254580 0.253 inosine smallmolecule CHEBI:17596 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 15926889 t Luana Adenosine deaminase (ADA; EC 3.5.4.4) catalyses the deamination of adenosine and 2′-deoxyadenosine to inosine and deoxyinosine. Two different isoenzymes of ADA designated as ADA1 and ADA2 were found in mammals and lower vertebrates SIGNOR-269734 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 16982699 t gcesareni Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.[...] We next investigated if phosphorylation of p21-t145 interfered with akt2 binding. As shown in fig. ?Fig.8e8e (right lane), phosphorylation of p21 on t145 effectively prevented akt2 interaction. SIGNOR-244180 0.2 OGA protein O60502 UNIPROT G6PD protein P11413 UNIPROT down-regulates activity deglycosylation Ser84 VADIRKQsEPFFKAT 9606 26399441 t lperfetto O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth|O-GlcNAcylation of G6PD activates enzyme activity|G6PD is dynamically modified by O-GlcNAc at serine 84|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267605 0.2 MAPK1 protein P28482 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t gcesareni In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e. SIGNOR-94003 0.483 PTMS protein P20962 UNIPROT NR3C1 protein P04150 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 16150697 t miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner SIGNOR-268460 0.332 SMAD5 protein Q99717 UNIPROT SMAD5/SMAD4 complex SIGNOR-C205 SIGNOR form complex binding 9606 BTO:0000165;BTO:0002974; BTO:0002809 9442019 t ggiuliani These data suggest that activation of Smad5 and subsequent Smad5-DPC4 complex formation are key steps in the BMP signaling pathway, which mediates BMP-2-induced osteoblastic differentiation of the C2C12 mesenchymal cells. SIGNOR-255775 0.665 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t lperfetto Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression SIGNOR-252486 0.758 AP1 complex SIGNOR-C154 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates activity 9606 21561061 f Luana AP-1 regulates transcription of many genes involved in viralpathogenesis, including pro-inflammatory and antiviral cytokineslike IL-6,33IL-8,34RANTES,35MCP-1,19interferons,9etc., thatare characteristic of an infection. SARS pathology is the result ofan exacerbated pro-inflammatory immune response by cytokinesin the lungs of patients and in infected animal models. SIGNOR-260765 0.7 DRD1 protein P21728 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257335 0.485 PLK1 protein P53350 UNIPROT RAD21 protein O60216 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser175 REIMREGsAFEDDDM 9606 BTO:0000567 15737063 t lperfetto We suspected that the observed enhancement of Scc1's cleavability in the presence of Plk1 might be due to phosphorylation at two sites that are directly adjacent to the cleavage sites, Ser175 and Ser454, which we had found to be phosphorylated in mitosis in vivo (Table 1). We therefore mutated these two residues to alanine, thereby creating mutant Scc1-S175A/S454A (see Figure 1C), and tested the cleavability of this mutant in the absence or presence of Plk1 in vitro. |Scc1 phosphorylation is dispensable for cohesin dissociation from chromosomes in early mitosis but enhances the cleavability of Scc1 by separase. SIGNOR-275535 0.731 ZAP70 protein P43403 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity phosphorylation Tyr323 DEPVADPyDQSFESR 9606 BTO:0000782 15735648 t lperfetto Thus, phosphorylation of tyr323 dependent on the tyrosine kinase lck and mediated by zap70 serves as an important mechanism for tcr activation of p38 in t cells. SIGNOR-134329 0.464 SF3A2 protein Q15428 UNIPROT SF3a complex SIGNOR-C345 SIGNOR form complex binding 9606 BTO:0000567 8349644 t miannu Components required for the splicing of nuclear messenger RNA precursors in vitro have been isolated from HeLa cells. Here we describe the separation of splicing factor SF3 into two components, SF3a and SF3b. SF3a has been purified to homogeneity by a combination of ion-exchange chromatography, gel filtration, and glycerol gradient sedimentation. It consists of a complex of three polypeptides of 60, 66, and 120 kDa. SIGNOR-263947 0.96 PRKCD protein Q05655 UNIPROT ITGB7 protein P26010 UNIPROT unknown phosphorylation Thr783 PLYKSAItTTINPRF 10090 BTO:0001825 12682249 t lperfetto Beta7 subunit is phosphorylated even in unstimulated TK-1 cells. Activation of TK-1 cells with anti-CD3 (Fig. 5_A) and PDBu (Fig. 5_B) increased the phosphorylation 15€“20%. | The result shows that the fourth amino acid of the tryptic peptide was phosphorylated. This phosphorylated threonine residue is most likely the first threonine (Thr782) of threonine triplet (Thr782€“784). SIGNOR-249205 0.309 JAK2 protein O60674 UNIPROT STAM protein Q92783 UNIPROT up-regulates phosphorylation 9606 9133424 t gcesareni Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2. SIGNOR-47834 0.609 NRBF2 protein Q96F24 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT down-regulates activity binding 9606 BTO:0001938 phosphorylation:Ser113;Ser120 AEDAEGQsPLSQKYS;SPLSQKYsPSTEKCL 28059666 t miannu NRBF2 S113 and S120 phosphorylation negatively regulates autophagy. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. Phosphorylated NRBF2 inhibits autophagy, preferentially binds a nonautophagic form of the PtdIns3K complex consisting of PIK3C3-PIK3R4 only, and this NRBF2-associated PtdIns3K complex has low lipid kinase activity. SIGNOR-265879 0.682 FBXO22 protein Q8NEZ5 UNIPROT BSG protein P35613 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 28117675 t miannu FBXO22 mediates poly-ubiquitination and degradation of CD147. Classically, F-box protein together with Skp1 and Cullin 1 constitute Skp-Cullin-F box ubiquitin E3 ligase (SCFs) SIGNOR-272787 0.434 C3 protein P01024 UNIPROT C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg748 ASHLGLArSNLDEDI 26489954 t complement C3b fragment: PRO_0000005911 lperfetto Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over) SIGNOR-263485 0.904 AGTR1 protein P30556 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 21289285 t gcesareni These results indicate that ang ii increases endothelial arginase activity/expression through galfa12/13 g proteins coupled to at(1) receptors and subsequent activation of rhoa/rock/p38 mapk pathways leading to endothelial dysfunction. SIGNOR-171763 0.418 AKT2 protein P31751 UNIPROT ESR1 protein P03372 UNIPROT up-regulates activity phosphorylation Ser167 GGRERLAsTNDKGSM 9534 BTO:0001538 11139588 t AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT. SIGNOR-251490 0.518 CSNK2A1 protein P68400 UNIPROT LEF1 protein Q9UJU2 UNIPROT up-regulates phosphorylation 9606 19623618 t gcesareni Here, we identify ck1 and ck2 as major kinases that directly bind to and phosphorylate lef-1 inducing distinct, kinase-specific changes in the lef-1/dna complex.CK1-dependent phosphorylation inhibits, whereas ck2 activates lef-1/beta-catenin transcriptional activity in reporter gene assays. SIGNOR-187209 0.306 TANK protein Q92844 UNIPROT TRAF2 protein Q12933 UNIPROT down-regulates activity binding 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262714 0.726 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH5 protein P33151 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265845 0.8 alvocidib hydrochloride chemical CHEBI:90998 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192458 0.8 EIF2B5 protein Q13144 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269133 0.728 RPS6KA3 protein P51812 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19112174 t gcesareni S6k1 regulates estrogen receptor alpha (eralpha) by phosphorylating it on serine 167, leading to transcriptional activation of eralpha. SIGNOR-182958 0.408 CCNY protein Q8ND76 UNIPROT CDK14 protein O94921 UNIPROT up-regulates binding 9606 20059949 t gcesareni L63 and its vertebrate homolog pftk are regulated by the membrane tethered g2/m cyclin, cyclin y, which mediates binding to and phosphorylation of lrp6. SIGNOR-162920 0.826 PDE1C protein Q14123 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI down-regulates quantity chemical modification 9606 22014080 t PDE1A and PDE1B preferentially hydrolyse cGMP, whereas PDE1C hydrolyses cAMP and cGMP with similar Km values SIGNOR-253399 0.8 MECP2 protein P51608 UNIPROT DLL1 protein O00548 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 25420914 t Luana As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1  SIGNOR-264674 0.2 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21524151 f miannu In its hypophosphorylated state, pRb binds transcription factors of the E2F family which are required for cell cycle progression. As the level of CyclinD/Cdk4/6 complexes increases, pRb becomes phosphorylated and progression through G1 occurs. At a critical level of phosphorylation, E2F is released from pRb. This activates the transcription of CyclinE which complexes with Cdk2 to fully release pRb repression by further phosphorylation, establishing a positive feedback loop. E2F further promotes the transcription of S-phase genes. Thus, CyclinD/Cdk4/6 and CyclinE/Cdk2 together regulate S-phase entry via phosphorylating pRb, which controls pRb binding to E2F SIGNOR-262532 0.7 MAPK7 protein Q13164 UNIPROT MAPK7 protein Q13164 UNIPROT up-regulates activity phosphorylation Ser803 QREIQMDsPMLLADL 9606 BTO:0000567 20667468 t miannu Activated ERK5 undergoes autophosphorylation on its C-terminal half, necessary for maximal activation of ERK5 transcriptional activation. The Ser731 and Thr733 sites were previously shown to be ERK5 autophosphorylation sites in vitro and also in ERK5-overexpressing cells.Our data coincide with a recent study examining whole protein phosphorylation in HeLa cells arrested in G1 and mitotic phases [37] reported that Ser731 and Thr733, as well as Ser720, are phosphorylated in ERK5 during mitosis. We also identified two unreported ERK5 phosphorylation sites, Ser567 and Ser803. SIGNOR-259826 0.2 EEF1A2 protein Q05639 UNIPROT Thr-tRNA(Thr) smallmolecule CHEBI:29163 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269536 0.8 PDK3 protein Q15120 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser293 TYRYHGHsMSDPGVS -1 11486000 t lperfetto Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes. SIGNOR-109647 0.868 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI ITPR1 protein Q14643 UNIPROT up-regulates activity chemical activation 9606 24646566 t miannu The key event in activation of fluid secretion is an increase in intracellular [ca2+] ([ca2+]i) triggered by ip3-induced release of ca2+ from er via the ip3r. ip3rs determine the site of initiation and the pattern of [ca2+]i signal in the cell. SIGNOR-256239 0.8 USF1 protein P22415 UNIPROT GATA5 protein Q9BWX5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22625849 f miannu The present study provides the first evidence that USF1 activates GATA5 gene expression through the E-box motif and suggests a potential mechanism (disruption of the E-box) by which GATA5 promoter methylation reduces GATA5 expression in cancer. SIGNOR-255596 0.339 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK10 protein P53779 UNIPROT down-regulates chemical inhibition 9606 15071501 t gcesareni We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm). To determine whether jnk activity is required for stress-induced translocation of bax to the mitochondria, we examined the effect of sp600125, a jnk inhibitor. SIGNOR-124034 0.8 HBB protein P68871 UNIPROT CYP2E1 protein P05181 UNIPROT up-regulates activity 9606 BTO:0000575 19325051 f Regulation miannu Hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. SIGNOR-251764 0.2 MC1R protein Q01726 UNIPROT Pigmentation phenotype SIGNOR-PH70 SIGNOR up-regulates 9606 19656324 f miannu Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses. SIGNOR-252374 0.7 MEIS1 protein O00470 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001271 19109563 f irozzo To discern the mechanisms by which Meis1 inhibition leads to reduced cell growth, we performed cell-cycle and apoptosis analyses.Meis1 knockdown also resulted in increased apoptosis, as evidenced by increased uptake of PI and a stain for activated caspases (CaspaTag) by M26-transduced cells compared with control cells. These results indicate that Meis1 is required for proliferation and survival of 4166 leukemia cells. SIGNOR-255860 0.7 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser8 MPLNRTLsMSSLPGL -1 6263629 t A reinvestigation of the phosphorylation of Rabbit Skeletal-muscle glycogen synthase by cyclic AMP dependent Protein Kinase: identification of the third site of phosphorylation at Serine-7 SIGNOR-253008 0.497 MCHR2 protein Q969V1 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257439 0.251 AURKA protein O14965 UNIPROT ALDH1A1 protein P00352 UNIPROT up-regulates activity phosphorylation Thr267 KSNLKRVtLELGGKS -1 28193222 t miannu AURKA phosphorylates ALDH1A1 at three critical residues which exert a multifaceted regulation over its level, enzymatic activity, and quaternary structure. While all three phosphorylation sites contribute to its increased stability, T267 phosphorylation primarily regulates ALDH1A1 activity. AURKA-mediated phosphorylation rapidly dissociates tetrameric ALDH1A1 into a highly active monomeric species.  SIGNOR-276750 0.378 miR-495 mirna URS000075C517_9606 RNAcentral Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 26055960 f miannu Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation. SIGNOR-255801 0.4 GRB2 protein P62993 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates binding 9606 12766170 t Grb2-associated binding (Gab) scaffolding/adapter proteins are a family of three members including mammalian Gab1, Gab2, and Gab3 that are highly conserved. lperfetto The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2 SIGNOR-235917 0.87 CALM1 protein P0DP23 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 24379783 t lperfetto Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-251615 0.756 MTOR protein P42345 UNIPROT ULK1 protein O75385 UNIPROT down-regulates activity phosphorylation Ser758 PVVFTVGsPPSGSTP 9606 BTO:0001938 21383122 t lperfetto When cells are replenished with rich medium, mtor is activated;it phosphorylates serine 638 and serine 758. The phosphorylation of ulk1 at serine 758 then leads to reassociation between ulk1 and ampk. SIGNOR-172541 0.846 TGFB1 protein P01137 UNIPROT MEF2D protein Q14814 UNIPROT down-regulates 10090 14739161 f lperfetto Tgf-beta was shown to inhibit myogenin and mef2d expression and myotube formation in c2c12. SIGNOR-235602 0.2 VKORC1L1 protein Q8N0U8 UNIPROT vitamin K smallmolecule CHEBI:28384 ChEBI up-regulates quantity chemical modification 9606 31226734 t lperfetto The epoxide form of vitamin K is reduced by epoxide reductase (vitamin K epoxide reductase complex 1; VKORC1 or vitamin K epoxide reductase complex 1-like 1; VKORC1L1) to a reduced form and then to the reduced hydroquinone form SIGNOR-265903 0.8 CBLB protein Q13191 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity 9606 BTO:0004175 27773928 f miannu We have also shown that the E3 ubiquitin ligase Cbl-b is crucial for activation of the p53 pathway through ubiquitinating and promoting degradation of Siva1, the E3 ubiquitin ligase targeting ARF, a positive regulator of p53. On the basis of our data presented in the study, we propose the model (Figure 2i) that Cbl-b negatively regulates Siva1 by ubiquitination and subsequent degradation of Siva1, which is followed by stabilization of ARF. This in turn downregulates MDM2, thereby promoting the induction of p53 and activation of its downstream targets. SIGNOR-261320 0.2 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT down-regulates activity phosphorylation Ser170 SFKLSGFsFKKNKKE -1 8557118 t gcesareni PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-249671 0.369 PRKACA protein P17612 UNIPROT PTPN11 protein Q06124 UNIPROT down-regulates activity phosphorylation Ser189 GGGERFDsLTDLVEH 9606 BTO:0002181 25802336 t miannu  We identified two key amino acids in Shp2 that are phosphorylated by PKA. Thr-73 contributes a helix cap to helix αB within the N-terminal SH2 domain of Shp2, whereas Ser-189 occupies an equivalent position within the C-terminal SH2 domain. Utilizing double mutant PKA phosphodeficient (T73A/S189A) and phosphomimetic (T73D/S189D) constructs, in vitro binding assays, and phosphatase activity assays, we demonstrate that phosphorylation of these residues disrupts Shp2 interaction with tyrosine-phosphorylated ligands and inhibits its protein-tyrosine phosphatase activity.  SIGNOR-276892 0.436 PPP2CA protein P67775 UNIPROT DCK protein P27707 UNIPROT down-regulates activity dephosphorylation Ser74 EFEELTMsQKNGGNV 24462681 t lperfetto Protein phosphatase 2A regulates deoxycytidine kinase activity via Ser-74 dephosphorylation|Deoxycytidine kinase (dCK) is a critical enzyme for activation of anticancer nucleoside analogs. Its activity is controlled via Ser-74 phosphorylation. Here, we investigated which Ser/Thr phosphatase dephosphorylates Ser-74. In cells, the PP1/PP2A inhibitor okadaic acid increased both dCK activity and Ser-74 phosphorylation SIGNOR-275803 0.2 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT unknown phosphorylation Tyr969 VSECPHTyQNRRPFS 10090 BTO:0001516 16627759 t lperfetto In vitro mapping of FLT3 autophosphorylation sites|Tryptic peptides covering more than 80% of the FLT3 kinase domain were recovered, and 5 tyrosine residues (Y591, Y726, Y842, Y955, and Y969) within this region were phosphorylated. SIGNOR-271920 0.2 MECOM protein Q03112 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 21695170 t lperfetto The oncoprotein EVI1 and the DNA methyltransferase Dnmt3 co-operate in binding and de novo methylation of target DNA|Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. SIGNOR-273432 0.297 PLAAT3 protein P53816 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates 9606 17374643 f miannu The alpha-isoform of the regulatory subunit a of protein phosphatase 2a (pr65alpha) as a new interaction partner of hrsl3 / we demonstrate that hrsl3 binds to the endogenous pr65alpha, thereby partially sequestering the catalytic subunit pr36 from the pr65 protein complex, and inhibiting pp2a catalytic activity. SIGNOR-153775 0.2 ATM protein Q13315 UNIPROT ZNF148 protein Q9UQR1 UNIPROT up-regulates phosphorylation Ser202 GEKPFQCsQCDMRFI 9606 17560543 t lperfetto Here we found that zbp-89 is phosphorylated by atm kinase in vitro and in vivo. Disruption of the atm phosphorylation motif (202)sq within the zinc finger domain of zbp-89 attenuated its ability to enhance p21(waf1) activation by butyrate. Moreover, disruption of the atm phosphorylation site abrogated the ability of zbp-89 to potentiate butyrate induction of endogenous p21(waf1) expression. SIGNOR-155634 0.366 LYST protein Q99698 UNIPROT RAB5A protein P20339 UNIPROT down-regulates activity binding 7227 33725482 t lperfetto Mauve interacts with Rab5, Msps, and gamma-tubulin|Mauve/LYST opposes Rab5, which promotes vesicle fusion affecting PCM recruitment SIGNOR-266001 0.268 pregnenolone smallmolecule CHEBI:16581 ChEBI progesterone smallmolecule CHEBI:17026 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 2243100 t lperfetto Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. SIGNOR-268630 0.8 PTK2B protein Q14289 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 16760434 t gcesareni Activated rock phosphorylates fak on ser732, which is essential for phosphorylation of tyr407 and for cell migration. We further show that pyk2 is activated by vegf-induced clustering of integrin v 3 and is responsible for the phosphorylation of tyr407. SIGNOR-147070 0.511 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Ser77 GEKGRALsTRCQPLE -1 2584239 t lperfetto We have now determined that PKC phosphorylated serine 43 (and/or serine 45), serine 78, and threonine 144 in the free Tn-I subunit SIGNOR-248890 0.347 CEP63 protein Q96MT8 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271725 0.379 PPM1D protein O15297 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates dephosphorylation Thr183 RQADSEMtGYVVTRW 9606 15870257 t gcesareni Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180. SIGNOR-135976 0.299 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser82 NPEDRSPsPEPIYNS 9606 16420481 t The effect has been demonstrated using Q15637-2 gcesareni Sf1 is phosphorylated on serines 80 and 82 in vitro and in vivo. Kis can phosphorylate sf1f on serine 80 and 82 with a high efficiency that particularly relies on the anchoring of its uhm domain to sf1. Serine phosphorylation of a conserved ser80-pro81-ser82-pro83 motif rigidifies a long unstructured linker in the sf1 helix hairpin and slightly enhances rna binding. SIGNOR-143841 0.413 GSK3B protein P49841 UNIPROT ETS1 protein P14921 UNIPROT up-regulates quantity by stabilization phosphorylation Ser269 DRLTQSWsSQSSFNS 9606 BTO:0000007 34023818 t miannu Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration. SIGNOR-277561 0.2 MMP10 protein P09238 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272355 0.7 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity phosphorylation Ser139 DNETGTEsMVSHRRE 9606 16965538 t lperfetto Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development. SIGNOR-217845 0.627 LATS2 protein Q9NRM7 UNIPROT YWHAG protein P61981 UNIPROT up-regulates phosphorylation Ser59 VVGARRSsWRVISSI 9606 25086053 t lperfetto Phosphorylation of 14-3-3_ on s59 by lats2. Ser(58) phosphorylation and lys(49) acetylation of 14-3-3_ occur in a coordinated time-dependent manner to regulate 14-3-3_ homodimerization. 14-3-3_ ser(58) phosphorylation is required for star interactions under control conditions, SIGNOR-205247 0.334 perfluorooctane-1-sulfonic acid chemical CHEBI:39421 ChEBI PPARG protein P37231 UNIPROT up-regulates activity chemical activation 10090 BTO:0000011 16731579 t miannu Taken together, these data show that of the NRs studied, PPARα is the most likely target of PFOA and PFOS, although PPARγ is also activated to some extent. SIGNOR-268787 0.8 IL5 protein P05113 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 21106848 f It has been reported that IL-5 family members and selected chemotactic factors can activate the PI3K-Akt pathway in human blood eosinophils SIGNOR-254351 0.402 ELOVL4 protein Q9GZR5 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267892 0.8 IYD protein Q6PHW0 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-267034 0.8 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 SIGNOR-C9 14691252 t gcesareni Taken together, our studies indicate that on tgf-beta treatment, pias3 can form a complex with smads and p300/cbp and activate smad transcriptional activity. SIGNOR-120359 0.587 AP2M1 protein Q96CW1 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19351721 t gcesareni The removal of the epidermal growth factor receptor (egfr) from the cell surface by endocytosis is triggered by receptor activation, but many facets of egfr trafficking remain unresolvedthe ap-2 complex is involved in the internalization of activated egfr. SIGNOR-185124 0.512 LHX3 protein Q9UBR4 UNIPROT FSHB protein P01225 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23766128 f miannu we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared with the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared with the wild-type FSHB promoter. SIGNOR-254557 0.374 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0000567 10673501 t gcesareni Chk1/chk2 and atm/atr also phosphorylate the effector p53, increasing its stability.We Have demonstrated that the human homologs of the checkpoint kinases, chk1 and chk2/hcds1, phosphorylate at least three dna damage-inducible phosphorylation sites in p53. SIGNOR-75017 0.787 CALM2 protein P0DP24 UNIPROT EEF2K protein O00418 UNIPROT up-regulates binding 9606 11015200 t miannu The calmodulin-binding region is located between amino acids 51 and 96 SIGNOR-266321 0.468 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR3 protein Q9UBY5 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193564 0.8 SRC protein P12931 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-247316 0.626 PRPF4B protein Q13523 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates phosphorylation 9606 17513757 t flangone Using yeast two-hybrid screening of a human thymus cdna library, prp4, a serine/threonine protein kinase, was identified as a klf13-binding protein...coexpression of prp4 and klf13 increases nuclear localization of klf13 and ccl5 transcription. SIGNOR-154951 0.346 MAPK14 protein Q16539 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Thr581 PDNQPLKtPCFTLHY 9606 15568999 t lperfetto Msk1 (mitogen- and stress-activated protein kinase) is a kinase activated in cells downstream of both the erk1/2 (extracellular-signal-regulated kinase) and p38 mapk (mitogen-activated protein kinase) cascades. In the present study, we show that, in addition to being phosphorylated on thr-581 and ser-360 by erk1/2 or p38, msk1 can autophosphorylate on at least six sites SIGNOR-131375 0.6 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 11237216 t lperfetto Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105454 0.658 NME1 protein P15531 UNIPROT MET protein P08581 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001567 17671192 f miannu To elucidate the molecular mechanism of Nm23-H1 motility suppression, expression microarray analysis of an MDA-MB-435 cancer cell line overexpressing wild-type Nm23-H1 was done and cross-compared with expression profiles from lines expressing the P96S and S120G mutants. Nine genes, MET, PTN, SMO, FZD1, L1CAM, MMP2, NETO2, CTGF, and EDG2, were down-regulated by wild-type but not by mutant Nm23-H1 expression. SIGNOR-255164 0.334 17beta-estradiol smallmolecule CHEBI:16469 ChEBI 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI up-regulates quantity precursor of -1 7779757 t Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. SIGNOR-269750 0.8 MINK1 protein Q8N4C8 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity phosphorylation Thr322 SNVNRNStIENTRRH 9606 BTO:0002181 21690388 t miannu Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.  SIGNOR-276336 0.2 MYC protein P01106 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates activity binding 9606 19786833 t irozzo Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. SIGNOR-255806 0.705 HRH4 protein Q9H3N8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256815 0.419 pazopanib hydrochloride chemical CHEBI:71217 ChEBI RTKs proteinfamily SIGNOR-PF38 SIGNOR down-regulates activity chemical inhibition -1 17620431 t miannu The present study describes an orally bioavailable, ATP-competitive, multitargeted kinase inhibitor, pazopanib (GW786034), and the drug concentration requirement for maximal in vivo activity. Pazopanib is a low nanomolar inhibitor of VEGFR, PDGFR, and c-Kit tyrosine kinases. Pazopanib inhibition of a number of kinases outside of the VEGFR family was also determined. These included Abl1; Akt3; activin-like kinase 6; cyclin-dependent kinase 1/cyclin A; cyclin-dependent kinase 2/cyclin A; c-fms; c-Kit; epidermal growth factor receptor; ErbB2; ErbB4; EphB4; focal adhesion kinase; FGF receptors (FGFR) 1, 2, and 3; Flt-3; glycogen synthase kinase 3; insulin-like growth factor type I receptor; insulin receptor; interleukin-2–inducible T-cell kinase; c-jun NH2-terminal kinases 1, 2, and 3; lymphocyte-specific protein tyrosine kinase (murine); Met; p38α; PDGFRα and PDGFRβ; protein kinase C-β1 and -β2; polo-like kinases 1 and 3; Ret; Src; Syk; Tie-2; and Wee1. All assays were conducted using purified, recombinantly expressed catalytic domains of the kinases. SIGNOR-259451 0.8 CRX protein O43186 UNIPROT RHO protein P08100 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 15277472 f miannu KLF15 repressed transactivation of rhodopsin and IRBP promoters alone and in combination with the transcriptional activators Crx and/or Nrl. SIGNOR-253820 0.48 ID2 protein Q02363 UNIPROT MYOD/E12E47 complex SIGNOR-C127 SIGNOR down-regulates activity binding 10090 BTO:0004058 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241149 0.573 BUD13 protein Q9BRD0 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270672 0.53 PRKAA2 protein P54646 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276838 0.2 TACR3 protein P29371 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257333 0.42 regorafenib chemical CHEBI:68647 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259177 0.8 pazopanib chemical CHEBI:71219 ChEBI PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 18620382 t Luana Pyrimidine 13 showed good potency against all the human VEGFR receptors with an IC50 of 10, 30, and 47 nM for VEGFR-1, -2, and -3, respectively. Significant activity was also seen against the closely related tyrosine receptor kinases PDGFRβ, c-Kit, FGF-R1, and c-fms with IC50’s of 84, 74, 140, and 146 nM, respectively. SIGNOR-257737 0.8 CHUK protein O15111 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation Ser177 AKELDQGsLCTSFVG -1 10022904 t llicata Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays. SIGNOR-250771 0.659 ROCK2 protein O75116 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. SIGNOR-90832 0.42 VHL protein P40337 UNIPROT HIF-1 complex complex SIGNOR-C418 SIGNOR down-regulates ubiquitination 9606 10944113 t miannu Here we show that the product of the von hippel-lindau (vhl) tumor suppressor gene mediated ubiquitylation and proteasomal degradation of hif-1 alpha under normoxic conditions via interaction with the core of the oxygen-dependent degradation domain of hif-1 alpha. SIGNOR-80969 0.681 CAMTA1 protein Q9Y6Y1 UNIPROT NPPA protein P01160 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002004 21857646 t Luana CAMTA1 itself stimulates the expression of the anti-proliferative peptide NPPA. SIGNOR-261570 0.437 MMP20 protein O60882 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE -1 10922468 t lperfetto Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development. SIGNOR-266979 0.486 RBBP4 protein Q09028 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263849 0.828 UBA1 protein P22314 UNIPROT Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270833 0.2 N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI acetic acid smallmolecule CHEBI:15366 ChEBI up-regulates quantity precursor of 9606 17194761 t miannu N-acetyl-l-aspartate (NAA) is one of the most abundant amino acid derivatives found in the vertebrate brain, second only to glutamate. Aspartoacylase catalyzes hydrolysis of N-acetyl-l-aspartate to aspartate and acetate in the vertebrate brain. SIGNOR-268085 0.8 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA1 protein Q9Y5H4 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265686 0.2 CDK1 protein P06493 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser465 MVPGGDRsPSRMLPP 9606 BTO:0000150;BTO:0001130 16407259 t llicata In vitro kinase assays using recombinant cdc2 kinase showed that runx2 was phosphorylated at ser(451) the cdc2 inhibitor roscovitine dose dependently inhibited in vivo runx2 dna-binding activity during mitosis and the runx2 mutant s451a exhibited lower dna-binding activity and reduced stimulation of anchorage-independent growth relative to wild type runx2. SIGNOR-143586 0.487 PLK1 protein P53350 UNIPROT TRIOBP protein Q9H2D6 UNIPROT up-regulates phosphorylation Thr2229 QAEEREHtLRRCQQE 9606 22820163 t lperfetto Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1 SIGNOR-198353 0.338 CSNK2A1 protein P68400 UNIPROT IGFBP3 protein P17936 UNIPROT up-regulates quantity by stabilization phosphorylation Ser138 PPAPGNAsESEEDRS 9606 BTO:0000093 10650937 t llicata The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment. SIGNOR-250903 0.342 MBOAT7 protein Q96N66 UNIPROT 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI down-regulates quantity chemical modification -1 18772128 t miannu The cycle of deacylation and reacylation of phospholipids plays a critical role in regulating availability of arachidonic acid for eicosanoid production. The major yeast lysophospholipid acyltransferase, Ale1p, is related to mammalian membrane-bound O-acyltransferase (MBOAT) proteins. MBOAT7 is a lysophosphatidylinositol acyltransferase with remarkable specificity for arachidonoyl-CoA. MBOAT5 and MBOAT7 are particularly susceptible to inhibition by thimerosal. Human neutrophils express mRNA for these four enzymes, and neutrophil microsomes incorporate arachidonoyl chains into phosphatidylinositol, phosphatidylcholine, PS, and phosphatidylethanolamine in a thimerosal-sensitive manner. These results strongly implicate MBOAT5 and MBOAT7 in arachidonate recycling, thus regulating free arachidonic acid levels and leukotriene synthesis in neutrophils. SIGNOR-267246 0.8 ABTB1 protein Q969K4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 11494141 f miannu Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G1/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. SIGNOR-260046 0.7 CDK1 protein P06493 UNIPROT ORC1 protein Q13415 UNIPROT up-regulates phosphorylation Thr375 AQNEATStPHRIRRK 9606 11931757 t lperfetto Horc1p contains three (s/t)px(k/r) consensus sites for cdk phosphorylation (ser258, ser273, and thr375). These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability. SIGNOR-116329 0.627 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 11812650 t gcesareni However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2. SIGNOR-114597 0.508 MRPL34 protein Q9BQ48 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262363 0.658 POLG2 protein Q9UHN1 UNIPROT DNA polymerase gamma complex SIGNOR-C378 SIGNOR form complex binding -1 19837034 t lperfetto Here, we report a crystal structure of human DNA Pol gamma holoenzyme. The holoenzyme is a heterotrimer containing one Pol gammaA subunit and a dimeric Pol gammaB subunit. SIGNOR-265718 0.73 TEC protein P42680 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr224 DSNSKKIyGSQPNFN 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. For bmx, we obtained two phosphorylated sites, y215 and y223 (fig. 6c). The bmx-y215 is a conserved tyrosine, which is homologous to btk-y223 and itk-y180 SIGNOR-98094 0.335 NARS1 protein O43776 UNIPROT asparagine smallmolecule CHEBI:22653 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270454 0.8 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 19464346 t gcesareni The hdac inhibitor tsa-induced cell-specific phosphatase release from the promoter, which serves as an 'on' mechanism for sp1 phosphorylation by phosphatidylinositol 3-kinase/protein kinase czeta (pi3k/pkczeta) at ser641, leading to p107 repressor derecruitment and lhr transcriptional activation. SIGNOR-185741 0.492 TNKS2 protein Q9H2K2 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates quantity by destabilization 9606 BTO:0000007 19759537 t Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. SIGNOR-261248 0.451 AKT2 protein P31751 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates activity phosphorylation 9606 21620960 t lperfetto Akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. In addition, phosphorylation of afx by protein kinase b inhibits its transcriptional activity. SIGNOR-233529 0.598 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 9606 10864927 t lperfetto Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-216769 0.842 YWHAB protein P31946 UNIPROT SRPK2 protein P78362 UNIPROT down-regulates binding 9606 phosphorylation:Thr492 PSHDRSRtVSASSTG 19592491 t lperfetto 14-3-3 interacts with akt-phosphorylated srpk2 and blocks its nuclear translocation. kt phosphorylates SRPK2 on Thr-492 and promotes its nuclear translocation leading to cyclin D1 up-regulation, cell cycle reentry, and neuronal apoptosis. In addition, SRPK2 phosphorylates SC35 and, thus, inactivates p53, resulting in cyclin D1 up-regulation. 14-3-3 binding to SRPK2, regulated by Akt phosphorylation, inhibits these events. SIGNOR-186767 0.333 NOTCH proteinfamily SIGNOR-PF30 SIGNOR ADAM19 protein Q9H013 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10933396 f gcesareni Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene. SIGNOR-254340 0.2 SPI1 protein P17947 UNIPROT GATA2 protein P23769 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12433372 f irozzo Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene.The above experiments suggested that PU.1 may physiologically downregulate the expression of the GATA-2 gene during the differentiation of myeloid progenitors into macrophages. SIGNOR-256069 0.589 UBE2N protein P61088 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000785 14713952 t lperfetto Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38. SIGNOR-121274 0.435 SRC protein P12931 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr142 MELALGQyHRNGCIS 10116 BTO:0000132 21992875 t miannu We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.  SIGNOR-276386 0.261 TGFB1 protein P01137 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 17326328 f lperfetto More than a dozen different proteins have been identified as angiogenic activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, platelet-derived endothelial growth factor, granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor SIGNOR-252282 0.7 ATR protein Q13535 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates activity phosphorylation Ser19 GTSKCPPsQRVPALT 9606 BTO:0002181 18536714 t miannu We have also demonstrated that DNA damage triggers disruption of the HIPK2-Siah-1 complex, resulting in HIPK2 stabilization and activation. Disruption of the HIPK2-Siah-1 complex is mediated by the ATM/ATR pathway and involves ATM/ATR-dependent phosphorylation of Siah-1 at Ser 19. SIGNOR-276167 0.2 MAPK3 protein P27361 UNIPROT PCYT1A protein P49585 UNIPROT down-regulates phosphorylation Ser315 GRMLQAIsPKQSPSS 9606 BTO:0000763 15788406 t gcesareni Oxysterols inhibit phosphatidylcholine synthesis via erk docking and phosphorylation of ctp:phosphocholine cytidylyltransferase. Mutagenesis of ser315 within cctalpha was both required and sufficient to confer significant resistance to 22-hc/9-cis-ra inhibition of ptdcho synthesis. SIGNOR-134841 0.447 POLR2M protein P0CAP2 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266169 0.459 IFNA1 protein P01562 UNIPROT ISGF3 complex complex SIGNOR-C124 SIGNOR up-regulates quantity by stabilization 9606 22171011 f 2 miannu IFN-I (IFN-_ and IFN-_) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. SIGNOR-240610 0.459 SMO protein Q99835 UNIPROT GNAI2 protein P04899 UNIPROT up-regulates activity binding 9606 23074268 t lperfetto it was proposed that Smo might signal through activation of Gi proteins to reduce PKA activity. SIGNOR-199162 0.413 EDNRB protein P24530 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257321 0.419 GRK2 protein P25098 UNIPROT CXCR2 protein P25025 UNIPROT down-regulates activity phosphorylation 10090 BTO:0000763 22634615 t miannu Upon activation, GRK2 phosphorylates CXCR2 and causes receptor desensitization and internalization, leading to down-regulation of neutrophil chemotaxis SIGNOR-260647 0.2 AURKA protein O14965 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity phosphorylation Ser960 SRLSPPHsPRDFTRM 9606 BTO:0000567 17488622 t miannu The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity. SIGNOR-276061 0.337 PRKCZ protein Q05513 UNIPROT ADARB1 protein P78563 UNIPROT up-regulates activity phosphorylation Ser211 GDLSLSAsPVPASLA 9606 BTO:0001615 29694894 t miannu  Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.  SIGNOR-277392 0.2 SLC9A9 protein Q8IVB4 UNIPROT hydron chemical CHEBI:15378 ChEBI down-regulates quantity relocalization 9606 BTO:0000938 31507243 t miannu Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes.  SIGNOR-265599 0.8 L3MBTL1 protein Q9Y468 UNIPROT TP53BP1 protein Q12888 UNIPROT down-regulates activity binding 9606 29018219 t lperfetto L3MBTL1, a tumor suppressor with high affinity for H4K20me2, can block 53BP1 binding at DSBs SIGNOR-262059 0.411 TXNL4A protein P83876 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270638 0.745 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2H protein P62256 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271362 0.498 Caspase 9 complex complex SIGNOR-C229 SIGNOR CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000567 9390557 t lperfetto Activated caspase-9 in turn cleaves and activates caspase-3. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade. SIGNOR-256462 0.628 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89213 0.555 WIPF1 protein O43516 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 19121306 f lperfetto However, we did detect WAFL binding to bothWIP and actin by immunoprecipitation (Fig. 4). In conclusion, we propose a model whereby WAFL associates toendocytic vesicles by its coiled-coil domain and is involved in actin-based movement of early endosomes via WIP and binding to actin. SIGNOR-260609 0.7 BMI1 protein P35226 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24392140 t lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253385 0.465 orantinib chemical CHEBI:91088 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207438 0.8 DYRK1A protein Q13627 UNIPROT DNM1 protein Q05193 UNIPROT down-regulates phosphorylation Ser857 ASPSRPEsPRPPFDL 9606 BTO:0000142 15287745 t lperfetto Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation. SIGNOR-127444 0.422 CHMP4B protein Q9H444 UNIPROT ESCRT-III complex SIGNOR-C379 SIGNOR form complex binding -1 26775243 t miannu The ESCRT machinery drives a diverse collection of membrane remodeling events, including multivesicular body biogenesis, release of enveloped retroviruses and both reformation of the nuclear envelope and cytokinetic abscission during mitotic exit. ESCRT-III subunits (CHMPs, for Charged Multivesicular Body Proteins [32], or Chromatin Modifying Proteins [33]) transition between soluble and polymerising states, and assemble in a defined order to form a membrane-remodeling filament that brings about membrane fission. SIGNOR-265533 0.725 GRID2IP protein A4D2P6 UNIPROT GRID2 protein O43424 UNIPROT up-regulates quantity binding 9606 11826110 t miannu We identified a novel GluRdelta2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluRdelta2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluRdelta2 with actin cytoskeleton and various signaling molecules. SIGNOR-264475 0.621 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser477 ELIERKTsSLDPNDQ 9606 BTO:0001109 17157788 t lperfetto Three putative Chk2 phosphorylation sites (Stevens et al., 2003) are present in Che-1 at resides Ser141, Ser474, and Ser508. Thus, we performed in vitro Chk2 kinase assays utilizing the GST-Che-1 fusion peptides spanning these residues as substrates.| Taken together, these results indicate that Chk2 phosphorylates Che-1 and this phosphorylation contributes to increase Che-1 stability. SIGNOR-264417 0.363 calcium(2+) smallmolecule CHEBI:29108 ChEBI Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 29953871 f miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. SIGNOR-264955 0.7 SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR FN1 protein P02751 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452;BTO:0002625 22223884 f alessandro Taken together, our results indicate that Snail1, p65NF-κB and PARP1 interact to activate the expression of fibronectin and other ECM genes involved in cell movement. This mechanism is functional not only in epithelial cells undergoing EMT but also in fibroblasts. SIGNOR-254529 0.417 EDNRB protein P24530 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257254 0.442 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269365 0.721 EGFR protein P00533 UNIPROT RASA1 protein P20936 UNIPROT unknown phosphorylation Tyr460 TVDGKEIyNTIRRKT 9606 1850098 t llicata We conclude that tyr-460 is a site of gap tyrosine phosphorylation by the egf receptor in vitro and likely in vivo. Gap tyr-460 is located immediately c terminal to the second gap sh2 domain, suggesting that its phosphorylation might have a role in regulating protein-protein interactions. SIGNOR-21875 0.646 PRKACA protein P17612 UNIPROT CIITA protein P33076 UNIPROT down-regulates activity phosphorylation Ser1050 AASLLRLsLYNNCIC 9606 BTO:0000984 11416140 t lperfetto Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription. SIGNOR-108569 0.311 MAPK8 protein P45983 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr57 NFDFVTEtPLEGDFA -1 12058028 t miannu P38Œ± and JNK1 Phosphorylate p21 in Vitro at Thr57 and Ser130. These data suggest that phosphorylation at Thr57 is necessary for stabilization of p21. SIGNOR-250118 0.664 PITRM1 protein Q5JRX3 UNIPROT APP protein P05067 UNIPROT down-regulates activity cleavage 9606 BTO:0000142 16849325 t Giorgia In the present study we have identified and characterized the human PreP homologue, hPreP, in brain mitochondria, and we show its capacity to degrade the amyloid beta-protein (Abeta). PreP belongs to the pitrilysin oligopeptidase family M16C containing an inverted zinc-binding motif. We show that hPreP is localized to the mitochondrial matrix. In situ immuno-inactivation studies in human brain mitochondria using anti-hPreP antibodies showed complete inhibition of proteolytic activity against Abeta. SIGNOR-260661 0.378 CASP3 protein P42574 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by destabilization cleavage Asp1155 ETPDDLLdDGEIKED 9606 12149654 t miannu We demonstrate the cleavage and the consequential downregulation of full-length BRCA1 by caspase-3 during UV-induced apoptosis. Finally, mutation of a caspase-3 specific cleavage site (D/A1154) rendered BRCA1 non-cleavable. SIGNOR-256326 0.481 AKT2 protein P31751 UNIPROT SH3RF1 protein Q7Z6J0 UNIPROT down-regulates phosphorylation Ser304 KNTKKRHsFTSLTMA 9606 17535800 t gcesareni Overexpression of posh induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase akt. We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac SIGNOR-155233 0.394 PLK1 protein P53350 UNIPROT KAT7 protein O95251 UNIPROT up-regulates phosphorylation Ser57 SQSSQDSsPVRNLQS 9606 18250300 t lperfetto Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate. SIGNOR-160751 0.512 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity phosphorylation Thr1074 QRGSSGHtPPPSGPP 9606 26190112 t Luana AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This in turn leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-259862 0.337 CDC25A protein P30304 UNIPROT CDK4 protein P11802 UNIPROT up-regulates activity dephosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 BTO:0000007 23429262 t lperfetto Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs. SIGNOR-267568 0.699 metyrapone chemical CHEBI:44241 ChEBI CYP11B2 protein P19099 UNIPROT down-regulates activity chemical inhibition -1 21129965 t Luana In an effort to develop and evaluate new classes of compounds as CYP inhibitors, we based our investigations on the structure of the well-known CYP inhibitor Metyrapone 2, which has been used for the treatment of hypercortisolism and Cushing’ssyndrome for several decades. SIGNOR-257885 0.8 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser19 PAPPVRMsSTIFSTG -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. The information resulting from manual Edman degradation and from automated sequencing clearly identified Ser-192, Ser-197, and Thr-402 as the phosphorylation sites SIGNOR-250224 0.2 MAPK3 protein P27361 UNIPROT GRB10 protein Q13322 UNIPROT up-regulates phosphorylation Ser476 MNILGSQsPLHPSTL 9606 15952796 t lperfetto Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation SIGNOR-138175 0.302 selumetinib chemical CHEBI:90227 ChEBI ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001950 25487801 t Luana Inhibitors of MEK1/2 (trametinib) and/or ERK1/2 (selumetinib) had the strongest and most conserved inhibitory activities, suggesting that MEK1/2 and ERK1/2 may have unique capabilities as stand-alone or combinatorial therapies for MERS-CoV infections.  SIGNOR-262313 0.8 PRKCA protein P17252 UNIPROT PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Thr475 TPLSSSNtIRRPRNY -1 1322130 t lperfetto The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme. SIGNOR-248844 0.444 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 11030354 t lperfetto Crystal structure of a ternary fgf-fgfr-heparin complex reveals a dual role for heparin in fgfr binding and dimerization. SIGNOR-83143 0.913 EIF2S2 protein P20042 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR form complex binding 9606 32955564 t lperfetto In eukaryotes, translation initiation generally occurs by a cap-dependent scanning mechanism, wherein the small (40S) subunit of the ribosome recruits methionyl initiator tRNA (Met-tRNAi) in a ternary complex (TC) with GTP-bound eukaryotic initiation factor 2 (eIF2), in a reaction stimulated by factors eIF1, eIF1A and eIF3. SIGNOR-269115 0.955 FBXW7 protein Q969H0 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 11585921 t gcesareni We show here that the f-box/wd40 repeat protein sel-10 negatively regulates notch receptor activity by targeting the intracellular domain of notch receptors for ubiquitin-mediated protein degradation. in conclusion, hsel-10 physically associates with mouse notch4(int-3) through the wd40 domain, whereas the f-box domain is not required for this interaction. SIGNOR-110955 0.508 TRPM6 protein Q9BX84 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates activity phosphorylation Ser2 sGRGKQGG -1 15010469 t miannu We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.  SIGNOR-276008 0.2 MLKL protein Q8NB16 UNIPROT Necroptosis phenotype SIGNOR-PH174 SIGNOR up-regulates activity 9606 24316671 t gianni Here, we report that MLKL forms a homotrimer through its amino-terminal coiled-coil domain and locates to the cell plasma membrane during TNF-induced necroptosis. By generating different MLKL mutants, we demonstrated that the plasma membrane localization of trimerized MLKL is critical for mediating necroptosis. Importantly, we found that the membrane localization of MLKL is essential for Ca(2+) influx, which is an early event of TNF-induced necroptosis. SIGNOR-266431 0.7 PRKCA protein P17252 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t lperfetto In vitro kinase assays show that Ser-59 can be uniquely phosphorylated by mitogen-activated protein kinase and that Ser-42 can be phosphorylated by either protein kinase A or protein kinase C. SIGNOR-248936 0.325 TP53 protein P04637 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001109 28073943 t miannu KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter. SIGNOR-263729 0.284 CASP9 protein P55211 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 15657060 t lperfetto Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. SIGNOR-133267 0.628 FGF2 protein P09038 UNIPROT BMP2 protein P12643 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15780951 f lperfetto Furthermore, FGF-2 and FGF-9 increased expression of other osteogenic factors BMP-2 and TGFbeta-1. Meanwhile, blocking endogenous FGF signaling, using a virally transduced dominant-negative FGF receptor (FgfR), resulted in drastically reduced expression of the BMP-2 gene, demonstrating for the first time that endogenous FGF/FgfR signaling is a positive upstream regulator of the BMP-2 gene in calvarial osteoblasts SIGNOR-134785 0.481 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000150;BTO:0000551 12475979 t gcesareni Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase dep-1 SIGNOR-96347 0.598 lurasidone chemical CHEBI:70735 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10030 20404009 t Luana Lurasidone was found to have potent binding affinity for dopamine D2, 5-hydroxytryptamine 2A (5-HT2A), 5-HT7, 5-HT1A, and noradrenaline 2C receptors. SIGNOR-257841 0.8 TPR protein P12270 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates binding 9606 BTO:0000567 18981471 t miannu Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20). SIGNOR-181918 0.493 WNK1 protein Q9H4A3 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates activity phosphorylation Ser382 LKRASFAkSVIGTPE 9606 12374799 t Manara Activation of WNKs requires autophosphorylation of at least one serine residue, serine 382 in WNK1, within the WNK activation loop. SIGNOR-260826 0.2 ATF1 protein P18846 UNIPROT IL10 protein P22301 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10540320 f miannu Our data suggest that intracellular cAMP may directly affect expression of the immunoregulatory cytokine IL-10 in monocytic cells via activation of the eukaryotic transcription factors CREB-1 and ATF-1 and their binding to CRE1 and CRE4 in the upstream enhancer of the IL-10 promoter SIGNOR-254521 0.251 GNAI1 protein P63096 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding -1 11007482 t Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src SIGNOR-256526 0.472 CSNK2A1 protein P68400 UNIPROT EXOSC9 protein Q06265 UNIPROT up-regulates phosphorylation Ser392 QDAPIILsDSEEEEM 9606 19217413 t lperfetto Indeed recombinant pmscl1 undergoes ck2-mediated phosphorylation in vitro at various serine residues, including serines 409 and 411, which reside within the phosphosim region. the exchange of hydrophobic core residues or serines 409 and 411 to alanine attenuates binding of sumo to the phosphosim-containing fragment of pmscl1 in a yeast two-hybrid assay SIGNOR-184031 0.2 SIK2 protein Q9H0K1 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates activity phosphorylation Ser343 RLKSHRSsFPVEQRL -1 27478041 t miannu SIK2 S358 Autophosphorylation Is a Marker of SIK2 Activity SIGNOR-277268 0.2 MKRN1 protein Q9UHC7 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002552 19536131 t miannu Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21.  SIGNOR-271845 0.316 BDKRB1 protein P46663 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256907 0.251 MAF protein O75444 UNIPROT MYB protein P10242 UNIPROT down-regulates binding 9606 9566892 t miannu Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity. SIGNOR-56811 0.651 KRAS protein P01116 UNIPROT RASSF1 protein Q9NS23 UNIPROT up-regulates activity binding 9606 22195963 t lperfetto Mutant K-Ras promotes MST2 activation in two ways (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex (Matallanas et al., 2008) and by forming an activating (i.e., by direct disruption of the inhibitory Raf-1-MST2 complex K-Ras-RASSF1A€“MST2 complex, as reported here SIGNOR-249585 0.642 FZR1 protein Q9UM11 UNIPROT DNM1L protein O00429 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000567 21325626 t Barakat Here we demonstrate that changes in mitochondrial dynamics as cells exit mitosis are driven in part through ubiquitylation of Drp1 catalyzed by the APC/Ccdh1 (anaphase-promoting complex/cyclosome and its coactivator (Cdh1) E3 ubiquiting ligase complex SIGNOR-274127 0.353 BMX protein P51813 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity phosphorylation Tyr400 RQGLDEMySDVWKQL 9534 11877430 t miannu Etk interacts with RUFY1 through its SH3 and SH2 domains. RUFY1 is tyrosine-phosphorylated and appears to be a substrate of Etk. Phosphorylation of the two tyrosine residues, Tyr-281 and Tyr-292, located in the linker region of the two coiled-coil domains by Etk seems to be critical for RUFY1 targeting to the endosomes. SIGNOR-262679 0.625 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates chemical activation 9606 22863277 t gcesareni Lpa binds to a family of gpcrs known as lpa receptors (lpa1-6) to initiate intracellular signaling. Lpa1 was highly expressed and lpa3 was detectable in hek293a cells compared to other lpa receptors. SIGNOR-198526 0.8 STK38 protein Q15208 UNIPROT PANX2 protein Q96RD6 UNIPROT up-regulates activity phosphorylation Ser514 KKHARHFsLDVHPYI 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263032 0.2 SERPINA1 protein P01009 UNIPROT F2 protein P00734 UNIPROT down-regulates activity binding 9606 BTO:0000131 17635716 t lperfetto Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days SIGNOR-263524 0.43 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t fspada Using ghr hyper-phosphorylated by elk kinase, we have identified tc-ptp, ptp- , pyst-2, sap1, meg-2, ptp1b, and ptph1 as having substrate specificity for this receptor. In addition, we have shown that these same ptps (or rather their nonmutated counterparts) can dephosphorylate the ghr. SIGNOR-104577 0.317 HBB protein P68871 UNIPROT Hemoglobin complex SIGNOR-C209 SIGNOR form complex binding 9606 18179859 t miannu AHSP does not bind to β-hemoglobin (βHb) or the hemoglobin tetramer, instead, it specifically binds to free αHb, avoiding its precipitation and its pro-oxidant activity. In the presence of βHb, the αHb-AHSP complex is dismembered and βHb displaces AHSP to generate the quaternary structure of hemoglobin SIGNOR-255275 0.702 CASP3 protein P42574 UNIPROT CASP6 protein P55212 UNIPROT up-regulates cleavage 9606 9922454 t amattioni Caspase-3 is required for the activation of caspases 6 SIGNOR-64179 0.607 AKT1 protein P31749 UNIPROT GATA2 protein P23769 UNIPROT down-regulates phosphorylation Ser401 QTRNRKMsNKSKKSK 9606 BTO:0000876 15837948 t PI-3K/Akt-dependent manner. fspada We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity SIGNOR-135614 0.534 NEDD4 protein P46934 UNIPROT LYN protein P07948 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001931 10683340 t miannu These findings suggest that LMP2A recruits Nedd4-like ubiquitin-protein ligases and B-cell signal transduction molecules, resulting in the degradation of LMP2A and Lyn by a ubiquitin-dependent mechanism.  SIGNOR-272558 0.447 tryptophan smallmolecule CHEBI:27897 ChEBI Trp-tRNA(Trp) smallmolecule CHEBI:29159 ChEBI up-regulates quantity precursor of 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270516 0.8 SELP protein P16109 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR up-regulates activity binding 9606 BTO:0000132 25297919 t lperfetto Besides VWF as a main ligand, GPIbα also binds multiple ligands such as thrombospondin, Factor XII, Factor XI, thrombin, High Molecular Weight kininogen, P-selectin and Mac-1. SIGNOR-261860 0.415 SPTAN1 protein Q13813 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 9624143 f Cleaved by CASP3 amattioni A-fodrin cleavage contributes to blebbing SIGNOR-57897 0.7 GART protein P22102 UNIPROT 5-amino-1-(5-phosphonato-beta-D-ribosyl)imidazol-3-ium smallmolecule CHEBI:137981 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267315 0.8 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser92 AAQMEVAsFLLSKEN 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250608 0.992 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT up-regulates activity palmitoylation Cys36 KEKASMLcFKRRKKA 10116 BTO:0004553 25589740 t Here, we report that the recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150 to regulate these plasticity signaling mechanisms SIGNOR-262295 0.336 BTF3 protein P20290 UNIPROT ABL2 protein P42684 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253947 0.2 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT down-regulates activity phosphorylation Ser537 REASRESsRDTSPVR 9534 BTO:0004055 19638411 t lperfetto GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells SIGNOR-264826 0.524 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser2612 MFVETQAsQGTLQTR 9606 BTO:0000773 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249155 0.2 ALDOB protein P05062 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Aldolase catalyzes the reversible conversion of FBP to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP; Figure 1). Aldolase is a tetramer of identical subunits of 40 kDa each, and 3 distinct isoenzymes have been identified: aldolase A, B, and C. SIGNOR-266480 0.8 C1QBP protein Q07021 UNIPROT Complement C1q complex SIGNOR-C308 SIGNOR down-regulates activity binding 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263401 0.379 HTR2C protein P28335 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257221 0.557 GTF2A1 protein P52655 UNIPROT TFIIA complex SIGNOR-C395 SIGNOR form complex binding 9606 BTO:0000567 7724559 t lperfetto TFIIA purified from HeLa extracts consists of 35-, 19-, and 12-kDa subunits. Here we describe the isolation of a cDNA clone (hTFIIA gamma) encoding the 12-kDa subunit. SIGNOR-266197 0.939 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT down-regulates activity cleavage Arg334 KNCPKKTrNLKKITR -1 7989361 t lperfetto The mechanism of inactivation of human factor V and human factor Va by activated protein C|Membrane-bound human factor V (250 nM) is cleaved by APC (2.5 nM) to give M(r) = 200,000, 70,000, 45,000, and 30,000 fragments and an M(r) = 22/20,000 doublet. These fragments are released after four sequential cleavages of the membrane-bound procofactor at Arg306, Arg506, Arg679, and Lys994. SIGNOR-263628 0.59 LONP2 protein Q86WA8 UNIPROT TYSND1 protein Q2T9J0 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000567 22002062 t miannu Self-cleavage of Tysnd1 in the active oligomer most likely inactivates its protease activity. Subsequently, the cleaved products are degraded by PsLon and removed from the Tysnd1 oligomer. SIGNOR-261054 0.652 DMTF1 protein Q9Y222 UNIPROT EGR1 protein P18146 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261584 0.2 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates activity chemical inhibition -1 19759537 t In biochemical activity assays, XAV939 strongly inhibited TNKS1 and TNKS2, with half-maximal inhibitory concentration values of 0.011 and 0.004 μM, respectively, but displayed much weaker effects on PARP1 and PARP2 SIGNOR-259994 0.8 LCK protein P06239 UNIPROT MUC1 protein P15941 UNIPROT up-regulates activity phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 14766232 t lperfetto The present results demonstrate that Lck phosphorylation of MUC1 on Y-46 also increases binding of MUC1 and _-catenin. The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 and _-catenin SIGNOR-247058 0.468 CALM3 protein P0DP25 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity binding 9606 BTO:0001853 24379783 t miannu Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer SIGNOR-266339 0.575 JMJD6 protein Q6NYC1 UNIPROT MEPCE protein Q7L2J0 UNIPROT down-regulates activity cleavage Arg171 HPAFKRRrRVNSDCD 10090 BTO:0002572 32048991 t miannu JMJD6 cleaves MePCE. we propose that JMJD6 is the cognate protease of MePCE and cleaves at the R171 site within MePCE. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. SIGNOR-261037 0.271 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t gcesareni The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells. SIGNOR-197622 0.871 NCOR2 protein Q9Y618 UNIPROT BCL6 protein P41182 UNIPROT up-regulates activity binding 9606 BTO:0000007 10898795 t miannu The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT. SIGNOR-252240 0.643 FYN protein P06241 UNIPROT CNN3 protein Q15417 UNIPROT down-regulates activity phosphorylation Tyr261 SQKGMSVyGLGRQVY 9534 BTO:0000298 15206927 t We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin SIGNOR-251159 0.336 FBXO32 protein Q969P5 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates activity 10090 25549588 f areggio Muscle-specific ubiq- uitin ligases, muscle-specific RING-finger 1 (MURF1; also known as TRIM63)12 and atrogin 1 (also known as MAFBX)8, are markedly induced in almost all types of atrophy. SIGNOR-254994 0.7 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1913 SPKYSPTsPTYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269345 0.721 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT down-regulates activity binding 9606 BTO:0000007;BTO:0000891 10929712 t amattioni Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria. SIGNOR-80222 0.893 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RCAN1 protein P53805 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000165 12063245 t inferred from 70% family members lperfetto Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin. SIGNOR-270026 0.2 MYC protein P01106 UNIPROT HLA-F protein P30511 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254605 0.2 CASP2 protein P42575 UNIPROT Caspase 2 complex complex SIGNOR-C227 SIGNOR form complex binding cleavage:Asp347 SPGCEESdAGKEKLP 21828056 t lperfetto Like other caspases, caspase-2 is synthesized as an inactive zymogen. The zymogen sequence includes a long prodomain containing a CARD followed by a large domain, a linker, and a small domain. Caspase-2 undergoes autocatalytic activation to remove the prodomain and linker region to generate a stable dimer consisting of the large subunit (p19) and the small subunit (p12). This p19/p12 dimer self-associates to form the active caspase-2 SIGNOR-256389 0.2 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120072 0.784 PRKACA protein P17612 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-97550 0.421 GPC6 protein Q9Y625 UNIPROT WNT5A protein P41221 UNIPROT down-regulates activity binding 9606 BTO:0000007 31756413 t miannu GPC6 binds to Wnt5a and inhibits its release from producing cells. Based on theseresults, and in our finding that GPC6 inhibits non-canonical Wnt signaling in the developing intestine,we tested the hypothesis that GPC6 binds to Wnt5aat the surface of the Wnt5a-producing mesenchymalcells and restrains its release from them. SIGNOR-264030 0.379 MAT2B protein Q9NZL9 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity binding 9606 BTO:0000599 23325601 t miannu We found both MAT2B variants interact with GIT1. MAT2B directly promoted binding of GIT1 and ERK2 to MEK1. MAT2B and GIT1 interact and are overexpressed in most human liver and colon cancer specimens. MAT2B and GIT1 require each other to activate MEK1/ERK and increase growth. SIGNOR-261244 0.405 NEK2 protein P51955 UNIPROT GAS2L1 protein Q99501 UNIPROT up-regulates activity phosphorylation Ser352 HPRSRRYsGDSDSSA 9606 32289147 t miannu Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation.  SIGNOR-273683 0.2 AMPK complex SIGNOR-C15 SIGNOR NEDD4L protein Q96PU5 UNIPROT up-regulates activity phosphorylation Ser795 VDLKPNGsEIMVTNE -1 21501591 t miannu The AMP-activated protein kinase (AMPK) down-regulates the inward rectifier K+ channel Kir2.1. Expression of wild type Nedd4-2 or of Nedd4-2S795A lacking an AMPK phosphorylation consensus sequence downregulated Kir2.1 currents. The effect of wild type Nedd4-2 but not of Nedd4-2S795A was significantly augmented by additional coexpression of AMPK. SIGNOR-276324 0.257 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 9841871 t lperfetto When truncated mapkkk4 (deltamapkkk4) was overexpressed in hek293 cells, it was constitutively activeco-expressed map kinase kinase (mkk)-1, mkk-4, mkk-3 and mkk-6 were activated in vivo by deltamapkkk4. All of the above mkks purified from escherichia coli were phosphorylated and activated by deltamapkkk4 immunoprecipitates in vitro. SIGNOR-62372 0.647 VEGFA protein P15692 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157100 0.817 PRKACA protein P17612 UNIPROT CHCHD3 protein Q9NX63 UNIPROT unknown phosphorylation Thr11 TTSTRRVtFEADENE -1 17242405 t miannu Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit. we used the recombinant GST-ChChd3 for an in vitro kinase assays to determine whether in vitro phosphorylation by PKA was direct. Fig. 6 demonstrates that PKA directly phosphorylates recombinant Chchd3 with a stoichiometry of 0.3 mol of phosphate incorporated per mol of ChChd3. Although three potential PKA phosphorylation sites exist in ChChd3, Thr10 represents the most likely site to be phosphorylated. SIGNOR-263116 0.2 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175825 0.626 MAPK1 protein P28482 UNIPROT RAI14 protein Q9P0K7 UNIPROT unknown phosphorylation Thr249 SQDADLKtPTKPKQH 10090 BTO:0000944 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262760 0.268 ponatinib chemical CHEBI:78543 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271;BTO:0000184 23526464 t miannu The RET tyrosine kinase encoding gene acts as a dominantly transforming oncogene in thyroid carcinoma and other malignancies. Ponatinib (AP24534) is an oral ATP-competitive tyrosine kinase inhibitor that is in advanced clinical experimentation in leukemia.Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma. SIGNOR-259275 0.8 EEF2K protein O00418 UNIPROT EEF2K protein O00418 UNIPROT down-regulates phosphorylation Ser445 SGDSGYPsEKRGELD 9606 22669845 t gcesareni The combination of eef2k autophosphorylation (targeting ser445) and a yet to be identified kinase (targeting ser441) would be needed to generate the eef2k phosphodegron specifically in response to dna damage. SIGNOR-197725 0.2 RAR proteinfamily SIGNOR-PF45 SIGNOR RXRA protein P19793 UNIPROT up-regulates binding 9606 1310351 t inferred from 70% family members gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins SIGNOR-269954 0.2 PP1 proteinfamily SIGNOR-PF54 SIGNOR IKZF1 protein Q13422 UNIPROT up-regulates dephosphorylation 9606 21750978 t lperfetto Ikarosis dephosphorylated by protein phosphatase 1 (pp1) via interaction at a consensus pp1-binding motif/ hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-264663 0.2 CDK5 protein Q00535 UNIPROT DRD2 protein P14416 UNIPROT down-regulates activity phosphorylation Ser321 GLHSTPDsPAKPEKN 9606 24391960 t miannu These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling. SIGNOR-259401 0.39 PRKCA protein P17252 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202780 0.2 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1110 GSVQNPVyHNQPLNP 9606 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236483 0.2 MAPK3 protein P27361 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser289 RSHSESAsPSALSSS 10090 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-143688 0.625 CGRRF1 protein Q99675 UNIPROT EGFR protein P00533 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002548 31801577 t miannu CGRRF1 ubiquitinates EGFR through K48-linked ubiquitination, which leads to proteasome degradation. SIGNOR-272220 0.2 ITGB2 protein P05107 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253192 0.748 CRHR1 protein P34998 UNIPROT Beta-endorphin protein P01189-PRO_0000024975 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 23504413 f lperfetto CRH, as a principal mediator of endocrine stress response, activates the HPA axis (Hypothalamic–pituitary–adrenal axis) by binding to the CRHR1 in the anterior pituitary. This, through a cascade of reactions, increases the expression of proopiomelanocortin (POMC) gene and the subsequent release of POMC-derived peptides, adrenocorticotropic hormone (ACTH) and β-endorphin. ACTH, in turn, stimulates the secretion of glucocorticoids from adrenal cortex (Vale et al. 1981). SIGNOR-268614 0.2 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity binding 9606 BTO:0000567 9390557 t lperfetto Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. SIGNOR-53576 0.954 HTR7 protein P34969 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257055 0.283 PPP2CA protein P67775 UNIPROT RB1 protein P06400 UNIPROT up-regulates dephosphorylation 9606 10702384 t gcesareni This dephosphorylation returns prb to its active, growth suppressive state. SIGNOR-75398 0.491 ponatinib chemical CHEBI:78543 ChEBI BCR-ABL fusion protein SIGNOR-FP6 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0001056 23409026 t miannu Pre-existing BCR-ABL mutations can be detected in a substantial number of chronic-phase CML patients by sensitive allele-specific PCR technique using CD34+ cells. These mutations are associated with imatinib resistance if affecting drug binding directly or indirectly. After the recent approval of nilotinib, dasatinib, bosutinib and ponatinib for treatment of chronic myeloid leukemia along with imatinib, all of which vary in their effectiveness against mutated BCR-ABL forms, detection of pre-existing BCR-ABL mutations can help in selection of appropriate first-line drug therapy. SIGNOR-259268 0.8 COL1A1 protein P02452 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 9606 BTO:0000664 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253247 0.557 RCOR1 protein Q9UKL0 UNIPROT SCN2A protein Q99250 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 10449787 f miannu We show here that CoREST, a newly identified human protein, functions as a corepressor for REST. A single zinc finger motif in REST is required for CoREST interaction. Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST/CoREST complex may mediate long-term repression essential to maintenance of cell identity. SIGNOR-220695 0.273 CUL2 protein Q13617 UNIPROT APOBEC3A protein P31941 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 29367246 t lperfetto Human Papillomavirus 16 E7 Stabilizes APOBEC3A Protein by Inhibiting Cullin 2-Dependent Protein Degradation|Here, we report that the HPV oncoprotein E7 stabilizes the APOBEC3A (A3A) protein in human keratinocytes by inhibiting ubiquitin-dependent protein degradation in a cullin-dependent manner. SIGNOR-261325 0.252 PRKDC protein P78527 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 9363941 t gcesareni We demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of mdm2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by dna-pk (or other protein kinases with similar specificity) in response to dna damage. SIGNOR-53030 0.788 ATP5F1C protein P36542 UNIPROT ATP synthase complex SIGNOR-C264 SIGNOR form complex binding 9606 21874297 t miannu Human mitochondrial ATP synthase, or complex V, consists of two functional domains, F1 and Fo. F1 comprises 5 different subunits (three α, three β, and one γ, δ and ε) and is situated in the mitochondrial matrix. Fo contains subunits c, a, b, d, F6, OSCP and the accessory subunits e, f, g and A6L. SIGNOR-261405 0.2 ATM protein Q13315 UNIPROT NKX3-1 protein Q99801 UNIPROT down-regulates quantity by destabilization phosphorylation Thr134 SRAAFSHtQVIELER 9606 BTO:0002181 23890999 t miannu ATM phosphorylates NKX3.1 on T166 and then T134, resulting in NKX3.1 ubiquitination and degradation resulting from an apparent regulatory interaction. SIGNOR-276499 0.368 PI3K complex SIGNOR-C156 SIGNOR PIK3CG protein P48736 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252721 0.592 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10611223 t lperfetto Pak phosphorylates bad in vitro and in vivo on ser112 and ser136, resulting in a markedly reduced interaction between bad and bcl-2 or bcl-x(l) and the increased association of bad with 14-3-3tau. SIGNOR-73533 0.338 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 10428798 t lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-217284 0.426 RERE protein Q9P2R6 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates activity binding 9606 BTO:0000932 28144959 t miannu In mammalian cells, RERE co‐immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over‐expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes. SIGNOR-264486 0.322 USP8 protein P40818 UNIPROT BACE1 protein P56817 UNIPROT up-regulates quantity by stabilization deubiquitination Lys501 ADDISLLk 9606 BTO:0003704 27302062 t irozzo Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization.Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. SIGNOR-259101 0.457 SARS1 protein P49591 UNIPROT tRNA(Ser) smallmolecule CHEBI:29179 ChEBI down-regulates quantity chemical modification 9606 24095058 t miannu As a member of the aminoacyl-tRNA synthetase family, seryl-tRNA synthetase (SerRS) catalyzes the aminoacylation reaction that charges serine onto its cognate tRNA for protein synthesis SIGNOR-270493 0.8 RPS6KA1 protein Q15418 UNIPROT TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-217900 0.717 CDK1 protein P06493 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 SIGNOR-C17 20150555 t gcesareni Moreover, we showed that sp1 is a novel mitotic substrate of cdk1/cyclin b1 and is phosphorylated by it at thr 739 before the onset of mitosis. SIGNOR-163738 0.472 FYN protein P06241 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Tyr18 MEDHAGTyGLGDRKD 9606 14999081 t lperfetto In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. SIGNOR-123099 0.546 NDN protein Q99608 UNIPROT EID1 protein Q9Y6B2 UNIPROT up-regulates activity binding 10090 BTO:0000165 18557765 t llicata The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation. SIGNOR-237614 0.38 SEC61B protein P60468 UNIPROT SEC61 complex complex SIGNOR-C368 SIGNOR form complex binding -1 33925740 t lperfetto The heterotrimeric Sec61 complex of the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER SIGNOR-265277 0.907 Inflammation phenotype SIGNOR-PH12 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000399 11290754 f apalma Our findings indicate that chemokines acting via CCR3-initiated signaling pathways can very rapidly mobilize preformed stores of IL-4 from within human eosinophils. The means of extracellular release was by noncytotoxic, vesicular transport SIGNOR-255494 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser853 LPLLPPEsPGPLRQR 9606 BTO:0000007 20622900 t miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. SIGNOR-263065 0.2 methylnaltrexone chemical CHEBI:136007 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10030 19282177 t Luana A series of novel high affinity opioid receptor ligands have been made whereby the phenolic-OH group of nalbuphine, naltrexone methiodide, 6-desoxonaltrexone, hydromorphone and naltrindole was replaced by a carboxamido group and the furan ring was opened to the corresponding 4-OH derivatives. These furan ring “open” derivatives display very high affinity for μ and κ receptors and much less affinity for δ. SIGNOR-258148 0.8 RARA protein P10276 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 10772826 f lperfetto Retinoic acid and its receptors repress the expression and transactivation functions of nur77 SIGNOR-76980 0.294 EED protein O75530 UNIPROT Polycomb repressive complex 2 complex SIGNOR-C130 SIGNOR form complex binding 9606 23110252 t lperfetto The PRC2 core, conserved from Drosophila to humans, is composed of four proteins that add up to about 230 kDa (Figure 1A) (see Margueron and Reinberg, 2010 for a recent review): EED (present in different isoforms), either one of the two methyltranferases Ezh1 or Ezh2 (Ezh1/2), Suz12, and either RbAp46 or RbAp48 (RbAp46/48). SIGNOR-241897 0.901 SMARCD2 protein Q92925 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270603 0.719 ESR2 protein Q92731 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 6153132 f lperfetto The human and rat OT promoters could be stimulated by the ligand-activated estrogen receptors ERalpha and ERbeta, the thyroid hormone receptor THRapha, and the retinoic acid receptors RARalpha and RARbeta in a variety of cells (3, 477, 478). However, it is important to note that these results were obtained from cotransfection experiments in cell lines, i.e., under nonphysiological circumstances. SIGNOR-268547 0.484 BRCA1 protein P38398 UNIPROT FOXC2 protein Q99958 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 22120723 f miannu We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. SIGNOR-253760 0.262 STK38 protein Q15208 UNIPROT PI4KB protein Q9UBF8 UNIPROT up-regulates activity phosphorylation Ser277 RTHQRSKsDATASIS 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. SIGNOR-263033 0.269 PTPRA protein P18433 UNIPROT LYN protein P07948 UNIPROT down-regulates activity dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397|Lyn expressed in CHO cells has a substantially higher specific activity than Lyn in RBL cells because of high levels of phosphorylation at its active site Tyr-397 (Fig. 1). Enhanced Lyn kinase activity in the CHO cells leads to spontaneous phosphorylation of multiple cellular proteins, including FcϵRI SIGNOR-248436 0.303 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HIF1A protein Q16665 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 18519666 t inferred from 70% family members lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-270191 0.2 sorafenib tosylate chemical CHEBI:50928 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259222 0.8 CSNK2A1 protein P68400 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser53 DEELEGIsPDELKDE -1 7598724 t llicata We report that recombinant glia maturation factor (GMF), a 17-kD brain protein, can be phosphorylated in vitro at the serine residue by protein kinase C (PKC), protein kinase A (PKA), and casein kinase II (CKII), and at the threonine residue by p90 ribosomal S6 kinase (RSK).  SIGNOR-250868 0.334 PRKACA protein P17612 UNIPROT SCRIB protein Q14160 UNIPROT unknown phosphorylation Ser1445 PSPTSRQsPASPPPL 9606 BTO:0000007 20622900 t miannu HScrib is a substrate of ERK and PKA. Under normal growth conditions, hScrib is phosphorylated at S853, most likely by ERK, and at S1445 by PKA. Interestingly, stimulation of MAPK by osmotic stress results in a marked loss of phosphorylation at the PKA site S1445, but a concomitant increase in phosphorylation at S1448, presumably also by ERK. At present, we have no information as to what are the functional consequences of ERK or PKA phosphorylation of hScrib. However, we can speculate that this will most likely affect the ability of hScrib to interact with some of its cellular partners, and studies are currently in progress to investigate these aspects further. SIGNOR-263066 0.251 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22703233 f lperfetto Our results establish a novel biological role for TGFbeta signaling in controlling expression of genes characteristic for alternatively activated macrophages. We speculate that lack of TbetaRII signaling reduces the anti-inflammatory M2 phenotype of macrophages because of reduced expression of these products. SIGNOR-249551 0.7 GRK2 protein P25098 UNIPROT SMO protein Q99835 UNIPROT up-regulates phosphorylation 9606 15618519 t gcesareni We find that two molecules interact with mammalian smo in an activation-dependent manner: g protein-coupled receptor kinase 2 (grk2) leads to phosphorylation of smo, and beta-arrestin 2 fused to green fluorescent protein interacts with smo. Ck1a, grk2, and another still-unidentified protein kinase phosphorylate the c-tail of mammalian smo in the presence of hh proteins SIGNOR-132669 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr62 RRPESFTtPEGPKPR 9606 BTO:0000567 18490441 t lperfetto Phosphorylation of threonine 61 by cyclin a/Cdk1 triggers degradation of stem-loop binding protein at the end of S phase SIGNOR-265259 0.417 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000669 15568017 t gcesareni Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression. SIGNOR-131307 0.57 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser444 QRKSQRSsYVSMRID -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The PKC family contains 12 identified mammalian isoenzymes that are universally expressed in all cells and tissues and generally have a cytosolic distributionExamination of two groups of serine and threonine mutations (Fig. 3A, lanes 2 and 3) enabled us to localize the phosphorylation to four specific residues at positions 419, 422, 423, and 426. Fig. 3B shows the levels of phosphorylation with different combinations of the four mutations. Elimination of all four serines completely eliminated phosphorylation (Fig. 3B, lane 1).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262755 0.339 ARID5B protein Q14865 UNIPROT TAL1 protein P17542 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu ARID5B positively regulates the expression of TAL1 and its regulatory partners. we also observed that ARID5B regulates the expression of four major components of the TAL1 complex (namely, TAL1,GATA3, RUNX1, and MYB) in Jurkat cells. Knockdown of ARID5B resulted in reductions of the H3K27ac signals at those enhancer loci (Supplemental Fig. S6E–H) and down-regulation of all four factors at the mRNA (Fig. 6E) and protein levels (Fig. 6F). SIGNOR-256157 0.267 PPP2R5C protein Q13362 UNIPROT PPP2CA protein P67775 UNIPROT up-regulates activity binding 9606 7592815 t We have identified by two-hybrid interaction a new human gene family encoding PP2A B subunits. This family, denoted B56, contains three distinct genes, one of which is differentially spliced. SIGNOR-268155 0.86 PLK1 protein P53350 UNIPROT NINL protein Q9Y2I6 UNIPROT down-regulates activity phosphorylation Thr161 SDEEAEStKEAQNEL -1 12852856 t lperfetto Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction SIGNOR-103364 0.693 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8892604 t lperfetto Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function SIGNOR-44669 0.722 MPHOSPH10 protein O00566 UNIPROT RPS5 protein P46782 UNIPROT up-regulates activity binding -1 28813493 t miannu Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. SIGNOR-261175 0.614 USF1 protein P22415 UNIPROT GCK protein P35557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9677331 f miannu Cotransfection of an expression plasmid encoding USF1 into HepG2 hepatoma cells resulted in the activation of the glucokinase promoter, dependent on the integrity of the P2 element SIGNOR-255597 0.292 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT up-regulates activity phosphorylation Ser79 EVTSTSQsPHSPDSS 9606 8650547 t lperfetto ...undergoes inducible phosphorylation on two adjacent serine residues (78 and 81). In vitro, chop is phosphorylated on these residues by p38 mitogen-activated protein kinase (map kinase). phosphorylation of chop on these residues enhanced its ability to function as a transcriptional activator. SIGNOR-42200 0.6 N-[4-(2-tert-butylphenyl)sulfonylphenyl]-2,3,4-trihydroxy-5-[(2-propan-2-ylphenyl)methyl]benzamide chemical CHEBI:95008 ChEBI MCL1 protein Q07820 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207465 0.8 CSAG2 protein Q9Y5P2 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates activity binding 9606 32761762 t miannu Here, we show that the previously undescribed CSAG2 protein is a direct activator of SIRT1.  Biochemical studies revealed that CSAG2 directly binds to and stimulates SIRT1 activity toward multiple substrates. Importantly, CSAG2 enhances SIRT1‐mediated deacetylation of p53, inhibits p53 transcriptional activity, and improves cell survival in response to genotoxic stress. SIGNOR-261670 0.2 HRAS protein P01112 UNIPROT JUN protein P05412 UNIPROT up-regulates activity phosphorylation Ser73 VGLLKLAsPELERLI 10116 BTO:0000452 1749429 t lperfetto Expression of oncogenic ha-ras augments transactivation by c-jun and stimulates its phosphorylation. Here we describe the mapping of the ha-ras-responsive phosphorylation sites to serines 63 and 73 of c-jun. Site-directed mutagenesis indicates that phosphorylation of these serines is essential for stimulation of c-jun activity and for cooperation with ha-ras in ocogenic transformation. SIGNOR-236686 0.51 EFR3B protein Q9Y2G0 UNIPROT PI4KA protein P42356 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 t miannu PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B SIGNOR-269093 0.519 OGT protein O15294 UNIPROT PFKM protein P08237 UNIPROT down-regulates activity glycosylation Ser530 VVIPATVsNNVPGSD 9606 26399441 t lperfetto Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively. SIGNOR-267584 0.351 GSK3B protein P49841 UNIPROT FGF14 protein Q92915 UNIPROT up-regulates activity phosphorylation Ser226 PKPGVTPsKSTSASA 9606 BTO:0000938 32599005 t lperfetto Our laboratory has also demonstrated that FGF14 is a key accessory protein that binds to the intracellular Nav1.6 C-terminal tail, and that GSK3β can phosphorylate FGF14 both in vitro and in vivo at S226 [20] in an experimental model of Alzheimer's disease SIGNOR-275746 0.261 SNRPE protein P62304 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270681 0.942 CCL3 protein P10147 UNIPROT CCR2 protein P41597 UNIPROT up-regulates activity binding 10090 15075201 t lperfetto The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days. SIGNOR-251723 0.552 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT up-regulates activity phosphorylation Ser300 KKDQEGDsAAALSLY 9606 20643644 t Manara We show that ULK3 autophosphorylation occurs at four serine residues (Ser-300, Ser-350, Ser-384, and Ser-464) situated outside of the KD | Thus, autophosphorylation of ULK3 may involve conformational changes resulted in exposure of CTD to KD and consequently in generation of the catalytically active kinase. SIGNOR-260793 0.2 NOTCH4 protein Q99466 UNIPROT MAML2 protein Q8IZL2 UNIPROT up-regulates binding 9606 12386158 t gcesareni We show here identification of two new members of human mam family (human mastermind-2 (hmam-2) and human mastermind-3 (hmam-3)), which retain characteristics similar to human mastermind-1 (hmam-1) and drosophila mastermind. Both hmam-2 and hmam-3 stabilize and participate in the dna-binding complex rbp-j/cbf-1 protein and the notch intracellular domains that serve as intermediates of the signaling. Both hmam-2 and hmam-3 enhanced the activation of transcription from a target promoter by notch signaling. However, we also show evidence that the activation of the target promoter by notch3 and notch4 is more efficiently potentiated by hmam-2 than by hmam-1 or -3. SIGNOR-94279 0.856 EXT1 protein Q16394 UNIPROT BMP4 protein P12644 UNIPROT up-regulates activity 9606 24860992 f miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. SIGNOR-264018 0.362 HRAS protein P01112 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 21779497 t lperfetto The first RAS effector pathway to be identified was the RAF-MEK-ERK pathway. This pathway is an essential, shared element of mitogenic signaling involving tyrosine kinase receptors, leading to a wide range of cellular responses, including growth, differentiation, inflammation, and apoptosis.23 The RAF family of proteins (Raf-1, A-Raf, and B-Raf) is serine/threonine kinases that bind to the effector region of RAS-GTP, thus inducing translocation of the protein to the plasma membrane. SIGNOR-236656 0.934 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258889 0.8 POGZ protein Q7Z3K3 UNIPROT CBX5 protein P45973 UNIPROT down-regulates activity binding 9606 BTO:0000932 20562864 t miannu POGZ was found to bind to HP1alpha through a zinc-finger-like motif. Binding by POGZ, mediated through its zinc-finger-like motif, competed with PxVxL proteins and destabilized the HP1alpha-chromatin interaction. SIGNOR-264487 0.439 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates activity phosphorylation 9606 23431053 t miannu Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity SIGNOR-256185 0.898 MMP7 protein P09237 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272374 0.7 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887;BTO:0001103 12058061 t lperfetto Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs. SIGNOR-236575 0.498 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 BTO:0000007 17035229 t SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248796 0.502 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270880 0.543 SMARCA2 protein P51531 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65432 0.909 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr106 EDPVTVEyITRYIAS 9606 25620702 t Manara PSMA7 degradation is suppressed by c-Abl-mediated tyrosine phosphorylation at Y106 SIGNOR-260937 0.403 SIRT1 protein Q96EB6 UNIPROT ACAN protein P16112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21337390 f miannu The inhibition of SIRT1 by siRNA induced OA-like gene expression changes, namely the significant down-regulation of aggrecan and up-regulation of COL10A1 and ADAMTS-5. SIGNOR-255142 0.32 ATM protein Q13315 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity 9606 BTO:0000887 18534819 f gcesareni The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity. SIGNOR-161434 0.457 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 BTO:0000007 22863277 t milica In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function. SIGNOR-198504 0.772 TP53 protein P04637 UNIPROT CRYAB protein P02511 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21556774 t miannu Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously|Taken together, our results indicate that AP-2_ up-regulates the transcription of the CRYAB gene through stabilizing p53 SIGNOR-253638 0.479 CDK5 protein Q00535 UNIPROT PPP1R1B protein Q9UD71 UNIPROT up-regulates activity phosphorylation Thr75 RPNPCAYtPPSLKAV 10116 BTO:0000142 10604473 t llicata We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. SIGNOR-250671 0.772 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT down-regulates activity dephosphorylation Ser660 QSEFEGFsFVNSEFL 10116 15880462 t Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform SIGNOR-248586 0.461 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT up-regulates activity phosphorylation Ser718 KEAEEESsEDD 9606 BTO:0000007 11500362 t llicata Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.  SIGNOR-250860 0.391 CDK2 protein P24941 UNIPROT GATA3 protein P23771 UNIPROT down-regulates quantity by destabilization phosphorylation Thr156 HLFTFPPtPPKDVSP 9606 BTO:0000567 24820417 t miannu Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. SIGNOR-276634 0.366 SP3 protein Q02447 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 t lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. SIGNOR-251741 0.2 SLC1A2 protein P43004 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity relocalization 9606 26687113 t miannu After release from presynaptic nerve terminals, glutamate is quickly removed from the synaptic cleft by a family of five glutamate transporters, the so-called excitatory amino acid transporters (EAAT1-5). SIGNOR-264803 0.8 SLBP protein Q14493 UNIPROT Histone H2B proteinfamily SIGNOR-PF68 SIGNOR up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265375 0.2 ANK3 protein Q12955 UNIPROT GABARAP protein O95166 UNIPROT up-regulates activity binding 10090 BTO:0003102 30504823 t miannu Importantly, the 480 kDa ankyrin-G isoform has also been shown to stabilize GABAergic synapses on the soma and AIS of excitatory pyramidal neurons by interacting with the GABAA receptor-associated protein (GABARAP) to inhibit GABAA receptor endocytosis SIGNOR-266709 0.45 PRKCA protein P17252 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249083 0.477 GCG protein P01275 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates 9606 23075495 f inferred from 70% of family members gcesareni On the other hand, galfas-coupled signals, such as epinephrine and glucagon, induce kinase activity of lats1/2, leading to phosphorylation and yap/taz. SIGNOR-269857 0.275 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt SIGNOR-252448 0.638 BZW2 protein Q9Y6E2 UNIPROT EIF3A protein Q14152 UNIPROT up-regulates activity binding 9606 31643092 t miannu BZW2, as an evolutionary highly conserved protein, interacts with eIF2 and eIF3 and promotes ternary complex formation in vitro SIGNOR-261221 0.327 TRIM27 protein P14373 UNIPROT PIK3C2B protein O00750 UNIPROT down-regulates ubiquitination 9606 22128329 t miannu We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity. SIGNOR-177935 0.407 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser71 SRRSGLCsPSYVAVT 9606 10551811 t gcesareni The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-72108 0.364 CSNK2A1 protein P68400 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation Thr102 RAAMFPEtLDEGMQI 9606 BTO:0000007 12432063 t llicata We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin SIGNOR-250847 0.546 SH3GLB1 protein Q9Y371 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 BTO:0000567 16227588 t gcesareni Here, we provide evidence that bif-1 plays a regulatory role in apoptotic activation of not only bax but also bak and appears to be involved in suppression of tumorigenesis. while bif-1 did not directly interact with bak, it heterodimerized with bax on mitochondria in intact cells, and this interaction was enhanced by apoptosis induction and preceded the bax conformational change. SIGNOR-141166 0.332 INPPL1 protein O15357 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates 9606 18486448 f gcesareni Ship2 positively modulated the mlk3/jip1-mediated jnk1 activation SIGNOR-178652 0.2 MAPK6 protein Q16659 UNIPROT KALRN protein O60229 UNIPROT up-regulates activity phosphorylation -1 22508986 t miannu The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements. SIGNOR-263094 0.39 CCKAR protein P32238 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257236 0.253 BCL7A protein Q4VC05 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269784 0.498 DCX DET1-COP1 complex SIGNOR-C24 SIGNOR JUN protein P05412 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 14739464 t miannu We report that human DET1 (hDET1) promotes ubiquitination and degradation of the proto-oncogenic transcription factor c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1.  Ablation of any subunit by RNA interference stabilized c-Jun and increased c-Jun-activated transcription. SIGNOR-271500 0.376 CDK1 protein P06493 UNIPROT NDUFV1 protein P49821 UNIPROT up-regulates activity phosphorylation Thr383 HESCGQCtPCREGVD 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275594 0.2 ABL1 protein P00519 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Tyr292 RLGHCHTyWAVSEEL 9606 BTO:0000007 30842273 t miannu The data in this study show that IRF3 is physically associated with c-Abl in vivo and directly binds to c-Abl in vitro. IRF3 is phosphorylated by c-Abl and c-Abl-related kinase, Arg, mainly at Y292. SIGNOR-277440 0.2 SAICAR(4-) smallmolecule CHEBI:58443 ChEBI 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 ChEBI up-regulates quantity precursor of 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266609 0.8 A11/b1 integrin complex SIGNOR-C168 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257710 0.56 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Thr175 GLLPFLLtHKKRLTD 9606 19661060 t Manara We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-260881 0.2 SOCS3 protein O14543 UNIPROT IRS1 protein P35568 UNIPROT down-regulates binding 9606 23115649 t gcesareni Irs-1 is the major signaling protein that socs3 targets to inhibit insulin signaling SIGNOR-199361 0.734 SYVN1 protein Q86TM6 UNIPROT HMGCR protein P04035 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0000944 14593114 t miannu In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols. SIGNOR-272594 0.573 EEF1A2 protein Q05639 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269532 0.8 SPAG9 protein O60271 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity binding 9606 BTO:0000222 17074887 t Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP lperfetto Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants. SIGNOR-149979 0.549 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275956 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK2 protein P24941 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189984 0.8 CLOCK protein O15516 UNIPROT CRY2 protein Q49AN0 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253632 0.924 FBLIM1 protein Q8WUP2 UNIPROT FLNB protein O75369 UNIPROT up-regulates activity binding 10090 BTO:0000944 24165133 t miannu Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton. SIGNOR-266106 0.737 PRKACA protein P17612 UNIPROT MIP protein P30301 UNIPROT down-regulates activity phosphorylation Ser229 LLFPRLKsISERLSV -1 2176601 t miannu Phosphorylation at one of these sites (serine 243) could be increased by A kinase in vitro. phosphorylation of MIP reconstituted into single bilayers increased the voltage dependence and long-term closures of the channels observed. SIGNOR-250018 0.314 HMOX1 protein P09601 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26722274 f irozzo The results of the present study indicated that knockdown of HMOX-1 significantly enhanced doxorubicin-induced apoptosis and downregulated the expression of Bcl-2 and Bcl-xL in breast cancer cells. SIGNOR-256303 0.251 CDK7 protein P50613 UNIPROT MCM2 protein P49736 UNIPROT up-regulates activity phosphorylation Ser27 GNDPLTSsPGRSSRR 9606 16899510 t Luana Taken together, these results indicate that Cdc7/Dbf4 phosphorylation of MCM2 is essential for the initiation of DNA replication in mammalian cells. | Because MCM2 was phosphorylated in vivo at Ser27, Ser41, and Ser139, which were phosphorylated by Cdc7/Dbf4 in vitro, the results suggested that Ser27, Ser41, and Ser139 are in vivo Cdc7/Dbf4 phosphorylation sites in MCM2. SIGNOR-259848 0.303 methionine smallmolecule CHEBI:16811 ChEBI Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity precursor of 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270402 0.8 BRCA1-C complex complex SIGNOR-C299 SIGNOR G2/M_transition-checkpoint phenotype SIGNOR-PH146 SIGNOR up-regulates 9606 BTO:0000567 16391231 f lperfetto This result implies that the BRCA1/BARD1–RMN–CtIP complex is required for activation of the G2/M checkpoint. SIGNOR-263229 0.7 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates activity phosphorylation 10090 BTO:0000011 19593385 t lperfetto In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis SIGNOR-252817 0.724 Naltriben chemical CID:5486827 PUBCHEM OPRD1 protein P41143 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258425 0.8 FIZ1 protein Q96SL8 UNIPROT CRX protein O43186 UNIPROT down-regulates activity binding 9913 12566383 t miannu Interaction of Fiz1 and NRL-leucine zipper was validated by GST pulldown assays and co-immunoprecipitation from bovine retinal nuclear extracts. Fiz1 suppressed NRL- but not CRX-mediated transactivation of rhodopsin promoter activity in transiently transfected CV1 cells. SIGNOR-223799 0.464 NFIA protein Q12857 UNIPROT NFIX protein Q14938 UNIPROT up-regulates quantity transcriptional regulation 10090 29106906 t Gianni We report that, in the absence of Nfia or Nfib, there is a marked reduction in the spinal cord expression of NFIX, and that NFIB can transcriptionally activate Nfix expression in vitro. These data demonstrate that NFIX is part of the downstream transcriptional program through which NFIA and NFIB coordinate gliogenesis within the spinal cord. SIGNOR-268871 0.2 GLS protein O94925 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 22049910 t miannu Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia. SIGNOR-266910 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 22369944 t lperfetto Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-217316 0.342 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR USP24 protein Q9UPU5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1616 NSHSPAGsAAISQQD 9606 BTO:0000018 27991932 t lperfetto Epidermal growth factor (EGF) treatment, and the KrasG12D and EGFRL858R mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. SIGNOR-275611 0.259 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15621017 f It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. SIGNOR-255481 0.7 APOC2 protein P02655 UNIPROT LPL protein P06858 UNIPROT up-regulates activity 9606 19956660 f Regulation miannu Triglycerides in VLDL are hydrolyzed by lipoprotein lipase, which in turn is activated by apolipoprotein CII on the surface but inhibited by apolipoprotein CIII. SIGNOR-251846 0.759 UBTF protein P17480 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0001412 7877691 t lperfetto Rb specifically inhibits the activity of the RNA polymerase I transcription factor UBF (upstream binding factor) in vitro. |These results indicate that there is an additional mechanism by which Rb suppresses cell growth, namely that Rb directly represses transcription of the rRNA genes. SIGNOR-262590 0.7 PPP2CB protein P62714 UNIPROT CARD11 protein Q9BXL7 UNIPROT down-regulates activity dephosphorylation Ser644 NLMFRKFsLERPFRP 9606 21157432 t NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation. SIGNOR-248607 0.2 PRKAA1 protein Q13131 UNIPROT NAMPT protein P43490 UNIPROT up-regulates quantity transcriptional regulation 10090 18477450 f gcesareni Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt SIGNOR-238598 0.301 romidepsin chemical CHEBI:61080 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257991 0.8 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates phosphorylation -1 14614828 t lperfetto We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli SIGNOR-217469 0.601 SRC protein P12931 UNIPROT WNK4 protein Q96J92 UNIPROT down-regulates activity phosphorylation Tyr1164 KKEIEDLySRLGKQP 9606 BTO:0002181 25805816 t miannu Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4.  SIGNOR-276896 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPC5 protein Q9UL62 UNIPROT down-regulates activity phosphorylation Ser796 GARAKSKsVSFNLGC 9606 BTO:0000007 21734191 t miannu We show that TRPC5 channels may become directly phosphorylated by PKA at serine residues 794 and 796, and that this phosphorylation abolishes the receptor-operated nonselective cation current mediated by TRPC5 channels in HEK-293 cells. SIGNOR-276339 0.2 KU-60019 chemical CID:15953870 PUBCHEM ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193597 0.8 ZFPM1 protein Q8IX07 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR up-regulates activity 10090 BTO:0000725 22068055 f We here use conditional removal of the GATA-1 and FOG-1 transcription factors to identify FOG-1 as required for the formation of all committed Mk- and E-lineage progenitors, whereas GATA-1 was observed to be specifically required for E-lineage commitment. SIGNOR-259964 0.7 WNT3A protein P56704 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 22653731 t gcesareni Structural basis of wnt recognition by frizzled. SIGNOR-197638 0.793 SYN3 protein O14994 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR down-regulates 9606 BTO:0000938 33809712 f miannu Synapsins are a family of peripheral proteins that bind to the SV membrane. Synapsins Maintain the SV Reserve Pool. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. SIGNOR-264107 0.7 SLBP protein Q14493 UNIPROT H2BC18 protein Q5QNW6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265394 0.2 NMUR1 protein Q9HB89 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256751 0.479 TPSAB1 protein Q15661 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity binding 10116 21999702 t lperfetto Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2).|Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2. SIGNOR-251744 0.253 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1735 SPTSPSYsPTSPSYS -1 22137580 t Phosphorylation and dephosphorylation of the C-terminal domain (CTD) of RNA polymerase II (Pol II) represent a critical regulatory checkpoint for transcription. Transcription initiation requires Fcp1/Scp1-mediated dephosphorylation of phospho-CTD. | This combined structure-function analysis discloses the residues in Scp1 involved in CTD binding and its preferential dephosphorylation of P.Ser5 of the CTD heptad repeat. SIGNOR-248788 0.437 TALDO1 protein P37837 UNIPROT D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI down-regulates quantity chemical modification 9606 19401148 t miannu Transaldolase (TAL, sedoheptulose 7-phosphate: d-glyceraldehyde 3-phosphate dihydroxyacetone transferase; EC number 2.2.1.2) is a cofactor-less enzyme of the pentose phosphate pathway (PPP) (Fig. 1A and B). It catalyzes the reversible transfer of a three carbon unit (“dihydroxyacetone”) between various sugar phosphates (from 3 to 8 carbon atoms in length). Physiological donor compounds are ketose sugar phosphates as fructose 6-phosphate or sedoheptulose 7-phosphate. Acceptor compounds are aldose sugar phosphates as glyceraldehyde 3-phosphate and erythrose 4-phosphate. SIGNOR-267090 0.8 FLT3 protein P36888 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity 9606 16266983 f gcesareni We show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. SIGNOR-245064 0.439 LATS2 protein Q9NRM7 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation -1 24157836 t miannu FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. SIGNOR-272138 0.537 PPP2CB protein P62714 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 8650155 t gcesareni These results confirm that the activity changes observed are achieved by a reversible phosphorylation mechanism, and also argue that pp2a may negatively regulate rac-pk activity in vivo. Dephosphorylation of the activated rac-pk in itro by pp2ac resulted in an 87% reduction of kinase activity SIGNOR-42123 0.467 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser20 ADDSLSNsEEEPDRQ 9606 21559372 t llicata Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist. SIGNOR-173672 0.2 TLE1 protein Q04724 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates activity binding -1 19460168 t Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical. SIGNOR-260109 0.681 DYRK1A protein Q13627 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation 9606 12138125 t Dyrk1 acts synergistically with Shh to induce transcription of a Gli-promoter-driven luciferase reporter gene and of endogenous alkaline phosphatase. gcesareni Dyrk1 phosphorylates gli1 on more than one domain. SIGNOR-90809 0.523 BTRC protein Q9Y297 UNIPROT GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 16421275 t lperfetto Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein SIGNOR-235631 0.655 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser53 LPPFEDEsEGLLGTE 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187400 0.961 DUSP4 protein Q13115 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates dephosphorylation 9606 9020184 t lperfetto Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2 SIGNOR-27756 0.707 EIF2AK2 protein P19525 UNIPROT AIM2 inflammasome complex SIGNOR-C222 SIGNOR up-regulates activity binding 9606 BTO:0000007 22801494 t miannu Here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. SIGNOR-263120 0.317 3-[({4-[4-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-3-methyl-1,2-oxazol-5-yl]phenyl}methyl)sulfanyl]propanoic acid chemical CHEBI:91194 ChEBI LPAR2 protein Q9HBW0 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193561 0.8 PPP3CC protein P48454 UNIPROT KSR2 protein Q6VAB6 UNIPROT up-regulates activity dephosphorylation Ser313 TALHRSKsHEFQLGH 10090 19560418 t These findings indicate that calcineurin modulates the phosphorylation state of KSR2, but not KSR1, and identifies S198, T287, and the S310 14-3-3 binding site as the KSR2 residues targeted by calcineurin.|the negative regulators 14-3-3 SIGNOR-248527 0.261 CSNK2A1 protein P68400 UNIPROT MAX protein P61244 UNIPROT down-regulates phosphorylation Ser11 NDDIEVEsDEEQPRF 9606 8018564 t gcesareni Max activity is affected by phosphorylation at two nh2-terminal sites, ser2 and ser11. SIGNOR-35768 0.365 MYO9B protein Q13459 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260510 0.529 COX4I1 protein P13073 UNIPROT Oxidative_phosphorylation phenotype SIGNOR-PH78 SIGNOR up-regulates 10090 23021218 f lperfetto PGC1a is known to drive the expression of many genes involved in mitochondrial oxidative phosphorylation, including cytochrome c (CytC) and the cyto- chrome C oxidative (COX) subunits (CoxIII, Cox4il, Cox5b, Cox7a, and Cox8b). SIGNOR-253101 0.7 CNOT8 protein Q9UFF9 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268310 0.788 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser126 RKETSARsLGSPLLH 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262715 0.738 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR RB1 protein P06400 UNIPROT down-regulates activity phosphorylation Ser608 TAADMYLsPVRSPKK BTO:0001968 10207050 t llicata In the present assay, ΔP3,4HA repressed E2F-mediated transcription similarly to wild-type pRB, suggesting that phosphorylation at other sites on ΔP3,4HA can disrupt its interaction with E2F and that these two sites are not sufficient to regulate E2F binding on DNA. This result is consistent with another report which showed that mutation of the human sites 8 and 9 (human Ser608 and Ser612) repressed E2F-mediated transcription to the same level as wild-type pRB (2). | Surprisingly, no one CDK site regulated the interaction of pRB with E2F when E2F was bound to DNA. Instead, disruption of transcriptional repression resulted from accumulation of phosphate groups on the RB molecule. SIGNOR-250747 0.744 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Ser64 LQTDGNRsSHSRLGR 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250805 0.348 SLIT2 protein O94813 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding -1 16226035 t miannu Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit. SIGNOR-268377 0.939 MYC protein P01106 UNIPROT CCNE1 protein P24864 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 9188852 f gcesareni Our results suggest that this activation may involve at least two myc-dependent steps: the induction of cyclin e gene transcription followed by accumulation of cyclin e mrna in a protein synthesis-independent manner and the p27(kip1) association with cyce/cdk2 complexes containing newly synthesised cyce. SIGNOR-49130 0.625 NR0B2 protein Q15466 UNIPROT ESRRG protein P62508 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11705994 f gcesareni The current study also demonstrates that shp inhibits err_ transactivation. SIGNOR-111620 0.472 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9534 BTO:0000298 19058965 t Luana Tazarotene and its analogue 8 are RAR-β,γ selective acetylenic retinoids, whereas analogue 9 is very active on the three subtypes.  SIGNOR-258138 0.8 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263788 0.8 8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid chemical CHEBI:95064 ChEBI PTPN11 protein Q06124 UNIPROT down-regulates activity chemical inhibition 9606 16717135 t These results identified NSC-87877 as the first PTP inhibitor capable of inhibiting Shp2 PTP in cell cultures without a detectable off-target effect. SIGNOR-261912 0.8 KDM4B protein O94953 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001109 28073943 f miannu JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. SIGNOR-263730 0.2 ZNRF3 protein Q9ULT6 UNIPROT FZD4 protein Q9ULV1 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260115 0.554 DCC-2036 chemical CHEBI:62166 ChEBI ABL1 protein P00519 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191313 0.8 BMP7 protein P18075 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18719589 f induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-180314 0.292 DAG1 protein Q14118 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255983 0.576 EEF1A1 protein P68104 UNIPROT Leu-tRNA(Leu) smallmolecule CHEBI:16624 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269513 0.8 JAK3 protein P52333 UNIPROT SIGLEC10 protein Q96LC7 UNIPROT up-regulates phosphorylation Tyr597 RHSTILDyINVVPTA 9606 11733002 t lperfetto These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling SIGNOR-112479 0.2 ITK protein Q08881 UNIPROT BTK protein Q06187 UNIPROT down-regulates activity phosphorylation Tyr223 LKKVVALyDYMPMNA -1 12573241 t Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role SIGNOR-251333 0.483 CSNK2A1 protein P68400 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates activity phosphorylation Thr23 ALGPFPDtQDDFLKW 10090 BTO:0004475 9722526 t 2 miannu Regulation of erythroid Krƒppel-like factor (EKLF) transcriptional activity by phosphorylation of a protein kinase casein kinase II site within its interaction domain. the transactivation capability of EKLF is augmented by co-transfection of CKIIalpha. in vitro assays demonstrate that CKIIalpha interacts with EKLF, and that the EKLF interaction domain is phosphorylated by CKII only at Thr-41 SIGNOR-241361 0.347 AURKB protein Q96GD4 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Ser184 GKKSGKKsYLSGGAG 9606 23226345 t lperfetto Aurora b kinase phosphorylates yy1 on serine 184 and to a lesser extent serine 180 at the g2/m stage of the cell cycle (fig. 7). We show that yy1 is rapidly dephosphorylated as the cells exit mitosis, likely by pp1. Also, our data indicates that phosphorylation at serine 180 and serine 184 can affect the dna binding activity of yy1 SIGNOR-200079 0.374 CXCL9 protein Q07325 UNIPROT CXCR3 protein P49682 UNIPROT up-regulates activity binding 9606 BTO:0000782 12750173 t miannu The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells. SIGNOR-260970 0.778 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Ser518 KYATPAPsAKSSPSK 9606 BTO:0000938 16611631 t lperfetto Using in vitro kinase assays and pharmacological inhibition of gsk3 as described above for crmp2 and crmp4, it was found that thr509 (and presumably ser518 and thr514) of human crmp1 is phosphorylated by gsk3, following priming of ser522 by cdk5 SIGNOR-145991 0.456 CAMK2A protein Q9UQM7 UNIPROT NOX5 protein Q96PH1 UNIPROT unknown phosphorylation Ser548 MRKSQRSsKGSEILL -1 21642394 t miannu In vitro phosphorylation assays revealed that CAMKII can directly phosphorylate Nox5 on Thr494 and Ser498 as detected by phosphorylation state-specific antibodies. Mass spectrometry (MS) analysis revealed the phosphorylation of additional, novel sites at Ser475, Ser502, and Ser675. Of these phosphorylation sites, mutation of only Ser475 to alanine prevented CAMKII-induced increases in Nox5 activity. Together, these results suggest that CAMKII can positively regulate Nox5 activity via the phosphorylation of Ser475. SIGNOR-276333 0.2 BDKRB2 protein P30411 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257399 0.2 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGB4 protein Q9UN71 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites. SIGNOR-265701 0.2 FRK protein P42685 UNIPROT YAP1 protein P46937 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr444 QQNRFPDyLEAIPGT 9606 BTO:0002035 35723276 t miannu Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP.  SIGNOR-275457 0.277 beta-D-fructofuranose 1,6-bisphosphate(4-) smallmolecule CHEBI:32966 ChEBI β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI up-regulates quantity precursor of 9606 30616754 t lperfetto FBPase converts fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P) and inorganic phosphate in the second rate-limiting reaction of gluconeogenesis.|FBP1 is ubiquitously present in tissues and is the key gluconeogenic enzyme in the liver and kidney, while FBP2 is restricted to the muscle SIGNOR-267589 0.8 BAK1 protein Q16611 UNIPROT ENDOG protein Q14249 UNIPROT up-regulates 9606 12941691 f gcesareni We show that the mitochondrial outer-membrane permeabilization induced by bax-, tbid- or bax/bak-dependent pro-apoptotic drugs results in the release of cytochrome c, smac/diablo and htra2/omi, but that subsequent caspase activation is required to induce the translocation of endog in addition to aif into the cytosol. SIGNOR-86406 0.295 CHUK protein O15111 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser1415 PTPAILEsLISINNK 9606 BTO:0002181 24990947 t miannu  Importantly, IKKα is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKKα is an effector of Akt in promoting mTORC1 activity. SIGNOR-276646 0.518 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser197 DRVSRSSsPLKTGEQ 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250124 0.879 PRKCA protein P17252 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t lperfetto Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. SIGNOR-115714 0.349 regorafenib chemical CHEBI:68647 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259205 0.8 KSR1 protein Q8IVT5 UNIPROT ARAF protein P10398 UNIPROT up-regulates activity binding 9606 BTO:0000007 29433126 t miannu In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically. SIGNOR-273876 0.556 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 10734133 t flangone Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1. SIGNOR-75922 0.611 MAFA protein Q8NHW3 UNIPROT PDX1 protein P52945 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17149590 f miannu the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. SIGNOR-254562 0.741 PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR MAP3K5 protein Q99683 UNIPROT up-regulates activity dephosphorylation Ser966 NEYLRSIsLPVPVLV 9606 27858941 t miannu DAB2IP also mediates recruitment of PP2A to ASK1, binding both proteins through its C2 domain; this favors removal of the inhibitory S967 phosphorylation and further activation of ASK1 SIGNOR-254756 0.289 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Ser61 PLSTPCSsVPSSPSF 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159462 0.259 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser156 KKPVRPVsRGCLHSH 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276740 0.2 CAMK2D protein Q13557 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates phosphorylation Thr554 RGLSRQEtFDSETQE 9606 20194790 t The effect has been demonstrated using Q08289-2 gcesareni We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells. SIGNOR-164067 0.404 CSNK1D protein P48730 UNIPROT PER1 protein O15534 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 11165242 t miannu Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2). SIGNOR-268001 0.802 PTPRR protein Q15256 UNIPROT MAPK7 protein Q13164 UNIPROT down-regulates activity dephosphorylation Tyr221 HQYFMTEyVATRWYR 9534 12042304 t In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal|Whereas inactivation of ERK5 by PTP-SL monitored in vitro is most probably simply due to the dephosphorylation of tyrosine 220 in the activating TEY motif SIGNOR-248721 0.457 Gbeta proteinfamily SIGNOR-PF4 SIGNOR JAK2 protein O60674 UNIPROT down-regulates phosphorylation 9606 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-270046 0.2 GRK2 protein P25098 UNIPROT ADRA2A protein P08913 UNIPROT down-regulates activity phosphorylation Ser313 LDLEESSsSDHAERP 10029 BTO:0000246 7876239 t The alpha 2A-adrenergic receptor (alpha 2AAR) undergoes rapid functional desensitization caused by phosphorylation of the receptor by the beta-adrenergic receptor kinase (beta ARK). beta ARK-mediated phosphorylation of alpha 2C10 occurs at Ser-296-299 in the third intracellular loop, and this represents the critical step in rapid agonist-promoted desensitization. SIGNOR-251442 0.2 FLT3 protein P36888 UNIPROT PARP1 protein P09874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 21228325 f Interestingly, quantitative RT-PCR analysis demonstrated a 2-fold increase in PARP-1 expression. Western blotting analysis of protein nuclear extracts from FLT3/ITD B-cells confirmed that PARP1 was up-regulated, compared with wild-type controls  SIGNOR-261554 0.252 SPTB proteinfamily SIGNOR-PF73 SIGNOR Non-erythrocytic spectrin complex SIGNOR-C385 SIGNOR form complex binding 9606 24302288 t lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266027 0.2 NMUR2 protein Q9GZQ4 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257218 0.45 PTH protein P01270 UNIPROT MMP13 protein P45452 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17656568 f miannu Parathyroid hormone (PTH) functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We have already shown that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for degrading components of extracellular matrix. SIGNOR-254234 0.455 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2J1 protein Q9Y385 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271342 0.577 FANCI protein Q9NVI1 UNIPROT Fanconi anemia ID complex complex SIGNOR-C302 SIGNOR form complex binding 9606 BTO:0000007 17412408 t lperfetto Immunoprecipitation of HA-FLAG-tagged FANCI expressed in 293T cells with antibodies against either HA or FLAG, but not MYC, resulted in coimmunoprecipitation of endogenous FANCD2|The FANCI protein associates with FANCD2 and, together, as the FANCI-FANCD2 (ID) complex, localize to chromatin in response to DNA damage. SIGNOR-263269 0.956 bufexamac chemical CHEBI:31317 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000664 21258344 t Luana  We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. SIGNOR-257892 0.8 TNF protein P01375 UNIPROT CTSK protein P43235 UNIPROT up-regulates quantity by expression transcriptional regulation 11920402 f lperfetto This is supported by our finding that inflammatory cytokines such as IL-1b and TNFa increase the expres- sion of cathepsin K mRNA 􏰌6–8-fold and increase the secretion of the mature enzyme. SIGNOR-253317 0.364 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 20363976 t Luana INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). SIGNOR-257832 0.8 HTR1E protein P28566 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257100 0.254 FRAT1 protein Q92837 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 9635432 t lperfetto The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway SIGNOR-227994 0.634 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser312 SKSHRRTsLPCIPRE 9606 19261611 t gcesareni Phosphorylation and activation of pde3a required the activation of pkc SIGNOR-184448 0.2 STIP1 protein P31948 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates activity binding 9606 BTO:0000007 27353360 t miannu Hsp90 chaperone cycle is tightly regulated by another group of proteins referred to as ‘co-chaperones'. Their stability does not depend on Hsp90 function but they interact with distinct Hsp90 conformational states, providing directionality to the Hsp90 cycle. Furthermore, certain co-chaperones, such as HOP and Cdc37p50 inhibit the Hsp90 chaperone cycle, assisting in delivery of distinct sets of client proteins (steroid hormone receptors and kinases, respectively) to the Hsp90 chaperone machine. SIGNOR-261411 0.933 CD38 protein P28907 UNIPROT NAD(+) smallmolecule CHEBI:15846 ChEBI down-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264246 0.8 SOX9 protein P48436 UNIPROT MITF protein O75030 UNIPROT up-regulates activity binding 10090 20530484 t miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255183 0.389 AKT1 protein P31749 UNIPROT PLN protein P26678 UNIPROT down-regulates activity phosphorylation Thr17 SAIRRAStIEMPQQA 10090 BTO:0003265 19696029 t Akt interacts with and phosphorylates PLN at Thr(17), the Ca(2+)-calmodulin-dependent kinase IIdelta site, whereas silencing Akt signaling, through the knock-out of phosphatidylinositol-dependent kinase-1, resulted in reduced phosphorylation of PLN at Thr(17). SIGNOR-252578 0.292 SEC24D protein O94855 UNIPROT COPII vesicle complex SIGNOR-C370 SIGNOR form complex binding 9606 BTO:0000567 30605680 t lperfetto The Core Components of COPII Vesicles from HeLa Cells|Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. Subsequently, together with cargo proteins recruited by the Sec24 subunit, Sar1 and Sec23/24 assemble into so-called pre-budding complexes. Finally, outer coat subcomplexes, comprising heterotetrameric Sec13/31 complexes, are recruited onto pre-budding complexes to complete the two-layered COPII coat SIGNOR-265291 0.684 OPTN protein Q96CV9 UNIPROT NEFL protein P07196 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22194658 f same result in PC12 cell miannu SiRNA effectively downregulated optineurin expression in RGC-5 and PC12 stable transfected cells. Optineurin siRNA significantly inhibited cell growth and increased apoptosis in RGC-5 and PC12 cells. Microarray analysis identified 112 differentially expressed genes in optineurin siRNA transfected RGC-5 cells. Quantitative real-time PCR and western blot confirmed that the expression of brain-derived neurotrophic factor (Bdnf), neurotrophin-3(Ntf3), synaptosomal-associated protein 25(Snap25), and neurofilament, light polypeptide(Nefl) was significantly downregulated in RGC-5 and PC12 cells transfected with optineurin siRNA. SIGNOR-259881 0.27 CDKN1A protein P38936 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 7626805 t gcesareni P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases. SIGNOR-29957 0.94 MAPK1 protein P28482 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90517 0.727 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250069 0.311 KIF5B protein P33176 UNIPROT Organelle_transport phenotype SIGNOR-PH159 SIGNOR up-regulates 9606 BTO:0000938 9438838 f miannu The kinesin superfamily of proteins plays a major role in this complex organelle transport. Kinesin is primarily associated with anterogradely transported membranous organelles in nerve axons. KIF5B and HsuKHC are expressed ubiquitously in many tissues, whereas KIF5A, KIF5C, and HsnKHC are specific to nerve tissue. SIGNOR-264068 0.7 EID1 protein Q9Y6B2 UNIPROT EP300 protein Q09472 UNIPROT down-regulates activity binding 11073990 t lperfetto Inhibition of MyoD may be explained by EID-1's ability to bind and inhibit p300's histone acetylase activity, an essential MyoD coactivator. SIGNOR-253377 0.427 BMP7 protein P18075 UNIPROT ACTR2 protein P61160 UNIPROT up-regulates binding 9606 16446785 t acerquone The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2 SIGNOR-144144 0.292 MLXIPL protein Q9NP71 UNIPROT ACACA protein Q13085 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000759 15496471 t Luana The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) SIGNOR-267946 0.443 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 16362042 t gcesareni Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. SIGNOR-143109 0.906 TRAF6 protein Q9Y4K3 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT up-regulates activity binding 9606 10075662 t miannu TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. SIGNOR-253045 0.721 CDK8 protein P49336 UNIPROT CCNH protein P51946 UNIPROT down-regulates phosphorylation Ser304 YEDDDYVsKKSKHEE 9606 10993082 t lperfetto Cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity SIGNOR-82033 0.659 GTF2I protein P78347 UNIPROT GSC protein P56915 UNIPROT up-regulates quantity by expression transcriptional regulation 16611241 f lperfetto For example, TFII-I binds to the Inr element of the T cell receptor Vbeta gene and activates its transcription in reporter gene assays (Cheriyath et al. 1998). TFII-I also activates transcription of c-fos and Goosecoid through binding to the serum response element and the distal element, respectively (Grueneberg et al. 1997; Ku et al. 2005). SIGNOR-268536 0.2 STARD13 protein Q9Y3M8 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260521 0.636 P2RY11 protein Q96G91 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257173 0.2 MAML1 protein Q92585 UNIPROT CDK8 protein P49336 UNIPROT up-regulates relocalization 9606 15546612 t gcesareni Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells. SIGNOR-130718 0.587 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268605 0.253 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser698 PEWPRRAsCTSSTSG -1 196939 t The results presented in this paper show that the phosphorylation of glycogen synthetase a by cyclic AMP-dependent protein kinase results in the phosphorylation of two distinct serines termed site-l and site-2, which account for 90% of the total phosphorylation SIGNOR-253009 0.497 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser745 SCLADSFsQAADEEE 9606 BTO:0000150 10910365 t llicata Atm phosphorylates ctip at serine residues 664 and 745 our study suggests another dna damage-response pathway in which the signal is transmitted through phosphorylation of ctip by atm, leading to dissociation of the ctip_ctbp repressor complex from brca1, which in turn, activate transcription of gadd45 SIGNOR-79876 0.825 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH6 protein P55285 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265846 0.8 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120076 0.784 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 21983014 f In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-κB and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression. SIGNOR-254258 0.403 PRKACA protein P17612 UNIPROT LCP1 protein P13796 UNIPROT up-regulates phosphorylation Ser5 sVSDEEMM 9606 BTO:0000007 16636079 t gcesareni Phosphorylation on ser5 increases the f-actin-binding activity of l-plastin and promotes its targeting to sites of actin assembly in cells. L-plastin phosphorylation require protein kinase a. SIGNOR-146287 0.33 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates quantity by destabilization phosphorylation Ser430 DTLTPPPsDAGSPFQ 9606 BTO:0000567 16825193 t lperfetto The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding SIGNOR-236645 0.494 PLK1 protein P53350 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr206 MTSELEStSLGDSDE 9606 20823832 t lperfetto Dvl2 bound to and was phosphorylated at thr206 by a mitotic kinase, polo-like kinase 1 (plk1), and this phosphorylation was required for spindle orientation and stable microtubule (mt)-kt attachment SIGNOR-167858 0.473 SMO protein Q99835 UNIPROT GPR161 protein Q8N6U8 UNIPROT down-regulates activity relocalization 10090 23332756 f Constitutive Gpr161 activity increases cAMP levels, which is reduced upon knockdown of Gαs, suggesting it to be a Gαs-coupled receptor. SIGNOR-259937 0.322 DIDO1 protein Q9BTC0 UNIPROT ITGA5 protein P08648 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001673 22469980 t Luana Dido1 upregulates the expression of Integrin αV, thereby influencing the attachment, apoptosis and migration of melanoma cells. SIGNOR-261580 0.2 PAX2 protein Q02962 UNIPROT Urogenital_tract phenotype SIGNOR-PH71 SIGNOR up-regulates activity 10090 8575306 f Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases. SIGNOR-252301 0.7 MARCHF9 protein Q86YJ5 UNIPROT VAMP8 protein Q9BV40 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271531 0.2 HNF1A protein P20823 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 f miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. SIGNOR-254447 0.333 CYSLTR1 protein Q9Y271 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257135 0.368 MAPK1 protein P28482 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser238 QGTPLTCsPNVENRG 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276101 0.289 RPS17 protein P08708 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262434 0.901 CBP/p300 complex SIGNOR-C6 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity acetylation 9606 21131905 t lperfetto These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. SIGNOR-265322 0.2 COL4A5 protein P29400 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 12778132 t Type IV collagen is the most abundant Type IV collagen is the most abundant constituent of the BM…All of the type IV collagen in mammals is derived from six genetically distinct alpha-chain polypeptides (alpha1-alpha6) SIGNOR-254669 0.7 BIRC2 protein Q13490 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity ubiquitination 9606 18570872 t amattioni CIAP1 and cIAP2 directly ubiquitinate RIP1 and induce constitutive RIP1 ubiquitination in cancer cells and demonstrate that constitutively ubiquitinated RIP1 associates with the prosurvival kinase TAK1. In this way RIP1 functions as a prosurvival scaffold molecule instead of a proapoptotic adaptor protein SIGNOR-179100 0.763 ATM protein Q13315 UNIPROT STK11 protein Q15831 UNIPROT unknown phosphorylation Thr363 IEDDIIYtQDFTVPG 9606 BTO:0000848 12234250 t llicata We demonstrate that both dna-pk and atm efficiently phosphorylate lkb1 at thr-366 in vitro and provide evidence that atm mediates this phosphorylation in vivo. however, phosphorylation of lkb1 at thr-366 may have some role in enabling lkb1 to suppress cell growth SIGNOR-92877 0.583 FBXW7 protein Q969H0 UNIPROT CCNE2 protein O96020 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002524 17298674 t miannu Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme SIGNOR-271642 0.443 Av/b1 integrin complex SIGNOR-C175 SIGNOR SOX2 protein P48431 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253273 0.317 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser20 LQYYYSSsEDEDSDH 9606 16717095 t lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. SIGNOR-146833 0.37 GTP smallmolecule CHEBI:15996 ChEBI EEF1A:GTP:aa-tRNA complex SIGNOR-C493 SIGNOR form complex binding 9606 8722040 t miannu The mechanism of elongation factor Tu (EF-Tu) catalyzed aminoacyl-tRNA (aa-tRNA) binding to the A site of the ribosome was studied. Two types of complexes of EF-Tu with GTP and aa-tRNA, EF-Tu.GTP-aa-tRNA (ternary) and (EF-Tu.GTP)2.aa-tRNA (quinternary), can be formed in vitro depending on the conditions. SIGNOR-270812 0.8 GRM8 protein O00222 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264939 0.8 2-Hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylic acid chemical CID:135461425 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t miannu Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259706 0.8 NFE2L2 protein Q16236 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000599 26194347 f irozzo Nrf2 was up-regulated in HCC, and expression of Nrf2 was correlated with tumor differentiation, metastasis, and tumor size. Further studies demonstrated that inhibition of Nrf2 expression inhibited proliferation by inducing apoptosis and repressed invasion, and up-regulation of Nrf2 expression resulted in opposite phenotypes. SIGNOR-256263 0.7 TNFRSF21 protein O75509 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR down-regulates 9606 32454942 f miannu Next to inhibition of sTNF/TNFR1 signaling, specific activation of TNFR2 may hold promise as a new MS therapy. Indeed, TNF promotes proliferation of oligodendrocyte progenitors and remyelination via TNFR2 SIGNOR-263832 0.7 NKX3-1 protein Q99801 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization 9606 16697957 f miannu NKX3.1 stabilizes p53.NKX3.1 can physically associate with HDAC1 and promotes p53 acetylation by recruiting HDAC1 from p53-MDM2-HDAC1 complex SIGNOR-251548 0.361 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Thr329 RALTEDStQTSDTAT -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249664 0.2 GSK3B protein P49841 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity phosphorylation Thr235 SSSSPPGtPSPADAK 10090 BTO:0001169 22355693 t We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188 SIGNOR-251644 0.465 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Thr207 FLTEYVAtRWYRAPE 9606 BTO:0000562 19060905 t lperfetto Here we show that autophosphorylation of erk1/2 on thr188 directs erk1/2 to phosphorylate nuclear targets known to cause cardiac hypertrophy. SIGNOR-244565 0.2 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18509061 t gcesareni We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf. SIGNOR-178713 0.487 glycine smallmolecule CHEBI:15428 ChEBI GLRB protein P48167 UNIPROT up-regulates activity chemical activation 9606 BTO:0001175;BTO:0001279;BTO:0000146 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264983 0.8 DNMT1 protein P26358 UNIPROT GAD1 protein Q99259 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254574 0.353 FGD2 protein Q7Z6J4 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260552 0.469 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR2A protein P28223 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257521 0.8 KAT2B protein Q92831 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269612 0.2 PITX1 protein P78337 UNIPROT GNRH1 protein P01148 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 19106114 f miannu Knockdown of PITX1 or PITX2 isoforms impaired GNRH1 induction, and endogenous PITX1 bound to the candidate PITX binding site on the LHB promoter. SIGNOR-254921 0.333 BGJ-398 chemical CHEBI:63451 ChEBI FGFR4 protein P22455 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190272 0.8 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser824 LVDKEHDsAEGSHTS 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276516 0.332 CREBBP protein Q92793 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates activity acetylation Lys399 SGPCERRkSPLQDPF 9606 BTO:0000007 17923090 t lperfetto By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2. SIGNOR-217783 0.35 CREB1 protein P16220 UNIPROT UXT protein Q9UBK9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 17761951 f lperfetto The DNA response elements that control the induction of ART-27 gene expression were also characterized. The major cis-acting element corresponds to a consensus cAMP-responsive element (CRE) and binds the CRE-binding protein (CREB) as shown by EMSA and chromatin immunoprecipitation assays. Furthermore, ART-27 promoter activity is induced upon CREB overexpression. Epidermal growth factor, which activates CREB via phosphorylation, also induces ART-27 expression, whereas a reduction in CREB phosphorylation or expression blocks this induction in prostate cells. SIGNOR-254092 0.2 CSNK2A1 protein P68400 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates quantity by stabilization phosphorylation Ser11 SFLVRKPsDPNRKPN 9606 19923321 t lperfetto Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively. SIGNOR-161771 0.352 GAST protein P01350 UNIPROT CCKBR protein P32239 UNIPROT up-regulates binding 9606 BTO:0000142 10368033 t gcesareni A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin, SIGNOR-66987 0.779 MTNR1B protein P49286 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257102 0.251 FOXN1 protein O15353 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 f miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. SIGNOR-254182 0.387 GRIK3 protein Q13003 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264944 0.8 TP53 protein P04637 UNIPROT PMS2 protein P54278 UNIPROT up-regulates quantity transcriptional regulation 9606 15781865 t .... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron. SIGNOR-257604 0.572 SNIP1 protein Q8TAD8 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270671 0.44 KPNA3 protein O00505 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. SIGNOR-254321 0.327 GRIK4 protein Q16099 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI up-regulates quantity relocalization 9606 BTO:0002609 12393813 t lperfetto Glutamate (L-Glu) released from neurons interacts with kainate-type of glutamate receptors (Kain-R) in astrocytes to stimulate release of D-serine SIGNOR-268275 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 BTO:0000944 11579209 t lperfetto Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor. SIGNOR-235411 0.2 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation 9606 19282669 t inferred from 70% family members lperfetto Phosphorylation of foxo3a by erk1/2 at residues ser 294, ser 344 and ser 425 increases foxo3amdm2 interaction and enhances foxo3a degradation via an mdm2-dependent ubiquitin-proteasome pathway SIGNOR-270020 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR RAC1 protein P63000 UNIPROT down-regulates activity phosphorylation Ser71 YDRLRPLsYPQTDVF 9606 BTO:0003476 10617634 t gcesareni The results suggest that Akt kinase of the phosphoinositide 3-kinase signal transduction pathway phosphorylates serine 71 of Rac1 as one of its authentic substrates and modulates the Rac1 signal transduction pathway through phosphorylation. SIGNOR-248036 0.2 AMFR protein Q9UKV5 UNIPROT SERPINI1 protein Q99574 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21507957 t miannu In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. SIGNOR-272756 0.299 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates activity dephosphorylation Tyr187 HTGFLTEyVATRWYR 9606 12754301 t llicata The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop SIGNOR-248448 0.395 PKA proteinfamily SIGNOR-PF17 SIGNOR TRPV4 protein Q9HBA0 UNIPROT up-regulates activity phosphorylation Ser162 FDIVSRGsTADLDGL -1 19661060 t miannu We conclude that the serine/threonine kinases PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. SIGNOR-276232 0.2 BRD9 protein Q9H8M2 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269787 0.482 CFB protein P00751 UNIPROT C3 convertase complex (C3bBb) complex SIGNOR-C314 SIGNOR form complex binding 9606 BTO:0000089 cleavage:Arg259 GPGEQQKrKIVLDPS 26489954 t complement factor B, b fragment: PRO_0000027547 lperfetto Surface‐associated C3b recruits FB, which leads to FB activation and the formation of C3bBb, the AP C3 convertase, which cleaves more C3 and amplifies complement activation. In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over) SIGNOR-263486 0.904 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Ser192 HMTNNKGsAAWMAPE 9606 10702308 t lperfetto A mutant of TAK1 that lacks kinase activity is not phosphorylated either following IL-1 treatment or when coexpressed with TAB1, indicating that TAK1 phosphorylation is due to autophosphorylation. Furthermore, mutation to alanine of a conserved serine residue (Ser-192) in the activation loop between kinase domains VII and VIII abolishes both phosphorylation and activation of TAK1. These results suggest that IL-1 and ectopic expression of TAB1 both activate TAK1 via autophosphorylation of Ser-192. SIGNOR-235758 0.2 UBE3A protein Q05086 UNIPROT DLG4 protein P78352 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 17121805 t miannu E6-induced degradation of DLG4 depends on E6AP in vivo.  Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro. SIGNOR-271397 0.354 CALM2 protein P0DP24 UNIPROT PPP3CC protein P48454 UNIPROT up-regulates binding 9606 11796223 t miannu Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-266324 0.53 corticosterone smallmolecule CHEBI:16827 ChEBI 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268674 0.8 LRRFIP2 protein Q9Y608 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15677333 t gcesareni In particular, a previously unrecognized activator, lrrfip2 (leucine-rich repeat in flightless interaction protein 2), was found that interacts with dvl to increase the cellular levels of _-catenin and activate _-catenin/lef/tcf-dependent transcriptional activity SIGNOR-133429 0.392 FZD3 protein Q9NPG1 UNIPROT DVL1 protein O14640 UNIPROT up-regulates activity binding 9606 22944199 t amattioni When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp. SIGNOR-134288 0.651 CXCL3 protein P19876 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates activity binding 9606 38309677 t miannu CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively SIGNOR-277719 0.717 EGFR protein P00533 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t gcesareni These results demonstrate that egfr-erbb2 oligomers are potent activators of mapk and akt, and this signaling does not require egfr kinase activity SIGNOR-106500 0.602 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNJ2 protein P63252 UNIPROT down-regulates activity phosphorylation Ser425 PRPLRREsEI -1 19843922 t done miannu KCNJ2 encodes Kir2.1, a pore-forming subunit of the cardiac inward rectifier current, I(K1). This PKA-simulated catecholaminergic stimulation caused marked reduction of outward I(K1) compared with Kir2.1-WT. PKA-induced reduction in I(K1) was eliminated by mutating the phosphorylation site at serine 425 (S425N). SIGNOR-273779 0.2 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1-pyrazolyl]-3-azetidinyl]acetonitrile chemical CHEBI:95341 ChEBI JAK1 protein P23458 UNIPROT down-regulates activity chemical inhibition 9606 20363976 t Luana INCB028050 is a selective orally bioavailable JAK1/JAK2 inhibitor with nanomolar potency against JAK1 (5.9 nM) and JAK2 (5.7 nM). SIGNOR-257833 0.8 PKC proteinfamily SIGNOR-PF53 SIGNOR NOS3 protein P29474 UNIPROT down-regulates activity phosphorylation 9606 BTO:0001853 24379783 t inferred from 70% family members lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-269971 0.2 ORC6 protein Q9Y5N6 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267562 0.943 TRIM17 protein Q9Y577 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization polyubiquitination 10090 BTO:0001976 22976837 t miannu Here, we identified Trim17 as a novel E3 ubiquitin-ligase for Mcl-1. Indeed, Trim17 co-immunoprecipitated with Mcl-1. Trim17 ubiquitinated Mcl-1 in vitro. Overexpression of Trim17 decreased the protein level of Mcl-1 in a phosphorylation- and proteasome-dependent manner. Finally, knock down of Trim17 expression reduced both ubiquitination and degradation of Mcl-1 in neurons. SIGNOR-272032 0.452 TP53 protein P04637 UNIPROT CCNG1 protein P51959 UNIPROT up-regulates quantity by expression transcriptional regulation 7957050 t lperfetto Using a DNA binding assay, a specific p53 binding site was identified upstream from the cyclin G gene, which functioned as a p53-dependent cis-acting element in a transient transfection assay. SIGNOR-268960 0.786 PRKAA1 protein Q13131 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs) SIGNOR-176483 0.344 MAPK3 protein P27361 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90529 0.732 STAT1 protein P42224 UNIPROT TBX21 protein Q9UL17 UNIPROT up-regulates 9606 16386358 f T-bet is a transcription factor detected in Th1, but not in Th0 or Th2 cells. Its expression is up-regulated by IFN-gamma, through a STAT-1-dependent mechanism SIGNOR-254293 0.501 trichostatin A chemical CHEBI:46024 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257941 0.8 MDM2 protein Q00987 UNIPROT NUMB protein P49757 UNIPROT down-regulates ubiquitination 9606 BTO:0001938 12646252 t gcesareni These data strongly suggest thatmdm2functions as the ubiquitin ligase toward hnumb and that it induces its degradation in intact cells. SIGNOR-99497 0.451 ACOT8 protein O14734 UNIPROT glutarate(2-) smallmolecule CHEBI:30921 ChEBI up-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271813 0.8 ZFAT protein Q4KMQ4 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates quantity 10090 24663380 f francesca Ano6 deficiency significantly reduces ERK/AKT phosphorylation. In addition, Ano6-KD also affected levels of phosphorylated and total AKT levels. SIGNOR-261215 0.2 IFNG protein P01579 UNIPROT ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu Taken together, these data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNα, IFNγ, IL-1β, IL-6, IL-12, IL-18, IL-33,TNFα, TGFβ) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatoryresponse. The cytokine storm is readily followed by theimmune system “attacking” the body, which in turn will cause ARDSand multiple organ failure, the final result being death, at least in themost severe cases of SARS-CoV-2 infection SIGNOR-261033 0.7 FOXP2 protein O15409 UNIPROT AUTS2 protein Q8WXX7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000142 25232744 t miannu By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets. SIGNOR-266832 0.33 ziprasidone chemical CHEBI:10119 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10116 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258505 0.8 trandolapril chemical CHEBI:9649 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition 10116 7527095 t miannu The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. SIGNOR-258427 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1864 SPKYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269358 0.721 SPRY4 protein Q9C004 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR down-regulates 9606 BTO:0002058 20501643 f miannu Spry4 expression induces a reversal of the epithelial to mesenchymal transition characteristic of tumor cells. Treatment of a non-transformed lung epithelial cell line with shRNA to Spry4 led to decreased expression of epithelial markers and increased cell growth, supporting the concept of Spry4 acting as a tumor suppressor. SIGNOR-253036 0.7 RSPO3 protein Q9BXY4 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t gcesareni Here, we show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling. SIGNOR-172756 0.43 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Ser4 sQKHRDFV 9606 BTO:0000567 16371512 t gcesareni We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell SIGNOR-143368 0.512 TUBB protein P07437 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 17429065 t lperfetto Smad2/3 also binds to _-tubulin, which provides a negative regulatory mechanism controlling tgf-_ activity. the results showed that the mh2 domain of smad2 binds to _-tubulin with almost the same efficiency as the full-length (wild-type) smad2. Similar results were obtained for the smad3 binding to _-tubulin. SIGNOR-217631 0.2 CDCA2 protein Q69YH5 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates activity binding 9606 BTO:0000567 32938714 t done miannu This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin. SIGNOR-274003 0.377 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 17389604 t lperfetto Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1 SIGNOR-216880 0.339 GSK3B protein P49841 UNIPROT FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization phosphorylation Ser274 TKASSVAsSDKGSCC 9606 BTO:0002181 27432879 t miannu Our previous study showed, by mass spectrometry analysis, that GSK-3β phosphorylates Foxp3 at Ser270 and Ser275 SIGNOR-277245 0.287 GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263809 0.8 GRK3 protein P35626 UNIPROT BDKRB2 protein P30411 UNIPROT down-regulates activity phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t gcesareni ...expression of GRK4Ž drastically increased the basal level of32P incorporation into B2R.[€]a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation. SIGNOR-249658 0.2 MAPK1 protein P28482 UNIPROT KCND2 protein Q9NZV8 UNIPROT up-regulates activity phosphorylation Ser616 EGDDRPEsPEYSGGN 10116 BTO:0000601 11080179 t miannu We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP. SIGNOR-262934 0.373 TNKS protein O95271 UNIPROT BLZF1 protein Q9H2G9 UNIPROT down-regulates quantity by destabilization ADP-ribosylation 9606 BTO:0000007 21478859 t lperfetto Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. SIGNOR-263385 0.355 EGR1 protein P18146 UNIPROT SLC9A3 protein P48764 UNIPROT up-regulates quantity by expression transcriptional regulation 7227 BTO:0001677 16464174 f Transcriptional stimulation of the human NHE3 promoter activity by PMA: PKC independence and involvement of the transcription factor EGR-1|Co-transfection of Sp1 or Sp3 into SL2 cells activated the NHE3-reporter constructs, suggesting that Sp1 and Sp3 act as positive regulators of the NHE3 expression. In addition, overexpression of EGR-1 was sufficient to transactivate the NHE3-reporter gene activity SIGNOR-254269 0.248 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARA protein Q07869 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000599 10187842 t inferred from 70% family members lperfetto We now demonstrate that amino acids 1-92 of hPPARalpha contain an activation function (AF)-1-like domain, which is further activated by insulin through a pathway involving the mitogen-activated protein kinases p42 and p44. Further analysis of the amino-terminal region of PPARalpha revealed that the insulin-induced trans-activation occurs through the phosphorylation of two mitogen-activated protein kinase sites at positions 12 and 21, both of which are conserved across evolution. SIGNOR-270180 0.2 HPS3 protein Q969F9 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR form complex binding 9606 15030569 t lperfetto Characterization of BLOC-2, a complex containing the Hermansky-Pudlak syndrome proteins HPS3, HPS5 and HPS6 SIGNOR-260688 0.707 NECAP1 protein Q8NC96 UNIPROT AP-2 complex complex SIGNOR-C245 SIGNOR up-regulates activity binding 9606 24130457 t lperfetto Knockdown and functional rescue studies demonstrate that through these interactions, NECAP 1 and AP-2 cooperate to increase the probability of clathrin-coated vesicle formation and to control the number, size, and cargo content of the vesicles. SIGNOR-260710 0.472 regorafenib chemical CHEBI:68647 ChEBI FGFR2 protein P21802 UNIPROT down-regulates activity chemical inhibition 9606 26254357 t miannu A novel multi-kinase inhibitor, regorafenib (Figure 1), inhibits vascular endothelial growth factor receptor (VEGFR) 1, VEGFR2, and VEGFR3, that play key roles in angiogenesis, and fibroblast growth factor receptor (FGFR) 1, platelet-derived growth factor receptor-β (PDGFR-β), tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) and the mutant oncogenic kinase KIT, RET, B-RAF SIGNOR-259178 0.8 PAX7-FOXO1 fusion protein SIGNOR-FP11 SIGNOR FGFR4 protein P22455 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25211658 f miannu Several deregulated signalling pathways enhance cell growth by modulating cell-cycle regulatory factors in RMS. The most frequently affected signalling pathways include the insulin-like growth factor (IGF), fibroblast growth factor (FGF), hepatocyte growth factor, and platelet-derived growth factor. In ARMS, PAX-FOXO1 activates these pathways by transcriptional activation of receptor genes including IGFR1, FGFR4, MET (c-Met), and PDGFRA. SIGNOR-251565 0.2 CDC42 protein P60953 UNIPROT PAK proteinfamily SIGNOR-PF13 SIGNOR up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248259 0.941 betamethasone chemical CHEBI:3077 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 17561562 t dermatitis gcesareni SIGNOR-251686 0.8 WNT5A protein P41221 UNIPROT FZD6 protein O60353 UNIPROT up-regulates activity binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141437 0.691 GATA1 protein P15976 UNIPROT CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0004475 19825991 f miannu Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein alpha (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. SIGNOR-254190 0.499 ADORA2A protein P29274 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257364 0.303 ODC1 protein P11926 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI down-regulates quantity chemical modification 9606 14617280 t miannu Arginase generates ornithine, an aminoacid that can be further metabolized to proline via ornithine aminotransferase and to polyamines via ornithine decarboxylase (ODC) SIGNOR-256037 0.8 MECP2 protein P51608 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates activity binding 9606 BTO:0000007 12473678 t Luana Thus, these results indicate that MeCP2-interacting Dnmt1 has significant maintenance DNA methyltransferase activity and that MeCP2 does not vanish Dnmt1 enzymatic activity. SIGNOR-264541 0.539 IRF3 protein Q14653 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 27337441 t lperfetto Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation SIGNOR-251721 0.414 SMAD3 protein P84022 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000165 11711431 t azuccotti We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. SIGNOR-252071 0.724 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260528 0.828 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 11113114 t gcesareni Ec mlck-1 is phosphorylated by p60(src) on tyr(464) and tyr(471), resulting in a 2- to 3-fold increase in ec mlck-1 enzymatic activity. SIGNOR-85009 0.423 SOX5 protein P35711 UNIPROT COL2A1 protein P02458 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10980415 f miannu Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 SIGNOR-251759 0.435 GATA1 protein P15976 UNIPROT GATA1 protein P15976 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12432220 f irozzo Furthermore, GATA-1 has been shown to auto-regulate its own gene expression. SIGNOR-256057 0.2 PRKCA protein P17252 UNIPROT TRPC3 protein Q13507 UNIPROT down-regulates phosphorylation Ser703 SLVPSPKsFVYFIMR 9606 16331690 t gcesareni There are two known phosphorylation-mediated inactivation mechanisms for trpc3 channels. Protein kinase g (pkg) inactivates trpc3 by direct phosphorylation on thr-11 and ser-263 of the trpc3 proteins, and protein kinase c (pkc) inactivates trpc3 by phosphorylation on ser-712. SIGNOR-142945 0.351 HSPH1 protein Q92598 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255242 0.487 PPP2R5C protein Q13362 UNIPROT ATF1 protein P18846 UNIPROT up-regulates dephosphorylation Ser36 AQQVSSLsESEESQD 9606 20730097 t lperfetto We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf1 SIGNOR-167560 0.2 MED13L protein Q71F56 UNIPROT CKM complex complex SIGNOR-C406 SIGNOR form complex binding 9606 23563140 t miannu The CDK8 kinase module (CKM) is a conserved, dissociable Mediator subcomplex whose component subunits were genetically linked to the RNA polymerase II (RNAPII) C-terminal domain (CTD) and individually recognized as transcriptional repressors before Mediator was identified as a pre-eminent complex in eukaryotic transcription regulation. SIGNOR-266702 0.765 GlyR proteinfamily SIGNOR-PF62 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18721822 t miannu The glycine receptor chloride channel (GlyR), a member of the pentameric Cys-loop ion channel receptor family, mediates inhibitory neurotransmission in the spinal cord, brainstem and retina. SIGNOR-264984 0.8 NCOA2 protein Q15596 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18584035 t gcesareni Collectively, our data provide the first evidence that erbeta-deficiency protects against diet-induced ir and glucose intolerance which involves an augmented ppargamma signaling in adipose tissue. Moreover, our data suggest that the coactivators src1 and tif2 are involved in this interaction. SIGNOR-179175 0.763 ADORA2B protein P29275 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257365 0.391 MAPK1 protein P28482 UNIPROT ARHGAP26 protein Q9UNA1 UNIPROT unknown phosphorylation Ser685 PMFSAPSsPMPTSST -1 9525907 t miannu In vitro, purified mitogen-activated protein (MAP) kinase catalyzed the phosphorylation of Graf on serine 510, suggesting that Graf phosphorylation may be mediated through MAP kinase signaling. SIGNOR-262944 0.2 CTCF protein P49711 UNIPROT RARRES1 protein P49788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 22615834 f miannu Epigenetic repression of RARRES1 is mediated by methylation of a proximal promoter and a loss of CTCF binding. knocking-down CTCF expression hampered RARRES1 expression, suggesting CTCF positively regulated RARRES1 transcription presumably by binding to unmethylated promoter poised at transcription-ready state. SIGNOR-253831 0.351 NFIL3 protein Q16649 UNIPROT IL3 protein P08700 UNIPROT up-regulates quantity by expression transcriptional regulation 9580 7565758 t Luana NF-IL3A transactivates the IL-3 promoter through the A region sequences. SIGNOR-266222 0.537 PRKAA1 protein Q13131 UNIPROT BTRC protein Q9Y297 UNIPROT down-regulates quantity by destabilization phosphorylation Ser82 SLRQTYNsCARLCLN 9606 BTO:0002419 31406304 t miannu Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.  SIGNOR-277475 0.2 CREB1 protein P16220 UNIPROT POMC protein P01189 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001073 11081181 t lperfetto Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein|Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE. SIGNOR-268620 0.376 APH1A protein Q96BI3 UNIPROT NCSTN protein Q92542 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain. SIGNOR-93259 0.967 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f gcesareni We found that both smad6 and smad7 inhibit the activation of smad1 and smad5 by bmpr-ia/alk-3 and bmpr-ib/alk-6, as well as that by alk-2 SIGNOR-236848 0.753 Gbeta proteinfamily SIGNOR-PF4 SIGNOR STMN1 protein P16949 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000007 9731215 t inferred from 70% family members lperfetto Stress-induced stathmin phosphorylation is not de- pendent on ERK. Stathmin is also known to be phos- phorylated by ERK on Ser-25 and Ser-38 (17). Thus, it is possible that ERK phosphorylates stathmin in 293 cells|In subsequent reports (28, 29) it was shown that phosphorylation of stathmin blocks its ability to destabilize MTs. SIGNOR-270082 0.2 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 f These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs SIGNOR-253602 0.379 ABL1 protein P00519 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Tyr1357 HPQAASIyQSSEMKG 9606 18765637 t lperfetto Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300, SIGNOR-180571 0.352 PTPN6 protein P29350 UNIPROT NFAT5 protein O94916 UNIPROT down-regulates activity dephosphorylation Tyr143 PKRHTVLyISPPPED 9606 BTO:0000007 20351292 t We confirmed that SHP-1 is inhibitory by overexpressing it, which reduces TonEBP/OREBP transcriptional activity at 500 mosmol/kg. SHP-1 dephosphorylates TonEBP/OREBP at a known regulatory site, Y143, both in vivo and in vitro. It inhibits TonEBP/OREBP by both reducing TonEBP/OREBP nuclear localization, which is Y143 dependent, and by lowering high NaCl-induced TonEBP/OREBP transactivating activity SIGNOR-248467 0.347 GRK2 protein P25098 UNIPROT FPR1 protein P21462 UNIPROT down-regulates activity phosphorylation Ser332 TEDSTQTsDTATNST -1 7836371 t gcesareni Kinetic studies demonstrated that GRK2 has a Km for the carboxyl-terminal domain of the FPR of approximately 1.5 microM and that denaturation of the substrate results in an almost complete loss of phosphorylation [€] simultaneous substitution of the upstream Ser328, Thr329, Thr331, and Ser332 or merely the Ser328 and Thr329 residues resulted in an approximately 80% reduction in phosphorylation. SIGNOR-249680 0.2 FGFR2 protein P21802 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates activity phosphorylation Tyr769 TLTTNEEyLDLSQPL 9606 BTO:0000567 15629145 t miannu Our data also show that tyrosine 769 is not involved in the regulation of the endocytic process of KGFR.Following ligand binding, KGFR is rapidly autophosphorylated on specific tyrosine residues SIGNOR-276026 0.2 ITGB4 protein P16144 UNIPROT PMP22 protein Q01453 UNIPROT up-regulates activity binding 10090 16436605 t Regulation miannu PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types. SIGNOR-251896 0.392 NR3C1 protein P04150 UNIPROT CEBPD protein P49716 UNIPROT up-regulates quantity transcriptional regulation 10090 BTO:0000011 1840554 t The expression levels of both C/EBPB and C/EBPD are increased dramatically during the time of hormonal stimulation (see Fig. 8). Furthermore, the C/EBPB- and C/EBPD encoding genes are activated directly by adipogenic hormones SIGNOR-251648 0.319 PPM1D protein O15297 UNIPROT MDM4 protein O15151 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser403 DLAHSSEsQETISSM 9606 19808970 t lperfetto Here, we present evidence that Wip1 specifically dephosphorylates MdmX at Ser403 and indirectly suppresses phosphorylation of MdmX at Ser342 and Ser376.|Thus, Wip1 may need to be inhibited in the early stage of DNA damage response to facilitate rapid MdmX degradation. SIGNOR-276951 0.439 CDK8 protein P49336 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-161557 0.554 PSMB4 protein P28070 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263355 0.887 POMT1 protein Q9Y6A1 UNIPROT POMT complex SIGNOR-C372 SIGNOR form complex binding 9606 BTO:0000007 16698797 t miannu  Here we have shown that POMT1 forms a complex with POMT2 and the complex possesses protein O-mannosyltransferase activity. Results indicate that POMT1 and POMT2 associate physically and functionally in vivo.  Mutations in the POMT1 and POMT2 genes are considered to be the cause of Walker-Warburg syndrome. Here, we have demonstrated that POMT1 and POMT2 form a functional complex in vivo using immunoprecipitating techniques. Furthermore, we showed that the mutations of POMT1 protein found in WWS patients do not prevent complex formation with POMT2 but they do abolish activity of the complex. SIGNOR-265428 0.593 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 17463226 t miannu Interaction with the ErbB-4 receptors occurs via the WW domains of AIP4/Itch. Functional analyses demonstrate that AIP4/Itch is recruited to the ErbB-4 receptor to promote its polyubiquitination and degradation, thereby regulating stability of the receptor and access of receptor intracellular domains to the nuclear compartment.  SIGNOR-272618 0.596 LRRC4 protein Q9HBW1 UNIPROT CDK2 protein P24941 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000142 25526788 f miannu LRRC4/NGL-2 can delay the cell cycle in late G1 by increasing the expression of cell cycle inhibitory molecules (p21, p27) and reducing the expression of cell cycle regulatory proteins (CyclinD1, CDK2, CyclinE, CDK4) via the inhibition of K-Ras/c-Raf/ERK/MAPK, PI-3K/AKT/NF- κB, p70S6/PKC and STAT3, and the upregulation of the JNK2/c-Jun/mp53 signaling pathway. SIGNOR-264058 0.352 EEF1A1 protein P68104 UNIPROT Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269521 0.8 HDAC1 protein Q13547 UNIPROT UBE2D3 protein P61077 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255175 0.266 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser300 SMSDPGVsYRTREEI 9606 17474719 t gcesareni Regulation of mammalian pdc activity is accomplished in large part by phosphorylation (resulting in inactivation) of the e1 component by a family of pyruvate dehydrogenase kinases (pdk 14 isozymes) and dephosphorylation (leading to activation) of phosphorylated e1 by a set of specific phosphatases (phosphopyruvate dehydrogenase phosphatase 12 isozymes) (1, 3-6). The subunit of the e1 component has three phosphorylation sites, named site 1 (ser-264), site 2 (ser-271), and site 3 (ser-203), and phosphorylation of any one of these three sites results in inactivation SIGNOR-154640 0.672 ATP synthase complex SIGNOR-C264 SIGNOR ATP smallmolecule CHEBI:15422 ChEBI up-regulates quantity chemical modification 9606 21874297 t miannu Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. SIGNOR-261410 0.8 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR Platelet_Adhesion phenotype SIGNOR-PH137 SIGNOR up-regulates 9606 BTO:0000132 25297919 f lperfetto VWF binding to GPIb-IX-V induces platelet activation, converting the major integrin αIIbβ3 from a low affinity to a high affinity receptor capable of engaging the C4 domain of VWF. This last step is essential for stable adhesion SIGNOR-261867 0.7 MC5R protein P33032 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257337 0.251 POLR2E protein P19388 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266138 0.887 CSNK2A2 protein P19784 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates quantity by stabilization phosphorylation Thr102 RAAMFPEtLDEGMQI -1 12432063 t miannu We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.  SIGNOR-275993 0.46 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys51 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272706 0.359 FOXO1 protein Q12778 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260101 0.26 AKT2 protein P31751 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 17386266 t gcesareni Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity. SIGNOR-153931 0.666 DLST protein P36957 UNIPROT OGDC complex SIGNOR-C397 SIGNOR form complex binding 9606 15953811 t miannu The α-ketoglutarate–dehydrogenase complex is a complex including multiple copies of three proteins: E1k (α-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266254 0.903 MAPK12 protein P53778 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10330170 f gcesareni Moreover, in addition to jnk, erk5, p38alpha, and p38gamma were found to stimulate the c-jun promoter by acting on distinct responsive elements. SIGNOR-67532 0.376 TLX1 protein P31314 UNIPROT ETS1 protein P14921 UNIPROT down-regulates activity binding 9606 BTO:0002504 22516263 t irozzo We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) α enhanceosome activity and blocked TCR-Jα rearrangement. SIGNOR-259097 0.475 ULK1 protein O75385 UNIPROT ATG9A protein Q7Z3C6 UNIPROT up-regulates activity phosphorylation Ser14 EYQRLEAsYSDSPPG 9606 27934868 t miannu Src phosphorylates mATG9 at Tyr8 to maintain its endocytic and constitutive trafficking in unstressed conditions. In response to starvation, phosphorylation of mATG9 at Tyr8 by Src and at Ser14 by ULK1 functionally cooperate to promote interactions between mATG9 and the AP1/2 complex, leading to redistribution of mATG9 from the plasma membrane and juxta-nuclear region to the peripheral pool for autophagy initiation. SIGNOR-266369 0.593 DEPTOR protein Q8TB45 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205603 0.719 EEF1A2 protein Q05639 UNIPROT Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269534 0.8 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164475 0.56 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT down-regulates activity phosphorylation Thr239 VPEMPGEtPPLSPID 9606 BTO:0000007 16023596 t lperfetto The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance SIGNOR-236717 0.705 NFE2L2 protein Q16236 UNIPROT G6PD protein P11413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22789539 f miannu We identified six genes involved in the PPP and NADPH production pathways as direct targets of Nrf2. To identify the target genes of NRF2 responsible for cell proliferation, we performed microarray analysis in A549 cells treated with NRF2 siRNA or control siRNA. We used three independent NRF2 siRNAs and selected genes whose expression levels were reduced to less than 66.7% of that of the control sample by all three siRNAs to minimize off-target effects (Table S1). In addition to the typical target genes of NRF2 encoding detoxifying enzymes and antioxidant proteins (cytoprotective genes), genes whose products are involved in the PPP (glucose-6-phosphate dehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD], transketolase [TKT], and transaldolase 1 [TALDO1]) and de novo nucleotide synthesis (phosphoribosyl pyrophosphate amidotransferase [PPAT] and methylenetetrahydrofolate dehydrogenase 2 [MTHFD2]) were decreased by the NRF2 knockdown (Figure 1B). Genes encoding enzymes for NADPH synthesis (malic enzyme 1 [ME1] and isocitrate dehydrogenase 1 [IDH1]) were also decreased (Figure 1B). We also confirmed the reduction of the enzyme proteins encoded by these genes in the NRF2-knockdown cells (Figure 1C). SIGNOR-267354 0.332 CD40LG protein P29965 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates 9606 BTO:0000776 19047375 f gcesareni Coimmunoprecipitation and western blot analysis showed that heptp was phosphorylated in a pka-dependent manner, which inactivated heptp and allowed for increased free p38 mapk to be phosphorylated by the mapk cascade that was activated by cd40l SIGNOR-182519 0.2 PYHIN1 protein Q6K0P9 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0001570 16479015 t miannu Here, we show that IFIXalpha1 downregulates HDM2, a principal negative regulator of p53, at the posttranslational level. IFIXalpha1 destabilizes HDM2 protein and promotes its ubiquitination. The E3 ligase activity of HDM2 appears to be required for this IFIXalpha1 effect. Importantly, HDM2 downregulation is required for the IFIXalpha1-mediated increase of p53 protein levels, transcriptional activity, and nuclear localization, suggesting that IFIXalpha1 positively regulates p53 by acting as a negative regulator of HDM2. SIGNOR-268493 0.42 PCSK7 protein Q16549 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto The levels of ikb_? Where reduced in cells overexpressing mkk6 [] these results indicated that mkk6 was able to promote the degradation of the NF-kappaB inhibitor, in a p38-dependent manner. SIGNOR-235837 0.2 IL1RAPL2 protein Q9NP60 UNIPROT NCS1 protein P62166 UNIPROT up-regulates activity binding 10116 BTO:0001009 12783849 t miannu IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction. SIGNOR-264476 0.325 FUBP1 protein Q96AE4 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30500954 f irozzo Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. SIGNOR-259132 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Thr235 QARKRKRtSIENRVR 9606 BTO:0004180 23041284 t flangone Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. SIGNOR-242092 0.2 CHEK1 protein O14757 UNIPROT CDC25B protein P30305 UNIPROT down-regulates activity phosphorylation Ser230 AFAQRPSsAPDLMCL 9606 17003105 t lperfetto Here, we show that cdc25b is phosphorylated by chk1 in vitro on multiple residues, including s230 and s563.We show that the s230-phosphorylated form of cdc25b is located at the centrosome from early s phase until mitosis. Furthermore, mutation of s230 to alanine increases the mitotic-inducing activity of cdc25b SIGNOR-149898 0.783 CDK4 protein P11802 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176515 0.286 PCK2 protein Q16822 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI down-regulates quantity chemical modification 9606 24632615 t miannu Phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32) is a key enzyme of gluconeogenesis. Two isoforms exist, a cytoplasmic form (PCK1, PEPCK-C) and a mitochondrial isoform (PCK2, PEPCK-M). PEPCK activity is present at significant levels in the liver, but also in the kidney and in brown and white adipose tissue. PEPCK, which converts oxaloacetate (OAA) to PEP, has an important role in glucose formation, but also for the generation of glycerol and serine. SIGNOR-266556 0.8 MAPKAPK2 protein P49137 UNIPROT ARPC5 protein O15511 UNIPROT unknown phosphorylation Ser77 AVKDRAGsIVLKVLI -1 12829704 t miannu MAPKAPK2 also phosphorylated p16-Arc in intact Arp2/3 complexes precipitated from neutrophil lysates. Mutation of serine-77 to alanine on the A isoform prevented phosphorylation by MAPKAPK2. SIGNOR-250144 0.356 entacapone chemical CHEBI:4798 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000759 9681662 t Simone Vumbaca Entacapone and tolcapone were powerful inhibitors of COMT and their IC50 estimates were 151 and 773 nM (P=0.008), respectively, in the liver; consistent results were obtained with the other tissues. SIGNOR-261088 0.8 MAPK1 protein P28482 UNIPROT IER3 protein P46695 UNIPROT up-regulates phosphorylation Thr18 MTILQAPtPAPSTIP 9606 12356731 t lperfetto Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors. SIGNOR-93740 0.54 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Thr577 SCRSSTTtCPEQDFF 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249301 0.44 CSNK2A1 protein P68400 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates phosphorylation Ser1479 HVYEKLSsIESDV 9606 BTO:0000938 15537897 t gcesareni Here we show that casein kinase ii (ck2) phosphorylates the serine residue (ser1480) within the c-terminal pdz ligand (iesdv) of the nr2b subunit of nmdar in vitro and in vivo. Phosphorylation of ser1480 disrupts the interaction of nr2b with the pdz domains of psd-95 and sap102 and decreases surface nr2b expression in neurons. SIGNOR-130336 0.327 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR AKT1S1 protein Q96B36 UNIPROT down-regulates binding 9606 SIGNOR-C3 20006481 t gcesareni Akt can phosphorylate pras40, a raptor binding protein that also acts as an inhibitor of torc1. Akt-mediated phosphorylation of pras40 again promotes 14-3-3 binding, in this case leading to relief from pras40-mediated inhibition. SIGNOR-162003 0.2 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Ser157 EHIERRVsNAGGPPA 9606 16197368 t llicata We show that, in human platelets, vasp is phosphorylated by pkc on ser157, but not ser239, in response to phorbol ester stimulation, in a manner blocked by the pkc inhibitor bim i (bisindolylmaleimide i). SIGNOR-140841 0.494 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT up-regulates activity phosphorylation Ser574 EEVSDKGsDSEEEET 9606 BTO:0000599 23287549 t lperfetto Sec63 was identified as a novel substrate and binding partner of protein kinase CK2. We identified serine 574, serine 576 and serine 748 as CK2 phosphorylation sites. Phosphorylation of Sec63 by CK2 enhanced its binding to Sec62. SIGNOR-265270 0.2 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity phosphorylation Ser666 RPPVRVPsWGLEDNV 10090 BTO:0002572 21765415 t The effect has been demonstrated using Q86VP1-2 lperfetto Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1). SIGNOR-175062 0.387 MAPK8IP1 protein Q9UQF2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates binding 9606 10490659 t gcesareni Both jip1 and jip2 selectively bind the mapkk isoform mkk7. SIGNOR-70848 0.718 SRC protein P12931 UNIPROT HNF4A protein P41235 UNIPROT down-regulates phosphorylation Tyr23 SAALDPAyTTLEFEN 9606 22308320 t lperfetto Here we show that c-src phosphorylates human hnf4_ on three tyrosines phosphomimetic mutants in the lbd decrease p1-hnf4_ protein stability, nuclear localization and transactivation function. SIGNOR-195883 0.37 MRGPRX1 protein Q96LB2 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257058 0.251 PPP1CC protein P36873 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-248502 0.388 PPP2CA protein P67775 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C134 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243433 0.904 FGF12 protein P61328 UNIPROT SCN3A protein Q9NY46 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253444 0.236 RAB22A protein Q9UL26 UNIPROT BLOC-2 complex SIGNOR-C252 SIGNOR up-regulates activity relocalization 9606 30404817 t lperfetto Recycling endosomes (REs) are transient endosomal tubular intermediates of early/sorting endosomes (E/SEs) that function in cargo recycling to the cell surface and deliver the cell type-specific cargo to lysosome-related organelles such as melanosomes in melanocytes.|Taken together, these findings suggest that Rab22A promotes the assembly of a BLOC-1-BLOC-2-KIF13A complex on E/SEs to generate REs that maintain cellular and organelle homeostasis. SIGNOR-260696 0.2 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr169 TEAPAVVtEEEDDDE 9606 BTO:0004828 32483448 t lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway SIGNOR-273112 0.2 NCK1 protein P16333 UNIPROT SOS1 protein Q07889 UNIPROT up-regulates binding 10029 BTO:0000246 7862111 t lperfetto We also found that nck binds directly to the guanine nucleotide exchange factor sos. / by binding to sos, nckmay bring sos to cell membrane where the ras protein is located. SIGNOR-236321 0.605 PRKCA protein P17252 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity phosphorylation Thr115 ADRRKAAtMRERRRL 9534 1335366 t lperfetto FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. SIGNOR-248845 0.367 PRKACB protein P22694 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. SIGNOR-81149 0.413 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 9606 BTO:0000130 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89217 0.454 topotecan chemical CHEBI:63632 ChEBI TOP1 protein P11387 UNIPROT down-regulates activity chemical inhibition 9606 11166732 t miannu Topotecan is a topoisomerase I inhibitor which is currently evaluated as an adjuvant agent for malignant glioma. SIGNOR-259317 0.8 PDPK1 protein O15530 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Thr308 KDGATMKtFCGTPEY 9606 12808134 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1). SIGNOR-252611 0.74 JAK2 protein O60674 UNIPROT ATOH1 protein Q92858 UNIPROT up-regulates quantity phosphorylation Tyr80 CTARAAQyLLHSPEL 9606 BTO:0004328 29168692 t Gianni We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling. SIGNOR-262201 0.344 HACE1 protein Q8IYU2 UNIPROT RAC1 protein P63000 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 22036506 t The CNF1 toxin of pathogenic Escherichia coli addresses Rac1 to ubiquitin-proteasome system (UPS). We report the essential role of the tumor suppressor HACE1, a HECT-domain containing E3 ubiquitin-ligase, in the targeting of Rac1 to UPS. HACE1 binds preferentially GTP-bound Rac1 and catalyzes its polyubiquitylation SIGNOR-255538 0.371 RNF123 protein Q5XPI4 UNIPROT CBX1 protein P83916 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 23077635 t miannu In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation. SIGNOR-272034 0.2 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI FGFR1 protein P11362 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258090 0.8 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK3 protein P27361 UNIPROT up-regulates phosphorylation 9606 12270934 t lperfetto Mek1 as indicated by extensive phosphorylation of erk1 and erk2 during the initial 2 h of adipogenesis. SIGNOR-244798 0.2 CEP135 protein Q66GS9 UNIPROT CENPJ protein Q9HC77 UNIPROT up-regulates activity binding 9606 23511974 t miannu In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation. SIGNOR-269677 0.805 MAPK3 protein P27361 UNIPROT MKNK1 protein Q9BUB5 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2. SIGNOR-48352 0.564 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Tyr152 ISEDIKSyYTVRQLE -1 11506178 t lperfetto Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B SIGNOR-249368 0.782 INTS14 protein Q96SY0 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261474 0.2 INSR protein P06213 UNIPROT CBL protein P22681 UNIPROT up-regulates activity phosphorylation Tyr700 EGEEDTEyMTPSSRP 10090 11997497 t Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation. SIGNOR-251305 0.514 SGK1 protein O00141 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 11154281 t lperfetto Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. SIGNOR-249134 0.79 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16239 0.568 FADS6 protein Q8N9I5 UNIPROT long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI down-regulates quantity chemical modification 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267910 0.8 AURKB protein Q96GD4 UNIPROT DIAPH2 protein O60879 UNIPROT up-regulates phosphorylation Ser196 SLTSNPVsWVNNFGH 9606 21397845 t lperfetto The microtubule binding fh2 domain of mdia3 is phosphorylated by aurora b kinase in vitro, and cells expressing the nonphosphorylatable mdia3 mutant cannot position chromosomes at the metaphase plate SIGNOR-172803 0.291 LEF1 protein Q9UJU2 UNIPROT DSG4 protein Q86SJ6 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000552 19683850 f miannu we studied the transcriptional regulation of DSG4 by transcription factors/pathways that are known regulators of hair keratin or KAP expression. We show that HOXC13, LEF1 and FOXN1 repress DSG4 transcription and provide in vitro and in vivo evidence correlating the Notch pathway with the activation and/or maintenance of DSG4 expression in the hair follicle. SIGNOR-254183 0.291 NDUFA1 protein O15239 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND2-module is formed by an initial intermediate that contains MT-ND2, NDUFC1 and NDUFC2 bound to NDUFAF1/CIA30 [49,50], ECSIT [51] and ACAD9 [52,53]. Then, MT-ND3 is added together with TMEM126B [54], forming a larger intermediate to which subunits MT-ND6 and MT-ND4L bind. The latest assembly stages involve the incorporation of subunits NDUFA1, NDUFA10 and NDUFS5 [24,34]. SIGNOR-262150 0.846 Av/b1 integrin complex SIGNOR-C175 SIGNOR NANOG protein Q9H9S0 UNIPROT up-regulates quantity by expression 10090 18757303 f lperfetto Recombinant human LN-511 alone was suffi- cient to enable self-renewal of mouse ES cells for up to 169 days (31 passages). Cells cultured on LN-511 maintained expression of pluripotency markers, such as Oct4, Sox2, Tert, UTF1, and Nanog|ES cells interacted with LN-511 via 􏰇1-integrins, mostly a6b1 and aVb1. SIGNOR-253276 0.326 SP3 protein Q02447 UNIPROT SCNN1A protein P37088 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004299 12684058 f Regulation of expression miannu Transcription factors Sp1 and Sp3 activate alpha-ENaC2 transcription through a GC-rich element (Sp1-binding site) in the promoter. Sp1 and Sp3 are essential for alpha-ENaC2 transcription in lung epithelial cells and that dephosphorylation of the Sp transcription factors by PP1 suppresses alpha-ENaC2 expression. SIGNOR-251951 0.2 CTDNEP1 protein O95476 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 9606 17141153 t lperfetto We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors (bmprs). Dullard preferentially complexes with the bmp type ii receptor (bmprii) and partially colocalizes with the caveolin-1-positive compartment, suggesting that dullard promotes bmpr degradation via the lipid raft-caveolar pathway SIGNOR-150998 0.293 ATG5 protein Q9H1Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR form complex binding 9606 BTO:0000007 18321988 t lperfetto Atg12 is conjugated to atg5 and forms an approximately 800-kda protein complex with atg16l (referred to as atg16l complex). SIGNOR-226693 0.948 MYCBP2 protein O75592 UNIPROT RAN protein P62826 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 26304119 t Monia MYCBP2 Is a Nuclear GEF for Ran in DRG Neurons—Next, we studied whether or not MYCBP2 modulates the interaction between Ran/RanGAP1. MYCBP2 contains an N-terminal RCC1-like domain (Fig. 8C) (13), and RCC1 is a known GEF for Ran, indicating a potential functional interaction between MYCBP2 and Ran. SIGNOR-261204 0.298 DAXX protein Q9UER7 UNIPROT FAS protein P25445 UNIPROT down-regulates binding 9606 9215629 t gcesareni A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation. SIGNOR-49473 0.695 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23979597 t miannu  We showed that PHF8 interacts with the CDC20-containing APC (APC(cdc20)) primarily during mitosis. we demonstrate that mutations of the LXPKXLF motif abrogate polyubiquitylation of PHF8 by the APC. APC substrates are typically cell cycle regulators, and consistent with this, the loss of PHF8 leads to prolonged G2 phase and defective mitosis. SIGNOR-272880 0.874 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ile) smallmolecule CHEBI:29174 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269501 0.8 H2BC11 protein P06899 UNIPROT Nucleosome_H3.3 variant complex SIGNOR-C339 SIGNOR form complex binding 9606 15776021 t miannu Variant histone H3.3 is incorporated into nucleosomes by a mechanism that does not require DNA replication and has also been implicated as a potential mediator of epigenetic memory of active transcriptional states. In this study, we have used chromatin immunoprecipitation analysis to show that H3.3 is found mainly at the promoters of transcriptionally active genes. SIGNOR-263875 0.2 MAP3K3 protein Q99759 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates 9606 10347227 f gcesareni However, the autocatalytic activities of both mkk6 and mkk7 were enhanced by their coexpression with either mekk3 or mekk2. SIGNOR-68020 0.417 TG protein P01266 UNIPROT Colloid phenotype SIGNOR-PH185 SIGNOR up-regulates 9606 24251883 f scontino The thyroid gland is unique among endocrine glands in storing its principle hormonal product—the two very small thyroid hormones (TH)—as components of a 1000-fold larger precursor—thyroglobulin (Tg)—that is secreted and stored in the colloid, outside of the thyroid cell. Moreover, the thyroid cell is part of a layer of similar cells—the thyroid follicular epithelium—that completely encloses the secreted Tg and segregates it from the circulation. SIGNOR-267135 0.7 PRKD1 protein Q15139 UNIPROT MFF protein Q9GZY8 UNIPROT up-regulates activity phosphorylation Ser155 GRLKRERsMSENAVR 9606 BTO:0002181 34010649 t miannu PKD directly phosphorylates MFF on serines 155, 172, and 275 SIGNOR-277558 0.2 P-TEFb complex SIGNOR-C238 SIGNOR AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 20153263 t miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. SIGNOR-239237 0.761 COPS3 protein Q9UNS2 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270769 0.916 CSNK2A1 protein P68400 UNIPROT PDCL protein Q13371 UNIPROT up-regulates phosphorylation Ser18 EKLQYYYsSSEDEDS 9606 16717095 t lperfetto Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2. SIGNOR-146825 0.37 PAMPs stimulus SIGNOR-ST11 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR up-regulates 9606 20404851 f lperfetto the discovery of Toll-like receptors (TLRs) in the mid-1990s showed that pathogen recognition by the innate immune system is instead actually specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as pathogen-associated molecular patterns (PAMPs) SIGNOR-216295 0.7 LCMT1 protein Q9UIC8 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity methylation Leu309 RRTPDYFl -1 18394995 t lperfetto Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1) SIGNOR-265751 0.652 BRCC3 protein P46736 UNIPROT H2AC11 protein P0C0S8 UNIPROT down-regulates deubiquitination 9606 20656690 t gcesareni Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a SIGNOR-167142 0.2 DHFR protein P00374 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI up-regulates quantity chemical modification 9606 21876184 t lperfetto Human dihydrofolate reductase (DHFR) was previously thought to be the only enzyme capable of the reduction of dihydrofolate to tetrahydrofolate; an essential reaction necessary to ensure a continuous supply of biologically active folate. SIGNOR-268258 0.8 CAMK2G protein Q13555 UNIPROT MYLK protein Q15746 UNIPROT down-regulates activity phosphorylation Ser1760 RAIGRLSsMAMISGL 2160950 t llicata Phosphorylation of MLC kinase by CaM protein kinase II increased the dissociation constant of MLC kinase for calmodulin about 10 times without changing the Vmax. The location of the phosphorylation sites was identified by isolating and sequencing the tryptic phosphopeptides of MLC kinase. The preferred site was identified as serine 512 and the second site as serine 525. These sites are the same as the sites phosphorylated by cAMP-dependent protein kinase. SIGNOR-250700 0.334 ADIPOQ protein Q15848 UNIPROT ADIPOR2 protein Q86V24 UNIPROT up-regulates binding 9606 16622416 t milica Two adiponectin receptors, adipor1 and adipor2, have recently been identified. SIGNOR-146173 0.769 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL10 protein P22301 UNIPROT up-regulates quantity by expression 22933625 f apalma P38 activation contributes to the macrophage phenotype switch in injured muscle, which could elevate production of IL-10 (63), creating positive feedback for the phenotype switch SIGNOR-255448 0.7 PLK1 protein P53350 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 11897663 t lperfetto The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase. SIGNOR-115993 0.799 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT down-regulates activity phosphorylation Ser756 HSCLEQAs 9606 10195894 t Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response. SIGNOR-251284 0.2 HSP90AA1 protein P07900 UNIPROT NOD2 protein Q9HC29 UNIPROT up-regulates quantity by stabilization binding 9606 23019338 t miannu Nod2 is constitutively associated with a chaperone protein, Hsp90, which is required for Nod2 stability and protects Nod2 from degradation. SIGNOR-252414 0.352 JARID2 protein Q92833 UNIPROT GATA4 protein P43694 UNIPROT down-regulates activity binding 10116 BTO:0003324 15542826 t miannu JMJ physically associates with Nkx2.5 and GATA4 in vitro and in vivo as determined by glutathione S-transferase pull-down and immunoprecipitation assays. we show that JMJ represses ANF gene expression by inhibiting transcriptional activities of Nkx2.5 and GATA4. SIGNOR-224697 0.463 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1346 SFDERQPyAHMNGGR -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246276 0.571 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT up-regulates activity phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0002181 24841198 t miannu When the CaMKI activity is elevated, it phosphorylates PME-1 at Ser15. SIGNOR-276636 0.401 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252835 0.909 NEK6 protein Q9HC98 UNIPROT BSG protein P35613 UNIPROT down-regulates activity phosphorylation Ser368 GSAPLKSsGQHQNDK 9606 31016558 t done miannu These results indicate that NEK6 directly interacts with CD147 and phosphorylates the protein at serine-252 in Huh-7 cells. SIGNOR-273882 0.2 AKT1 protein P31749 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser34 HKRRRSRsWSSSSDR 9606 BTO:0000567 20682768 t lperfetto Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva SIGNOR-167336 0.395 ACAN protein P16112 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 16051604 t lperfetto Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix of the musculoskeletal system.  SIGNOR-266983 0.7 NRF1 protein Q16656 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268999 0.547 Sin3B_complex complex SIGNOR-C409 SIGNOR H3Y2 protein P0DPK5 UNIPROT down-regulates activity binding 9606 21041488 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266976 0.2 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257961 0.8 AKT1 protein P31749 UNIPROT BCL2L11 protein O43521 UNIPROT down-regulates activity phosphorylation Ser87 FIFMRRSsLLSRSSS 9606 16282323 t lperfetto Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL). SIGNOR-252487 0.579 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser285 SSASPALsRRGSLGE 10090 17213202 t lperfetto Serines 281 and 285 of the nfat3 protein might be target amino acids of rsk2 phosphorylationrsk2 induced nuclear localization of nfat3. Rsk2 phosphorylated nfat3 in vitro (km=3.559 microm), and activation of nfat3 by rsk2 enhanced the promoter activity of nfat3 downstream target genes in vivo. SIGNOR-234469 0.391 IKK-complex complex SIGNOR-C14 SIGNOR NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 15494311 t Translocation from Nucleus to Cytoplasm lperfetto Nf-kappab transcription requires ikkalpha to phosphorylate smrt on chromatin, stimulating the exchange of corepressor for coactivator complexes. Ikk directly phosphorylates smrt to stimulate nuclear export. Ikkalpha orchestrates smrt derepression, a prerequisite for nf-kappab transcription and survival. SIGNOR-216393 0.415 INS protein P01308 UNIPROT LPL protein P06858 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001487 21966368 f Regulation miannu Insulin has a major effect on LPL regulation in adipose tissue since in mature adipocytes insulin not only increases the level of LPL mRNA but also regulates LPL activity through both posttranscriptional and posttranslational mechanisms SIGNOR-251857 0.473 PIP5K1C protein O60331 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity chemical modification 9606 9367159 t miannu Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities SIGNOR-277287 0.8 STK3 protein Q13188 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates phosphorylation -1 BTO:0000007 16930133 t milica In vitro phosphorylation experiments indicate that the phosphorylation of Sav by Mst is direct. The stabilizing effect of Mst was much greater on N-terminally truncated hSav mutants, as long as they retained the ability to bind Mst. Mst mutants that lacked the C-terminal coiled-coil domain and were unable to bind to hSav, also failed to stabilize or phosphorylate hSav SIGNOR-230716 0.829 abiraterone chemical CHEBI:68642 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-204810 0.8 N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 ChEBI (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI up-regulates quantity precursor of 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-268091 0.8 POLR3K protein Q9Y2Y1 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266135 0.821 MAPK3 protein P27361 UNIPROT RPS3 protein P23396 UNIPROT up-regulates phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t lperfetto Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-137175 0.356 CDK1 protein P06493 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser160 PVRLLGHsPVLRNIT 9606 SIGNOR-C17 12107172 t lperfetto We demonstrate that serine 146 is required for two crucial features of cdc25b1. It is essential for cdc25b1 to function as a mitotic inducer and to prevent cdc25b1 export from the nucleus. We also show that serine 146 is phosphorylated in vitro by cdk1-cyclin b. Serine 146 phosphorylation is proposed to be a key event in the regulation of the cdc25b function SIGNOR-90451 0.826 NDUFA5 protein Q16718 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262156 0.824 PHF21A protein Q96BD5 UNIPROT BHC complex complex SIGNOR-C353 SIGNOR form complex binding 9606 BTO:0000567; BTO:0000007 15325272 t miannu BRAF–HDAC complex (BHC) consisting of six subunit proteins, BRAF35, BHC80, BHC110, HDAC1, HDAC2, and CoREST, has been purified from HeLa and HEK293 cells SIGNOR-264502 0.735 ITGB5 protein P18084 UNIPROT Av/b5 integrin complex SIGNOR-C178 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253208 0.767 DZIP3 protein Q86Y13 UNIPROT H2AC1 protein Q96QV6 UNIPROT up-regulates activity monoubiquitination Lys119 IQAVLLPkKTESHHH 9606 BTO:0000007 18206970 t miannu  2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation. SIGNOR-271761 0.2 ATM protein Q13315 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates activity phosphorylation Thr172 SDGEFLRtSCGSPNY 23871434 t lperfetto ATM phosphorylates AMPKalpha2 to induce inhibitory phosphorylation of HIPK2| SIGNOR-275488 0.266 FGF1 protein P05230 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates binding 9606 22298955 t gcesareni Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation SIGNOR-195585 0.796 AKT1 protein P31749 UNIPROT PHF20 protein Q9BVI0 UNIPROT down-regulates phosphorylation Ser291 ELRRRKIsKGCEVPL 9606 22334668 t llicata Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function. SIGNOR-252529 0.541 CPT1C protein Q8TCG5 UNIPROT palmitoyl-CoA(4-) smallmolecule CHEBI:57379 ChEBI down-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267128 0.8 GPR119 protein Q8TDV5 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257415 0.251 PPP1CB protein P62140 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 14633703 t Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-252604 0.391 GPHN protein Q9NQX3 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264975 0.7 SP1 protein P08047 UNIPROT SP1/STAT3 complex SIGNOR-C74 SIGNOR form complex binding 9606 19723038 t miannu Sp1 and stat3 seem to synergistically augment renalase transcription. SIGNOR-187790 0.462 FAS protein P25445 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 10090 BTO:0000944 7538908 t lperfetto Fas associates with rip. Rip is a novel form of apoptosis-inducing protein SIGNOR-235430 0.643 PRKCD protein Q05655 UNIPROT PTPN22 protein Q9Y2R2 UNIPROT down-regulates phosphorylation Ser35 FLKLKRQsTKYKADK 9606 BTO:0000782 18056643 t llicata We show that lyp is phosphorylated exclusively at ser-35 by pkc both in vitro and in vivo. our data establish a mechanism by which pkc could attenuate the cellular function of lyp, thereby augmenting t cell activation. SIGNOR-159591 0.316 MEF2C protein Q06413 UNIPROT MYH2 protein Q9UKX2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001103 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238718 0.439 MRGPRX2 protein Q96LB1 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257059 0.2 FYN protein P06241 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11005864 t lperfetto Study of t cells from a fyn-deficient tcr transgenic mouse also showed that fyn was required for tyrosine phosphorylation and activation of vav induced by both antagonist and agonist peptides. SIGNOR-82287 0.626 FUS protein P35637 UNIPROT SHANK1 protein Q9Y566 UNIPROT up-regulates quantity post transcriptional regulation 10090 BTO:0000142 32118033 t lperfetto These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition. SIGNOR-262104 0.2 PTGIR protein P43119 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257078 0.406 TRPS1 protein Q9UHF7 UNIPROT GDF5 protein P43026 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0005092 18363966 f Regulation of expression miannu Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1. SIGNOR-251866 0.309 CDK1 protein P06493 UNIPROT NUMA1 protein Q14980 UNIPROT down-regulates phosphorylation Thr2055 MAFSILNtPKKLGNS 9606 23921553 t llicata Cdk1-mediated phosphorylation at t2055 negatively regulates numa cortical localization and that this phosphorylation is counteracted by ppp2ca phosphatase activity. SIGNOR-194825 0.577 haloperidol chemical CHEBI:5613 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258372 0.8 APC-c complex SIGNOR-C150 SIGNOR KIF2C protein Q99661 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 25504441 t miannu Our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis.We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20.  In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. SIGNOR-276864 0.28 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258734 0.8 ATG7 protein O95352 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-195236 0.869 GOLGA2 protein Q08379 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT up-regulates activity binding 9606 23555793 t miannu The “cis-golgin tether” is one of the most well-characterized golgin tether complexes. It is composed of the COPI vesicle-associated golgin giantin linked to Golgi membrane-associated GM130 via p115. GM130 is in turn linked to GRASP65 via a PDZ-like domain. GRASP65 is anchored to the Golgi membrane through N-terminal myristoylation as well as through binding to other Golgi proteins [10]. Together, these proteins appear to mediate vesicle tethering at the cis-Golgi membrane. SIGNOR-261239 0.877 pimozide chemical CHEBI:8212 ChEBI DRD2 protein P14416 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 8301582 t miannu The most selective compound from this group were (+)butaclamol and domperidone which showed 5-fold D3 selectivity. A number of high affinity dopamine receptor agonists, including apomorphine and bromocriptine, also failed to demonstrate selectivity. In contrast, the natural ligand dopamine and the efficacious synthetic agonists quinpirole, (+)4-propyl-9-hydroxynapthoxazine (PHNO), 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (6,7-ADTN), 7-OH DPAT and N-0434 showed marked apparent human dopamine D3 (hD3) receptor selectivity. In the aminotetralin series, this selectivity was observed preferentially with analogs of the 6,7-rotamer compared with compounds from the 5,6-rotamer series. Functional coupling of the hD3 receptor was investigated in a number of cell lines in which the hD3 receptor was stably expressed, including CHO cells, the neuroblastoma-glioma hybrid cell line NG108-15 and a rat 1 fibroblast cell line. SIGNOR-258719 0.8 STK3 protein Q13188 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser872 HQRCLAHsLVGTPNY 9606 21808241 t gcesareni Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2. SIGNOR-175797 0.599 DUSP5 protein Q16690 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 10224087 t inferred from 70% of family members gcesareni Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway SIGNOR-269912 0.2 RIMS2 protein Q9UQ26 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 31679900 t miannu N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle SIGNOR-264377 0.76 CPSF complex complex SIGNOR-C53 SIGNOR PAPOLA protein P51003 UNIPROT up-regulates activity relocalization 9606 14749727 t lperfetto Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna. SIGNOR-268323 0.791 POLR2F protein P61218 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266148 0.898 AKT proteinfamily SIGNOR-PF24 SIGNOR SP7 protein Q8TDD2 UNIPROT up-regulates phosphorylation 9606 21777568 t gcesareni We found that Akt phosphorylates Osterix and that Akt activation increases protein stability, osteogenic activity and transcriptional activity of Osterix. We also found that BMP-2 increases the protein level of Osterix in an Akt activity-dependent manner. SIGNOR-174017 0.2 SKI protein P12755 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 10575014 t lperfetto Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling. SIGNOR-217658 0.734 RPL13A protein P40429 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262485 0.833 ARHGEF2 protein Q92974 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260529 0.802 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 7737130 t gcesareni Stimulation of atf-2-dependent transactivation by genotoxic agents requires the presence of threonines 69 and 71 located in the n-terminal transactivation domain. These sites are the target of p54 and p46 stress-activated protein kinases (sapks) which bind to, and phosphorylate atf-2 in vitro. SIGNOR-32433 0.691 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89260 0.399 NOTCH1 protein P46531 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 BTO:0000776 9528794 t gcesareni We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk. SIGNOR-56150 0.434 F2R protein P25116 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 t milica The protease-activated receptors (PAR)2 are a class of G protein-coupled receptors (GPCR) that are activated by the proteolysis of the N-terminal exodomain. Upon proteolysis, the newly formed n terminus acts as a tethered ligand that activates the receptor and initiates signaling cascades through multiple g proteins (galfaq, galfai, and galfa12/13). SIGNOR-196006 0.588 bisindolylmaleimide i chemical CID:2396 PUBCHEM PRKCE protein Q02156 UNIPROT down-regulates chemical inhibition 9606 Other t CellSignaling gcesareni SIGNOR-190353 0.8 OST-A complex complex SIGNOR-C535 SIGNOR Protein_glycosylation phenotype SIGNOR-PH144 SIGNOR up-regulates 9606 31831667 t miannu Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum. Mammals express two distinct OST complexes that act in a cotranslational (OST-A) or posttranslocational (OST-B) manner. Here, we present high-resolution cryo-electron microscopy structures of human OST-A and OST-B. Although they have similar overall architectures, structural differences in the catalytic subunits STT3A and STT3B facilitate contacts to distinct OST subunits, DC2 in OST-A and MAGT1 in OST-B. In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle that can bind to a translating ribosome, whereas the equivalent region is disordered in OST-B.  SIGNOR-272055 0.7 ZNF503 protein Q96F45 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 10090 25538248 f Monia Zpo2-overexpressing cells demonstrated high levels of pFAK compared with the control (Fig. 6A). Additionally, Western blot analysis indicated that, in response to Zpo2 expression, both EpH4.9 and PyMT cells increase FAK activity, as demonstrated by higher levels of pFAK staining (Fig. 6B). SIGNOR-261191 0.2 PAK5 protein Q9P286 UNIPROT GATA1 protein P15976 UNIPROT up-regulates activity phosphorylation Ser161 SSLPVPNsAYGGPDF 9606 BTO:0000150 25726523 t lperfetto GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells. SIGNOR-275655 0.2 ELANE protein P08246 UNIPROT F5 protein P12259 UNIPROT up-regulates activity cleavage Ile847 LQPDVTGiRLLSLGA -1 9242537 t lperfetto Human neutrophil elastase activates human factor V but inactivates thrombin-activated human factor V|NH2-terminal sequence analysis of F.V treated with HNE indicated cleavage at Ile819 and Ile1484 under conditions during which the procofactor expressed enhanced cofactor activity in the prothrombinase complex. SIGNOR-263637 0.37 EGFR protein P00533 UNIPROT PCNA protein P12004 UNIPROT up-regulates phosphorylation Tyr211 QLTFALRyLNFFTKA 9606 BTO:0000150 17115032 t lperfetto Here, we show that the chromatin-bound pcna protein is phosphorylated on tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of egf receptor (egfr) in the nucleus. Phosphorylation on tyr 211 by egfr stabilizes chromatin-bound pcna protein and associated functions. SIGNOR-150852 0.344 MYC protein P01106 UNIPROT SHMT2 protein P34897 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003291 18628958 t miannu Myc regulates the de novo purine and pyrimidine synthetic genes in multiple biological systems. Intriguingly, MYC was found to directly activate the expression of SHMT1, and SHMT2, which are enzymes involved in single carbon metabolism and are essential for dNTP synthesis SIGNOR-267380 0.294 glutamic acid smallmolecule CHEBI:18237 ChEBI GRID1 protein Q9ULK0 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264468 0.8 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation 9606 17396146 t gcesareni The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells. SIGNOR-154178 0.404 RPS6K proteinfamily SIGNOR-PF26 SIGNOR EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 15071500 t gcesareni S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function. SIGNOR-252783 0.2 CDK7 protein P50613 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity phosphorylation Thr160 GVPVRTYtHEVVTLW -1 10085115 t llicata Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP. SIGNOR-250768 0.559 RUNX1 protein Q01196 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17725493 f miannu We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. SIGNOR-254193 0.481 TRIM11 protein Q96F44 UNIPROT PHOX2B protein Q99453 UNIPROT down-regulates ubiquitination 9606 22307522 t miannu The e3 ubiquitin ligasetrim11mediates the degradation of congenital central hypoventilation syndrome-associated polyalanine-expandedphox2b. SIGNOR-195878 0.494 PRKACA protein P17612 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000007 16199882 t gcesareni Although pka did not affect the formation of a complex between glycogen synthase kinase 3beta (gsk-3beta), beta-catenin, and axin, phosphorylation of beta-catenin by pka inhibited ubiquitination of beta-catenin in intact cells and in vitro. SIGNOR-140902 0.466 KDM6A protein O15550 UNIPROT HOXA11 protein P31270 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260021 0.265 2-methylpropanethioic acid S-[2-[[[1-(2-ethylbutyl)cyclohexyl]-oxomethyl]amino]phenyl] ester chemical CHEBI:95001 ChEBI CETP protein P11597 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191265 0.8 DEPDC5 protein O75140 UNIPROT GATOR1 complex SIGNOR-C192 SIGNOR form complex binding 9606 23723238 t miannu Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and 2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, Sec13) suppresses mTORC1 signaling and epistasis analysis shows that GATOR2 negatively regulates DEPDC5 SIGNOR-255280 0.949 4-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]aniline chemical CHEBI:92250 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258852 0.8 bosutinib chemical CHEBI:39112 ChEBI ABL1 protein P00519 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258088 0.8 NOTCH proteinfamily SIGNOR-PF30 SIGNOR CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11486031 f gcesareni Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo SIGNOR-254349 0.2 CEBPA protein P49715 UNIPROT SOX4 protein Q06945 UNIPROT down-regulates transcriptional regulation 9606 24183681 t apalma In summary, our data demonstrate that C/EBPα negatively regulates Sox4 transcription via direct DNA-binding. SIGNOR-255675 0.388 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC8 protein Q9BY41 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002428 31908417 t miannu The present study aimed to detect HDAC1 expression in and around ESCC tissues and comprehensively assess the anti-ESCC effects of AR-42, a phenylbutyrate-derived pan-HDAC inhibitor with low nanomolar IC50s against HDACs including HDAC1. AR-42 developed by Chen et al is an orally bioavailable hydroxamate-tethered phenylbutyrate derivative with strong inhibitory activity against class I (HDAC 1, 2, 3 and 8) and class IIb (HDAC 6 and 10) HDACs. SIGNOR-262248 0.8 STK38 protein Q15208 UNIPROT YAP1 protein P46937 UNIPROT down-regulates activity phosphorylation Ser127 PQHVRAHsSPASLQL 9606 25601544 t Luana We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells. SIGNOR-259855 0.389 CSNK1D protein P48730 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity phosphorylation Thr1493 NPPPSPAtERSHYTM 9606 35487243 t miannu Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493 SIGNOR-275403 0.2 FANCG protein O15287 UNIPROT D1-D2-G-X3 complex complex SIGNOR-C301 SIGNOR form complex binding 9606 BTO:0000567 18212739 t lperfetto These results argue that FANCG has a role independent of the FA core complex, and we propose that phosphorylation of serine 7 is the signalling event required for forming a discrete complex comprising FANCD1/BRCA2-FANCD2-FANCG-XRCC3 (D1-D2-G-X3).  SIGNOR-263254 0.731 SLIT1 protein O75093 UNIPROT ROBO proteinfamily SIGNOR-PF14 SIGNOR up-regulates binding 9606 16226035 t gcesareni Here we describe and compare two human robo3 isoforms, robo3a and robo3b, which differ by the insertion of 26 amino acids at the n-terminus, and these forms appear to be evolutionary conserved. We investigated the bioactivity of these isoforms and show that they have different binding properties to slit. SIGNOR-141111 0.895 CTH protein P32929 UNIPROT L-cystathionine dizwitterion smallmolecule CHEBI:58161 ChEBI down-regulates quantity chemical modification 9606 BTO:0000671;BTO:0000759;BTO:0002688 19961860 t lperfetto the role of CSE in this reaction pathway is to convert l-cystathionine into l-cysteine whilst generating α-ketobutyrate and ammonia (Fig. 1). The reaction proceeds via an α,γ-elimination mechanism where the C–γ–S bond of l-cystathionine is specifically cleaved to yield l-cysteine.12 Defects in this metabolic pathway are associated with cystathioninuria, l-cysteine deficiency and subsequent impairment of glutathione metabolism, as well as higher plasma homocysteine concentrations.13, 14, 15, 16, 17 Besides its role in the conversion of l-cystathionine into l-cysteine, studies have also shown that CSE can utilize l-cysteine as a substrate for producing H2S via an α,β-elimination reaction (Fig. 1).18, 19, 20 However, to date, no reports have clearly demonstrated the residues that affect CSE-mediated H2S production. SIGNOR-275822 0.8 MST1R protein Q04912 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation 35569509 t lperfetto This suggests that by interacting with Sdc4, either directly or indirectly, RON is activated via transphosphorylation when clustered, engages the ABL1 SH2 domain, and activates ABL1 by phosphorylation. SIGNOR-272999 0.275 SMURF2 protein Q9HAU4 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates activity ubiquitination 9606 11163210 t lperfetto Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. SIGNOR-104999 0.703 TP53 protein P04637 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14522900 f miannu  In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction SIGNOR-254484 0.874 NUP58 protein Q9BVL2 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262077 0.2 GABA-B receptor complex SIGNOR-C336 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 9872316 f brain lperfetto GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. SIGNOR-263794 0.7 NR3C1 protein P04150 UNIPROT CAV1 protein Q03135 UNIPROT up-regulates binding 9606 23339905 t gcesareni He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay. SIGNOR-251683 0.385 ELP4 protein Q96EB1 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269711 0.866 RPS6K proteinfamily SIGNOR-PF26 SIGNOR STK11 protein Q15831 UNIPROT down-regulates activity phosphorylation Ser428 SSKIRRLsACKQQ 9606 BTO:0001271 25846811 t lperfetto Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cellsBRAFV600E activates downstream molecules, including ERK and p90 ribosomal S6 kinase (RSK), and leads to the phosphorylation of LKB-1 at Ser428 by these kinases. This cascade results in the dissociation of LKB1 from AMPK. SIGNOR-252805 0.2 TTK protein P33981 UNIPROT MAP4 protein P27816 UNIPROT down-regulates quantity by destabilization phosphorylation Thr927 LSRLATNtSAPDLKN 9606 BTO:0000567 31253867 t miannu We further uncovered that Mps1 is a kinase of MAP4, and E7-MAP4 binding blocks Mps1 phosphorylation of MAP4, thereby interrupting phosphorylation-dependent MAP4 degradation.  SIGNOR-277462 0.2 SERPINE1 protein P05121 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 10368279 f gcesareni Pai-1 is now being identified as a key player in the link between coagulation and the cell adhesion pathways involved in tissue remodeling and metastasis. Active pai-1 (but not its latent or cleaved forms) binds tightly to the adhesive glycoprotein vitronectin in the extracellular matrix. SIGNOR-68478 0.7 SH3GLB1 protein Q9Y371 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263886 0.7 APH1A protein Q96BI3 UNIPROT PSENEN protein Q9NZ42 UNIPROT up-regulates binding 9606 12522139 t gcesareni Furthermore, overexpression of aph-1 facilitates pen-2-mediated ps1 proteolysis, resulting in a significant increase in ps1 fragments. Our data reveal a direct role of pen-2 in proteolytic cleavage of ps1 and a regulatory function of aph-1, in coordination with pen-2, in the biogenesis of the ps1 complex. SIGNOR-97104 0.962 PTPN5 protein P54829 UNIPROT GRIN2B protein Q13224 UNIPROT down-regulates activity dephosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 19625523 t lperfetto In addition, STEP 61 dephosphorylates the tyr 1472 on the NR2B subunit of the NMDAR, which promotes internalization of the NMDAR complex. SIGNOR-276991 0.558 POLR1B protein Q9H9Y6 UNIPROT RNA Polymerase I complex SIGNOR-C390 SIGNOR form complex binding 22260999 t lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266154 0.869 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20921405 f gcesareni Nf-kb activation following t-cell receptor engagement induces the expression of mdm2 through interaction with nf-kb sites in its p1 promoter SIGNOR-168296 0.377 ITGAL protein P20701 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma This leads to further neutrophil-endothelial cell interactions through the binding of LFA-1 to its endothelial counterreceptor ICAM-1 during the slow rolling phase SIGNOR-255040 0.921 NF2 protein P35240 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates activity binding 10090 BTO:0003324 27402866 t Hippo pathway Gianni NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart. SIGNOR-269948 0.418 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249322 0.758 RIMS2 protein Q9UQ26 UNIPROT CACNA1D protein Q01668 UNIPROT up-regulates activity binding 9606 BTO:0005822 28642685 t miannu Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. SIGNOR-264356 0.352 CACNA2D3 protein Q8IZS8 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR up-regulates activity 9606 31746409 f miannu The results indicated that the overexpression of CACNA2D3 induced an increase in intracellular Ca2+ and increased the levels of p-p38 MAPK. These data indicated that the p38 MAPK pathway is activated by overexpression of CACNA2D3 and P4 induction. SIGNOR-266857 0.2 CDH1 protein P12830 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20940130 t gcesareni P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin. SIGNOR-168464 0.369 PPM1F protein P49593 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates dephosphorylation Thr286 SCMHRQEtVDCLKKF 9606 BTO:0000938 15140879 t gcesareni Ppm1f specifically dephosphorylates the phospho-thr-286 in autophosphorylated camkii substrate and thus deactivates the camkii in vitro. SIGNOR-124309 0.334 MAPK8 protein P45983 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 BTO:0000150 18676833 t gcesareni Mcl-1 can be rapidly degraded by certain death-inducing signals, but it is able to be readily induced by diverse survival cytokines such as epidermal growth factor, vascular endothelial growth factor, granulocyt-macrophage colony-stimulating factor, and interleukin 3 through phosphatidy-linositol-3-oh kinase/akt, mek/mapk, or janus-activated kinase/stat signaling cascades SIGNOR-179816 0.537 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr730 SNCTNELyMMMRDCW 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1.We have proposed that the role of the third stage of autophosphorylation is to enable the efficient tyrosine phosphorylation of substrate proteins that are physically bound to the receptor molecule by a maximally activated fgfr1 SIGNOR-235686 0.2 CRK protein P46108 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t HPK1 phosphorylated Crk mainly on threonine and weakly on serine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. SIGNOR-63988 0.679 C5 convertase complex (C3bBbC3b) complex SIGNOR-C315 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 9606 BTO:0000089 26489954 t lperfetto In addition to the surface‐bound C3 convertase, a fluid‐phase convertase can be formed by association of water‐reacted C3, termed C3(H20), to FB thus constantly maintaining a low level of complement activation in solution (tick‐over). Both of the surface‐bound C3 convertases can bind a C3b molecule whereby the C5 convertases are formed. These cleave C5 into C5a and C5b, thus initiating the terminal pathway and leading to formation of the membrane attack complex (MAC). SIGNOR-263481 0.546 PTEN protein P60484 UNIPROT PI3K complex SIGNOR-C156 SIGNOR down-regulates activity 9606 BTO:0000938 18794881 f lperfetto The pten tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (pi3k)-dependent by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (ptdinsp(3)). SIGNOR-252725 0.712 GSK3B protein P49841 UNIPROT JUNB protein P17275 UNIPROT down-regulates quantity by destabilization phosphorylation Ser251 QTVPEARsRDATPPV 9606 BTO:0000567 22710716 t miannu  Thus, JunB phosphorylation at S251 and T255 by GSK3β is primed by phosphorylation at S259 by a yet to-be-identified kinase.Phosphorylation at S251, T255 and S259 is required for JunB degradation. SIGNOR-276418 0.2 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t Here we show that the wild-type p53-induced phosphatase 1 (Wip1), or PPM1D, downregulates p53 protein levels by stabilizing Mdm2 and facilitating its access to p53. Wip1 interacts with and dephosphorylates Mdm2 at serine 395, a site phosphorylated by the ATM kinase. SIGNOR-248324 0.674 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276515 0.332 BAMBI protein Q13145 UNIPROT DVL2 protein O14641 UNIPROT up-regulates binding 9606 2662247 t gcesareni Bmp-2 mediates phosphorylated smad1 (psmad1) or, with loss of bmprii, psmad3-dependent recruitment of disheveled (dvl) to promote rhoa-rac1 signaling necessary for motility. SIGNOR-23037 0.505 FBXL12 protein Q9NXK8 UNIPROT CAMK1 protein Q14012 UNIPROT down-regulates quantity ubiquitination 10090 BTO:0002268 23707388 t Monia Here, we show that a ubiquitin E3 ligase component, F-box protein Fbxl12, mediates CaMKI degradation via a proteasome-directed pathway leading to disruption of cyclin D1/cdk4 complex. Endogenous Fbxl12 and CaMKI interacted as demonstrated after Fbxl12 immuno-precipitation followed by immunoblot analysis with CaMKI antibodies assembly and resultantG1 arrest in lung epithelia. Fbxl12 targets CaMKI for ubiquitination. SIGNOR-261193 0.484 TKT protein P29401 UNIPROT D-xylulose 5-phosphate(2-) smallmolecule CHEBI:57737 ChEBI down-regulates quantity chemical modification 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-267085 0.8 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t lperfetto The genomic activity of ppargamma is modulated, in addition to ligand binding, by phosphorylation of a serine residue by mapks, such as extracellular signal-regulated protein kinases-1/2 (erk-1/2), or by nucleocytoplasmic compartmentalization through the erk activators mapk kinases-1/2 (mek-1/2). These mapks phosphorylate (in humans) ser 84 in the ppargamma1 and ser 114 in ppargamma2 isoform. SIGNOR-244971 0.2 RAB14 protein P61106 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-260619 0.421 CSNK2A1 protein P68400 UNIPROT CREB3 protein O43889 UNIPROT down-regulates quantity by destabilization phosphorylation Ser46 LPLSEVPsDWEVDDL -1 31941600 t miannu Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3. SIGNOR-277501 0.2 SMARCC2 protein Q8TAQ2 UNIPROT Brain-specific SWI/SNF SMARCA2 variant complex SIGNOR-C485 SIGNOR form complex binding 9606 BTO:0000142 11790558 t miannu  Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression . The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core. SIGNOR-270746 0.839 AMPK complex SIGNOR-C15 SIGNOR TSC complex SIGNOR-C101 SIGNOR up-regulates activity phosphorylation 10090 BTO:0002572 SIGNOR-C15 16959574 t lperfetto GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation SIGNOR-217749 0.472 SRC protein P12931 UNIPROT BDKRB2 protein P30411 UNIPROT up-regulates phosphorylation Tyr347 RKKSWEVyQGVCQKG 9606 16226010 t lperfetto Here we demonstrate that egf is capable of inducing src-mediated phosphorylation of the tyrosine residues 177 and 347 of bkr. Their replacement by phenylalanine led to bkr mutants which are unable to activate the camp pathway. SIGNOR-141107 0.264 PRKACA protein P17612 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates activity phosphorylation Thr130 GEKSRYEtSLNLTTK 9606 BTO:0000007 33110360 t miannu We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. SIGNOR-277536 0.2 RFC5 protein P40937 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 t lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned SIGNOR-265509 0.762 KDM6B protein O15054 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys28 LATKAARkSAPATGG 9606 24561908 t This tri-methylation is associated with the downregulation of nearby genes via the formation of heterochromatic regions. miannu Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX) and Jumonji D3 (JMJD3) as novel histone demethylases that catalyze the removal of di- and trimethyl groups on histone H3 lysine 27, thereby promoting target gene activation. SIGNOR-260018 0.2 IL17A protein Q16552 UNIPROT KLF15 protein Q9UIH9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23332504 f fspada Specifically, il-17 suppresses klf15, a pro-adipogenic tf, and enhances expression of klf2 and klf3, which are anti-adipogenic. SIGNOR-192474 0.2 PDGFRA protein P16234 UNIPROT PDGFRA protein P16234 UNIPROT up-regulates activity phosphorylation Tyr1018 RLSADSGyIIPLPDI 9823 BTO:0004007 7535778 t miannu We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF α-receptor carboxyl-terminal tail bind PLC-γ, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-γ. SIGNOR-250250 0.2 BTG2 protein P78543 UNIPROT NFE2L2 protein Q16236 UNIPROT up-regulates activity binding 9606 BTO:0000093 22493435 t miannu BTG2 stimulation of antioxidant gene expression is also NFE2L2-dependent. We further demonstrate that BTG2 is a binding partner for NFE2L2 and increases its transcriptional activity. SIGNOR-254647 0.2 estrone smallmolecule CHEBI:17263 ChEBI ESR2 protein Q92731 UNIPROT up-regulates activity chemical activation -1 9048584 t miannu In total 37 substances were tested for both ER subtypes (Fig. 3 and Table 1). In Fig. 3 several examples of typical competitor curves obtained are shown. In all cases monophasic curves were obtained for compounds with significant affinity. . The present study is the first in which the ligand binding properties of both ER subtypes are measured separately, and caution is needed when comparing RBAs from this study with the previous studies involving mixtures of ER subtypes. SIGNOR-258583 0.8 SREBF2 protein Q12772 UNIPROT PON2 protein Q15165 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19497963 f miannu UPA upregulated PON2 expression in a sterol regulatory binding protein-2 (SREBP-2)-dependent manner, since blocking SREBP-2 maturation by 4-(2-aminoethyl)-benzenesulfonyl fluoride abolished uPA-stimulation of PON2, whereas inhibition of SREBP-2 catabolism by N-acetyl-leucyl-norleucinal had an opposite effect. SIGNOR-255225 0.278 FHIT protein P49789 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18077326 f miannu In binding to the beta-catenin c-terminal domain, fhit represses transcription of target genes such as cyclin d1, axin2, mmp-14, and survivin. SIGNOR-159867 0.273 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser221 DHEKKAYsFCGTVEY 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219308 0.752 TBX5 protein Q99593 UNIPROT SNCG protein O76070 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20802524 f miannu TBX5 suppressed tumor cell proliferation and metastasis through the upregulation of cyclin-dependent kinase inhibitor 2A, metastasis suppressor 1 and downregulation of synuclein gamma and metastasis-associated protein 1 family member 2. SIGNOR-255255 0.2 glycogen smallmolecule CHEBI:28087 ChEBI alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity precursor of 9606 3346228 t Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267950 0.8 CYSLTR2 protein Q9NS75 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257140 0.368 PEX6 protein Q13608 UNIPROT PEX5 protein P50542 UNIPROT up-regulates activity binding 10029 16314507 t Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. ​(Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner. SIGNOR-253619 0.581 PIK3R1 protein P27986 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI up-regulates quantity 10116 21798082 f lperfetto Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate. (pip2). SIGNOR-175678 0.8 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser217 YTRTGSEsPKVCSDQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248553 0.336 TET2 protein Q6N021 UNIPROT WT1 protein P19544 UNIPROT up-regulates activity binding 9606 BTO:0000670;BTO:0000738 25601757 t irozzo  In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes. SIGNOR-255703 0.456 CDC42 protein P60953 UNIPROT WAS protein P42768 UNIPROT up-regulates activity binding 9606 BTO:0000132 27871158 t lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex SIGNOR-261869 0.957 ATF2 protein P15336 UNIPROT POLB protein P06746 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001025 10518804 f miannu We identified the heterodimeric transcription factor ATF2/CREB as constitutively binding to the essential cAMP response element (CRE) site within the Ca2+-regulated DNA polymerase beta promoter and contributing to the activation of this promoter. SIGNOR-253744 0.2 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 16751101 t lpetrilli Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads. SIGNOR-146922 0.613 TRIM33 protein Q9UPN9 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization binding 9606 25639486 t Luana Tumour suppressor TRIM33 targets nuclear β-catenin degradation SIGNOR-260896 0.464 5,15-Diphenyl-21H,23H-porphine chemical CID:10895852 PUBCHEM STAT3 protein P40763 UNIPROT down-regulates activity chemical inhibition 9606 26260587 t gcesareni 15-DPP is an effective STAT3 inhibitor and blocks IL10-mediated signalling in macrophages leading to altered regulation of CNV SIGNOR-238549 0.8 AR protein P10275 UNIPROT CYP7B1 protein O75881 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 16630558 f miannu DHT and overexpression of androgen receptor (AR) suppressed CYP7B1 promoter activity and CYP7B1-mediated catalysis in kidney-derived HEK293 cells. SIGNOR-253739 0.291 TGFB1 protein P01137 UNIPROT SALL2 protein Q9Y467 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 21228219 f miannu TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. SIGNOR-255427 0.2 SLC5A5 protein Q92911 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 10116 28192058 t scontino Active iodide (I-) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na+/I- symporter (NIS). In the thyroid, NIS-mediated I- uptake plays a pivotal role in thyroid hormone (TH) biosynthesis.  SIGNOR-266961 0.8 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Thr366 QSSASRKtQKKKKKK 9606 BTO:0004737 11325528 t lperfetto We found that Ebp1 was basally phosphorylated in AU565 breast cancer cells on serine/threonine residues and that this phosphorylation was enhanced by heregulin treatment. Both serine and threonine residues of a GST-Ebp1 fusion protein were phosphorylated by PKC in vitro. In vivo, we demonstrated that basal Ebp1 phosphorylation was dependent upon PKC. SIGNOR-249092 0.437 PKA proteinfamily SIGNOR-PF17 SIGNOR KCNK18 protein Q7Z418 UNIPROT down-regulates activity phosphorylation Ser252 QAMERSNsCPELVLG -1 18397886 t miannu Phosphorylation of serine 264 in mouse TRESK was required for the binding of 14-3-3η. PKA was used to phosphorylate serine 264 in our further in vitro experiments. SIGNOR-263154 0.2 NR3C1 protein P04150 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity transcriptional regulation 10116 15793248 f We show here that dexamethasone upregulates transcription and expression of the serum- and glucocorticoid-inducible kinase 1 (SGK1) in insulin-secreting cells, an effect reversed by mifepristone (RU486), an antagonist of the nuclear glucocorticoid receptor. SIGNOR-255926 0.469 TRIM37 protein O94972 UNIPROT TRIM37 protein O94972 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 14561866 t miannu In this paper, we present data showing that TRIM37, a member of the TRIM subfamily of RING finger proteins, is autoubiquitinated in a RING domain-dependent manner.  However, we feel tempted to speculate that the most likely mechanism, in which TRIM37-mediated ubiquitination could be involved, is proteasomal degradation of a target protein and, possibly, its own turnover. SIGNOR-271503 0.2 HEXIM1 protein O94992 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR down-regulates activity binding 9606 18371977 t miannu Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. The mislocalization of HEXIM1 and the increased P-TEFb-dependent transcription caused by NPMc+ suggests that the misregulated activity of PTEFb may contribute to the tumorigenesis of NPMc+ AML. SIGNOR-260135 0.734 PRKCB protein P05771 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E . SIGNOR-248946 0.352 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr575 RQSPEDVyFSKSEQL -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246031 0.652 IRX1 protein P78414 UNIPROT KDR protein P35968 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002392 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Upregulation of PTGS2, ANPEP, KDR, UGT8, INHBA, ERMAP, RALGPS1 and SPON1 was confirmed. SIGNOR-261664 0.2 olanzapine chemical CHEBI:7735 ChEBI HTR1B protein P28222 UNIPROT up-regulates activity chemical activation 10116 BTO:0001311 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258507 0.8 SRC protein P12931 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 12707358 t lperfetto These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation. SIGNOR-217442 0.381 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Thr509 PVCEVSVtPKTVTPA 9606 phosphorylation:Ser522 PASSAKTsPAKQQAP 25040932 t lperfetto Cdk5 and DYRK2 phosphorylate CRMP2 and CRMP4, respectively, priming these proteins at S522 before their subsequent phosphorylation by GSK-3b at T509, T516 and S518|e CRMP2 phosphorylation by GSK-3b disrupts its interaction with tubulin (Yamashita & Goshima, 2012), leading to growth inhibition SIGNOR-264839 0.717 SREBF1 protein P36956 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity 10090 9539737 f gcesareni Finally, we demonstrate directly that cells expressing ADD1/SREBP1 produce and secrete lipid molecule(s) that bind directly to PPARgamma, displacing the binding of radioactive thiazolidinedione ligands SIGNOR-170607 0.456 BAD protein Q92934 UNIPROT BCL2L2 protein Q92843 UNIPROT down-regulates binding 9606 15694340 t gcesareni Bad, however, bound tightly to bcl-2, bcl2l1, and bcl2l2. SIGNOR-133805 0.547 CEBPA protein P49715 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0004730 16319681 f lperfetto The transcription factor C/EBPalpha controls differentiation and proliferation in normal granulopoiesis in a stage-specific manner. Loss of C/EBPalpha function in myeloid cells in vitro and in vivo leads to a block to myeloid differentiation similar to that which is observed in malignant cells from patients with acute myeloid leukemia. The finding of C/EBPalpha alterations in subgroups of acute myeloid leukemia patients suggests a direct link between critically decreased C/EBPalpha function and the development of the disorder. SIGNOR-249632 0.7 IFITM3 protein Q01628 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates activity binding 10090 32879487 t miannu IFITM3 directly binds to γ-secretase. IFITM3 KO reduced γ-secretase activity for both Aβ40 and Aβ42 cleavages as compared to the EV (empty vector guide RNA) cell line by 36% and 27%, respectively (Fig. 2d, bar 1 and 3). SIGNOR-266303 0.2 FBXL7 protein Q9UJT9 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002268 25778398 t miannu Fbxl7 targets survivin for polyubiquitylation and proteasomal degradation.these data suggest that the Skp1·Cul1·F-box protein complex subunit Fbxl7 modulates mitochondrial function by controlling the cellular abundance of survivin. These results suggest that both Lys-90 and Lys-91 are critical for Fbxl7-mediated polyubiquitylation. SIGNOR-272436 0.309 MYD88 protein Q99836 UNIPROT DHX9 protein Q08211 UNIPROT up-regulates activity binding 9606 BTO:0002042 20696886 t miannu We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing. SIGNOR-260955 0.478 adrenaline smallmolecule CHEBI:33568 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257877 0.8 PHLPP1 protein O60346 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 18162466 t These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation.|n contrast, results from siRNA depletion and overexpression experiments indicate that the hydrophobic motif site (Ser660) is regulated by PHLPP isoforms, SIGNOR-248326 0.344 ENO2 protein P09104 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266525 0.8 S1PR2 protein O95136 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257215 0.517 RPS6KA4 protein O75676 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 BTO:0000452 12773393 t lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin. SIGNOR-249216 0.339 MYO3A protein Q8NEV4 UNIPROT MYO3A protein Q8NEV4 UNIPROT down-regulates activity phosphorylation Thr919 TRHARETtNMKTQTV 9534 24214986 t Manara We demonstrate by mass spectrometry that Thr-178 and Thr-184 in the kinase domain activation loop and two threonines in the loop 2 region of the motor domain are autophosphorylated (Thr-908 and Thr-919) | Thus, the phosphorylation sites in loop 2 (Thr-908 and Thr-919) are likely responsible for the down-regulation of MYO3A motor activity observed in our current and previous work SIGNOR-260924 0.2 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2L5 protein A0A1B0GUS4 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271331 0.2 DNMT1 protein P26358 UNIPROT IL32 protein P24001 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000018 20889550 f lperfetto A virus or dsRNA in human PBMCs from healthy volunteers. We demonstrate that the NF-κB and CREB pathways play key roles in the activation of IL-32 production in response to influenza virus infection in A549 human lung epithelial cells.|Overexpression assays combined with RNA interference show that DNA methyltransferases DNMT1 and DNMT3b are critical for IL32 promoter methylation and gene silencing before viral infection. SIGNOR-254126 0.346 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 15241418 t lperfetto We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity SIGNOR-232134 0.737 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 BTO:0000567 8621729 t lperfetto Our data demonstrated that a-raf is, indeed, a mek1 activator and may play a role in growth factor signaling. SIGNOR-244813 0.747 MARCHF9 protein Q86YJ5 UNIPROT SLAMF1 protein Q13291 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271537 0.2 C8B protein P07358 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263444 0.582 GNAS protein P63092 UNIPROT SRC protein P12931 UNIPROT up-regulates activity binding -1 11007482 t Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src SIGNOR-256527 0.497 PPARGC1A protein Q9UBK2 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 23217713 t miannu PGC-1 alpha specifically induces IGF1 and represses myostatin, and expression of PGC-1a 4 in vitro and in vivo induces robust skeletal muscle hypertrophy SIGNOR-256152 0.345 PRKCB protein P05771 UNIPROT TRPV6 protein Q9H1D0 UNIPROT down-regulates activity phosphorylation Ser184 LARRASVsARATGTA -1 19805577 t miannu  This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload. SIGNOR-276265 0.2 FOXL2 protein P58012 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000975 16153597 f miannu We observed that foxl2 induces apoptosis in the ovarian cells unveiling a novel function of foxl2 SIGNOR-140391 0.7 NCOA1 protein Q15788 UNIPROT ALDOB protein P05062 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255061 0.2 Caspase 3 complex complex SIGNOR-C221 SIGNOR Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 25787076 f miannu The UPS by itself degrades actomyosin and myofibrillar proteins slowly, but when caspase-3 is activated, it cleaves actomyosin and the myofibrillar proteins to provide substrates for degradation in the UPS . Caspase-3 also can cleave specific subunits of the 19 S proteasome particle, which stimulates the proteolytic activity of the 26S proteasome[...] These results indicate that caspase-3 participates in the muscle proteolysis that is present in tumor-bearing mice SIGNOR-256475 0.7 MBL2 protein P11226 UNIPROT MASP1 protein P48740 UNIPROT up-regulates activity binding 9606 BTO:0000392 9087411 t lperfetto The results (Fig. 3A) show that the anti-MBL antibody, in addition to binding MBL captures both MASP-1 and MASP-2|Our results emphasize the similarity between complement activation through the MBL, or 'MBLectin' pathway of the innate immune system and the classical pathway of complement activation (Fig. 5). SIGNOR-263414 0.746 PTPN22 protein Q9Y2R2 UNIPROT LCK protein P06239 UNIPROT down-regulates activity dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 16461343 t In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22. SIGNOR-248836 0.745 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000527 21419810 t lperfetto In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer SIGNOR-172890 0.322 CSNK2A1 protein P68400 UNIPROT HSP90AB1 protein P08238 UNIPROT down-regulates phosphorylation Ser255 PKIEDVGsDEEDDSG 9606 18591256 t gcesareni Although the kinase responsible for hsp90? Phosphorylation in vivo is not known, it has been reported that ck2 can phosphorylate these sites in vitro (24). Thus, we prephosphorylated recombinant hsp90? With ck2 before addition to the reaction. Remarkably, hsp90? Phosphorylation greatly reduced its ability to inhibit apaf-1 oligomerization and caspase-9 recruitment (fig. 5b). These results indicate that the phosphorylation status of hsp90? Significantly impacts its ability to inhibit apoptosome formation. SIGNOR-179264 0.337 CDK1 protein P06493 UNIPROT EIF4G2 protein P78344 UNIPROT up-regulates activity phosphorylation Thr508 AQPPRTQtPPLGQTP 9606 BTO:0000007 29530922 t miannu To test whether CDK1 phosphorylates T508, Flag-DAP5 was purified from dox-induced HEK293 cells and incubated with active recombinant JNK2 or CDK1 in the presence of ATP (Fig. 3G). DAP5(T508) was phosphorylated only upon incubation with CDK1 (Fig. 3G). SIGNOR-266387 0.343 CDK5 protein Q00535 UNIPROT ADD1 protein P35611 UNIPROT up-regulates activity phosphorylation Thr724 KKKKKFRtPSFLKKS 9606 BTO:0000815 31548578 t miannu We found that Cdk5 directly phosphorylated the actin-binding protein adducin-1 (ADD1) at T724 in vitro and in intact cells. SIGNOR-277487 0.257 TCF3 protein P15923 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000150 26212009 t lperfetto The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial-mesenchymal transition (EMT). |In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation SIGNOR-275654 0.314 SNAI2 protein O43623 UNIPROT CD44 protein P16070 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 20509143 f miannu SLUG up-regulation engenders breast cancer cells with stem cell-like properties including enhanced expression of CD44 and Jagged-1 in conjunction with estrogen receptor alpha down-regulation, growth as mammospheres, and extracellular matrix invasiveness. SIGNOR-255153 0.415 METTL3 protein Q86U44 UNIPROT EGFR protein P00533 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007;BTO:0000567 27117702 t miannu Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells.  SIGNOR-265954 0.336 BTG2 protein P78543 UNIPROT CAT protein P04040 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 22493435 f miannu BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2 SIGNOR-254648 0.2 PRKCB protein P05771 UNIPROT DAB2 protein P98082 UNIPROT unknown phosphorylation Ser24 QAAPKAPsKKEKKKG 9534 BTO:0004055 10542228 t lperfetto We have mapped the TPA-induced DOC-2/DAB2 protein phosphorylation site to Ser24, which appears to modulate the DOC-2/DAB2 inhibition of AP-1 transcription activity. Results indicate that phosphorylation of Ser24 is mediated by PKCbetaII, PKC_, and PKCdelta, but not CKII. This suggests that the PKC phosphorylation of Ser24 in DOC-2/DAB2 may be an underlying mechanisms for its tumor-suppressive function. SIGNOR-249026 0.299 DGC complex SIGNOR-C217 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626543 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265442 0.2 BAX protein Q07812 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 23567751 f miannu The mitochondrial pathway of apoptosis proceeds when the outer mitochondrial membrane (OMM) is compromised by the pro-apoptotic BCL-2 family members, BAK and BAX. Once activated, BAK and BAX form proteolipid pores in the OMM leading to mitochondrial outer membrane permeabilization (MOMP), and the release of inner membrane space proteins, such as cytochrome c, which promotes caspase activation. SIGNOR-261494 0.7 HCRTR2 protein O43614 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257008 0.254 lapatinib chemical CHEBI:49603 ChEBI KIT protein P10721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001949 21443688 t Luana YN968D1 potently suppressed the kinase activities of VEGFR-2, c-kit and c-src, and inhibited cellular phosphorylation of VEGFR-2, c-kit and PDGFRβ. SIGNOR-257901 0.8 DRD5 protein P21918 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256771 0.468 TNFRSF17 protein Q02223 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 10903733 f miannu Bcma overexpression activates elk-1 nuclear factor SIGNOR-79486 0.2 MAPK11 protein Q15759 UNIPROT PIAS2 protein O75928 UNIPROT up-regulates activity phosphorylation Ser116 VTPHSPSsPVGSVLL 9606 BTO:0000007 16713578 t miannu The switch between the coactivating and inhibitory actions of PIASxα is controlled, at least in part, through PIASxα phosphorylation. PIASxα is itself phosphorylated by p38 in vitro and in vivo in response to the activation of stress signaling pathways (Figure 2, Figure 3, Figure 4). We identify Ser113 and Ser 116 as two residues that are phosphorylated by p38 and have important functional roles SIGNOR-262947 0.265 RUNX1 protein Q01196 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR down-regulates activity binding 9606 22021368 t apalma We found that AML1 inhibits NF-κB signaling through interaction with IκB kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-κB signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-κB signaling SIGNOR-255690 0.2 LRIG1 protein Q96JA1 UNIPROT EGFR protein P00533 UNIPROT down-regulates binding 9606 BTO:0001253 15282549 t gcesareni Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation SIGNOR-127304 0.73 GAD2 protein Q05329 UNIPROT gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI up-regulates quantity chemical modification 9606 32041144 t miannu Glutamate decarboxylase (GAD; EC 4.1.1.15) is a unique pyridoxal 5-phosphate (PLP)-dependent enzyme that specifically catalyzes the decarboxylation of L-glutamic acid to produce Œ≥-aminobutyric acid (GABA), which exhibits several well-known physiological functions. SIGNOR-267555 0.8 ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 t inferred from 70% family members gcesareni Like erbb1, erbb4 recruits grb2, shc and stat5. SIGNOR-269962 0.2 NF2 protein P35240 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR up-regulates activity binding 9606 33058421 t miannu The Hippo pathway tumor suppressor Merlin/NF2 is known to be regulated by phosphorylation. Here, the E3 ubiquitin ligase NEDD4L is shown to promote Hippo pathway activation via ubiquitination of Merlin. SIGNOR-263663 0.751 PARP1 protein P09874 UNIPROT CHD2 protein O14647 UNIPROT up-regulates quantity binding 9606 26895424 t miannu Non-homologous end-joining (NHEJ) is the dominant DSB repair pathway in human cells, but our understanding of how it operates in chromatin is limited. Here, we define a mechanism that plays a crucial role in regulating NHEJ in chromatin. This mechanism is initiated by DNA damage-associated poly(ADP-ribose) polymerase 1 (PARP1), which recruits the chromatin remodeler CHD2 through a poly(ADP-ribose)-binding domain. CHD2 in turn triggers rapid chromatin expansion and the deposition of histone variant H3.3 at sites of DNA damage. SIGNOR-264526 0.2 TNFSF11 protein O14788 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT up-regulates activity binding 9606 12897775 t miannu RANKL, a member of the tumour necrosis factor superfamily, is most abundantly expressed as a cell-surface protein by bone-marrow stromal cells. It interacts with its receptor RANK (which is encoded by Tnfrsf11a) on macrophages and mature osteoclasts. SIGNOR-253042 0.894 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT down-regulates activity phosphorylation Ser163 KENPRNFsDNQLQEG 21577206 t lperfetto This newly identified oncogene–tumor suppressor cascade, where oncogenic PFTK1 inactivates a tumor suppressor gene TAGLN2 via phosphorylation|. Our data therefore underline much importance for S83 and S163 residues on TAGLN2 in its actin-binding capacity. SIGNOR-265105 0.319 CDK2 protein P24941 UNIPROT RNF4 protein P78317 UNIPROT up-regulates activity phosphorylation Thr112 DVYVTTHtPRNARDE 9606 BTO:0002181 25948581 t miannu Here we reported that CDK2 could phosphorylate RNF4 on T26 and T112 and enhance RNF4 E3 ligase activity, which is important for MDC1 degradation and proper HR repair during S phase.  SIGNOR-276901 0.2 CKM complex complex SIGNOR-C406 SIGNOR CCNH protein P51946 UNIPROT down-regulates activity phosphorylation Ser5 sSQKRHWT 9606 10993082 t gcesareni Here we show that cdk8/cyclin c can regulate transcription by targeting the cdk7/cyclin h subunits of the general transcription initiation factor iih (tfiih). cdk8 phosphorylates mammalian cyclin h in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of tfiih to activate transcription and its ctd kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin h in vivo has a dominant-negative effect on cell growth. SIGNOR-273139 0.444 ADX-47273 chemical CID:11383075 PUBCHEM MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates chemical activation 9606 Other t Selleck|inferred from family member gcesareni SIGNOR-270276 0.8 MAPK11 protein Q15759 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 17254968 t gcesareni We show that prak activates p53 by direct phosphorylation. SIGNOR-152843 0.6 CPT1A protein P50416 UNIPROT coenzyme A(4-) smallmolecule CHEBI:57287 ChEBI up-regulates quantity chemical modification 9606 14517221 t miannu Carnitine palmitoyltransferase 1A (CPT1A) is the key regulatory enzyme of hepatic long-chain fatty acid beta-oxidation. The first component of this system is CPT1, an integral mitochondrial outer membrane protein, which catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA, the first intermediate in fatty acid biosynthesis. Three CPT1 isoforms with various tissue distribution and encoded by distinct genes have been identified (1., 2.): a liver (CPT1A or L-CPT1) (8.), a muscle (CPT1B or M-CPT1) (9.), and a brain isoform (CPT1C). SIGNOR-267132 0.8 MKNK2 protein Q9HBH9 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 9606 17724079 t lperfetto Inhibition of mammalian target of rapamycin induces phosphatidylinositol 3-kinase-dependent and mnk-mediated eukaryotic translation initiation factor 4e phosphorylation.Therefore, eif4e is considered a survival protein involved in cell cycle progression, cell transformation, and apoptotic resistance. Phosphorylation of eif4e (usually at ser209) increases its binding affinity for the cap of mrna and may also favor its entry into initiation complexes. SIGNOR-157537 0.571 NODAL protein Q96S42 UNIPROT ACVR1C protein Q8NER5 UNIPROT up-regulates activity binding 9606 BTO:0004094 15531507 t Indirect_regulation of expression miannu Human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. activation of the Nodal-ALK7 signaling pathway leads to induction of apoptosis and inhibition of cell proliferation. SIGNOR-251936 0.627 NCOA1 protein Q15788 UNIPROT APOA5 protein Q6Q788 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255064 0.391 SNRNP27 protein Q8WVK2 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270642 0.434 TP73 protein O15350 UNIPROT PMAIP1 protein Q13794 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17700533 f miannu Dissociation of p73 and HDM2 leads to increased p73 transcriptional activity with upregulation of p73 target genes noxa, puma and p21, as well as enhanced apoptosis. SIGNOR-255469 0.325 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252832 0.909 UBE3A protein Q05086 UNIPROT LAMTOR1 protein Q6IAA8 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 30020076 t Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity SIGNOR-256145 0.2 zotepine chemical CHEBI:32316 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 BTO:0000331 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258552 0.8 UBA6 protein A0AVT1 UNIPROT Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR form complex binding 9606 24816100 t miannu The activation of ubiquitin by the ubiquitin-activating enzyme Uba1 (E1) constitutes the first step in the covalent modification of target proteins with ubiquitin. This activation is a three-step process in which ubiquitin is adenylated at its C-terminal glycine, followed by the covalent attachment of ubiquitin to a catalytic cysteine residue of Uba1 and the subsequent adenylation of a second ubiquitin. SIGNOR-270835 0.2 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161597 0.597 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT up-regulates activity phosphorylation Tyr418 LSGEDDAyCTFPSRD 9534 BTO:0000298 8700888 t In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc. SIGNOR-251340 0.622 STRN protein O43815 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates activity binding 10090 BTO:0000938 29802198 t miannu The striatin family proteins interact with the structural (A) and catalytic (C) subunits of the protein phosphatase, PP2A, and are also termed the B‴ family of PP2A subunits (4). Within heterotrimeric PP2A complexes, striatins function as one of many regulatory B subunits thought to be responsible for substrate selection and localization of PP2A isoforms SIGNOR-261700 0.605 DLGAP4 protein Q9Y2H0 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 9115257 t miannu SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area. SIGNOR-264212 0.798 PRKCA protein P17252 UNIPROT KCNE1 protein P15382 UNIPROT down-regulates activity phosphorylation Ser102 VQARVLEsYRSCYVV -1 1553557 t lperfetto Inhibition of the current was not seen in channels in which Ser103 was replaced by Ala, although other properties of the current were unchanged. These results indicate that inhibition of the potassium current results from direct phosphorylation of the channel subunit protein at Ser103. SIGNOR-248852 0.309 CSNK2A1 protein P68400 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250935 0.309 MVD protein P53602 UNIPROT NRAS protein P01111 UNIPROT up-regulates quantity by stabilization 9534 12646231 f miannu An overexpression of mot-2 resulted in reduced level of Ras and phosphorylated ERK2. These were rescued by co-expression of MPD from an exogenous promoter demonstrating a functional link between mot-2, MPD, and Ras. Ras and its oncogenic forms act as key players in controlling proliferation of normal and cancerous cells. Assigning mot-2 upstream of p21Ras offers an important mechanism for influence over cell proliferation. Therefore, we ra tionaled to investigate if overexpression of MPD could affect the steady state levels of Ras by affecting its prenylationTransient transfections of MPD-myc in COS 7 cells resulted in higher stable levels of Ras as compared to the untransfected cells (Fig. 3A, compare lanes 4 and 8 and Fig. 3B) SIGNOR-265889 0.2 CPSF4 protein O95639 UNIPROT CPSF complex complex SIGNOR-C53 SIGNOR form complex binding 9606 BTO:0000007 19224921 t lperfetto The CPSF complex consists of five subunits, named CPSF160, CPSF100, Fip1, CPSF73, and CPSF30. SIGNOR-268334 0.915 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR1A protein P37288 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257461 0.8 PIM proteinfamily SIGNOR-PF34 SIGNOR FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 18593906 t fspada Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42). SIGNOR-259428 0.2 TGFB1 protein P01137 UNIPROT SLC5A5 protein Q92911 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 14623893 f miannu The sodium/iodide symporter mediates the active transport of iodide in thyroid follicular cells. A number of agents regulate NIS expression; among these, TGF-β is a potent inhibitor of both iodide uptake and NIS gene expression SIGNOR-259912 0.2 CDK1 protein P06493 UNIPROT NME1 protein P15531 UNIPROT up-regulates phosphorylation Ser120 GRNIIHGsDSVESAE 9606 SIGNOR-C17 18234856 t gcesareni Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates. SIGNOR-160493 0.268 Guanfacine chemical CHEBI:5558 ChEBI ADRA2B protein P18089 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258920 0.8 TACR3 protein P29371 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256937 0.2 TRAF6 protein Q9Y4K3 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity ubiquitination Lys34 NFEEIDYkEIEVEEV 9606 18758450 t lperfetto Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6. SIGNOR-236071 0.89 ISYNA1 protein Q9NPH2 UNIPROT 1D-myo-inositol 1-phosphate smallmolecule CHEBI:18297 ChEBI up-regulates quantity chemical modification 9606 15464731 t lperfetto Human myo-inositol 1-phosphate synthase (IP synthase; E.C. 5.5.1.4), encoded by ISYNA1, catalyzes the de novo synthesis of inositol 1-phosphate from glucose 6-phosphate. SIGNOR-254131 0.8 UHMK1 protein Q8TAS1 UNIPROT CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 12093740 t lperfetto Hkis is a nuclear protein that binds the c-terminal domain of p27(kip1) and phosphorylates it on s10 in vitro and in vivo, promoting its nuclear export to the cytoplasm.Phosphorylation at serine 10, a major phosphorylation site of p27(kip1), increases its protein stability SIGNOR-90274 0.373 FLI1 protein Q01543 UNIPROT KLF1 protein Q13351 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 t irozzo FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets SIGNOR-256044 0.375 TSHR protein P16473 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0001379 32698392 t scontino Activation of TSHR and the linked signaling cascades through binding of circulating TSH plays a pivotal role in controlling thyrocyte growth and in regulating thyroid hormone production/secretion. This is executed through switching on different subtypes of G proteins and signaling pathways. Among them, the Gαs- and Gαq-induced cascades are of the greatest importance, as they have been tightly linked to specific intracellular signal transductions downstream of TSHR in response to stimulations SIGNOR-267138 0.552 PAK1 protein Q13153 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Ser299 KNLGYRDsGYYWEVP 9606 BTO:0000848 15710605 t lperfetto Phosphorylation of endogenous a-raf, b-raf and raf-1 on the homologous pak phosphorylation sites (serine 299, serine 445, or serine 338 respectively)we found that the phosphorylation of a-raf on serine 299 was also stimulated by egf, although the duration of phosphorylation on this site was much shorter than for raf-1. Thus, by analogy with raf-1, phosphorylation of this site may play an important role in the a-raf activation mechanism. SIGNOR-236342 0.269 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242599 0.8 PTPN1 protein P18031 UNIPROT LAT protein O43561 UNIPROT down-regulates dephosphorylation 9606 12857726 t gcesareni Our results demonstrate that ptp1b plays an important role in the integrin-mediated dephosphorylation of lat in human platelets and is involved in the control of irreversible aggregation upon fcgammariia stimulation. SIGNOR-103599 0.49 PRKACA protein P17612 UNIPROT APC protein P25054 UNIPROT down-regulates activity phosphorylation Ser2054 MPKKKKPsRLKGDNE 9606 11050185 t miannu Changing a serine residue (Ser(2054)) to aspartic acid mutated the potential protein kinase A site adjacent to NLS2(APC), resulting in both inhibition of the NLS2(APC)-mediated nuclear import of a chimeric beta-galactosidase fusion protein and a reduction of full-length APC nuclear localization. SIGNOR-250335 0.309 EEF1D protein P29692 UNIPROT EEF1B complex complex SIGNOR-C460 SIGNOR form complex binding 9606 23699257 t lperfetto An inactive eEF1A-GDP moiety leaves the ribosome and must be recycled to eEF1A-GTP before binding another aa-tRNA. This GTP exchange process is the function of the nucleotide exchange factor eEF1B complex, which exchanges GDP for GTP to regenerate active eEF1A. The requirement for a guanine nucleotide exchange factor, the eEF1B complex, which in metazoans is composed of the subunits α, δ, and γ (also called eEF1B, eEF1D, and eEF1G, respectively) SIGNOR-269392 0.817 bethanechol chemical CHEBI:3084 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258623 0.8 PPP5C protein P53041 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates activity dephosphorylation Ser211 PGKETNEsPWRSDLL 9606 BTO:0000093 19586900 t Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription. SIGNOR-248538 0.529 PDGFRA protein P16234 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni Crk can interact directly with tyrosine kinase receptors (for example pdgfr?) And can transmit signals downstream SIGNOR-185664 0.636 PRKG1 protein Q13976 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Thr143 RCFTRKYtLPPGVDP 9606 19593530 t 11383510: to test the hypothesis that cGK could inhibit platelet aggregation by phosphorylating Hsp27 and interfering with the MAPKAP kinase phosphorylation of Hsp27, the known MAPKAP kinase 2-phosphorylation sites (Ser15, Ser78, and Ser82) as well as Thr143 were replaced by negatively charged amino acids, which are considered to mimic phosphate groups, and tested in actin polymerization experiments. Mimicry at the MAPKAP kinase 2 phosphorylation sites led to mutants with a stimulating effect on actin polymerization lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186792 0.276 AKT2 protein P31751 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates activity phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 t lperfetto Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14-3-3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function akt phosphorylates members of the foxo factors (forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localisation. In particular, akt phosphorylates foxo1 on thr24, ser256 and ser319. Foxo 3alfa and foxo4 are phosphorylated on equivalent sites. SIGNOR-236675 0.746 TGFB1 protein P01137 UNIPROT TFAP4 protein Q01664 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000452 21228219 f miannu TGFβ effectively inhibits expression of SALL2 and its regulator AP4 when added to quiescent fibroblasts. SIGNOR-255428 0.2 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207672 0.8 PRKACA protein P17612 UNIPROT ABCA1 protein O95477 UNIPROT up-regulates activity phosphorylation Ser1042 GGMQRKLsVALAFVG 10090 BTO:0000801 12196520 t miannu Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins. SIGNOR-250326 0.494 WNT5B protein Q9H1J7 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 BTO:0000551;BTO:0000848 16273260 t gcesareni Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors. SIGNOR-141440 0.628 SAAL1 protein Q96ER3 UNIPROT CDK6 protein Q00534 UNIPROT up-regulates quantity by expression post transcriptional regulation 9606 30513680 f Giorgia This study was performed to elucidate the molecular function of the synoviocyte proliferation-associated in collagen-induced arthritis (CIA) 1/serum amyloid A-like 1 (SPACIA1/SAAL1) in mice CIA, an animal model of rheumatoid arthritis (RA), and human RA-synovial fibroblasts (RASFs). Expression levels of cdk6, but not cdk4, which are D-type cyclin partners, were downregulated by SPACIA1/SAAL1 siRNA at the post-transcriptional level. The CDK6, expression of which is up-regulated by the SPACIA1/SAAL1 expression, might be a critical factor in the exacerbation of CIA. SIGNOR-260386 0.2 EPX protein P11678 UNIPROT RNASE3 protein P12724 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 t miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. SIGNOR-261705 0.487 ESR1 protein P03372 UNIPROT PGR protein P06401 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11000528 f gcesareni We observed the transcriptional inhibition of the progesterone and glucocorticoid receptors when eralpha was cotransfected SIGNOR-82161 0.614 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser710 GEKSFRRsVVGTPAY 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275957 0.2 EDA protein Q92838 UNIPROT EDA2R protein Q9HAV5 UNIPROT up-regulates binding 9606 BTO:0001253 12084975 t gcesareni Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed. SIGNOR-90040 0.673 RAP1GDS1 protein P52306 UNIPROT RHOB protein P62745 UNIPROT up-regulates binding 9606 21242305 t miannu Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob SIGNOR-171615 0.281 STAT1 protein P42224 UNIPROT STAT1/STAT3 complex SIGNOR-C118 SIGNOR form complex binding 10090 BTO:0000667 15284024 t lperfetto Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. SIGNOR-235661 0.603 Macropinosomes formation phenotype SIGNOR-PH227 SIGNOR Early macropinosomes phenotype SIGNOR-PH228 SIGNOR up-regulates 9606 33722976 t miannu Completion of macropinosome formation requires membrane fusion and is followed by maturation of the resulting vacuole, which proceeds to merge with endosomes and, ultimately, lysosomes.  SIGNOR-277775 0.7 PRKD1 protein Q15139 UNIPROT RTKN protein Q9BST9 UNIPROT up-regulates activity phosphorylation Ser448 QALAKQGsLYHEMAI 22228765 t Phosphosite positions are derived from Figure 2 lperfetto Here, we show that rhotekin, an effector of RhoA GTPase, is a novel substrate of PKD. We identified Ser-435 in rhotekin as the potential site targeted by PKD in vivo. Expression of a phosphomimetic S435E rhotekin mutant resulted in an increase of endogenous active RhoA GTPase levels. Phosphorylation of rhotekin by PKD2 modulates the anchoring of the RhoA in the plasma membrane. SIGNOR-275511 0.361 abarelix chemical CHEBI:337298 ChEBI GNRHR protein P30968 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001033 22416801 t miannu Two GnRH antagonists are currently available: abarelix and degarelix. SIGNOR-259159 0.8 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser282 EGRGEVGsAGDMRAA 9606 BTO:0000150;BTO:0000567 20043841 t lperfetto Additionally protein kinase ck2 was identified as a kinase that phosphorylated eralpha at s282 and s559 s282 and s559 represent the second and third sites of er_ regulation by ck2. Remarkably, mutation of s282 or s559 to alanine resulted in near opposite functional effects on er_ as compared to mutation of s167 to alanine. Er_ ligand independent transcriptional activity was markedly enhanced upon mutation of s282 and s559 to alanine SIGNOR-162653 0.247 Pyridostigmine chemical CHEBI:8665 ChEBI ACHE protein P22303 UNIPROT down-regulates activity chemical inhibition -1 20627738 t Luana The compounds 3-[(dimethylamino)carboxyl]oxy]-N,N,N-trimethylammonium methyl sulfate, better known as neostigmine methyl sulfate (3),1 and 3-[(dimethylcarbamoyl)oxy]-1-methylpyridinium bromide, pyridostigmine bromide (4)2 (Figure 1) are well known peripheral cholinesterase inhibitors  SIGNOR-257879 0.8 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Thr373 VNVIPPHtPVRTVMN 9606 1756735 t lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21564 0.68 DUSP2 protein Q05923 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 8626452 t fstefani Pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively. SIGNOR-40915 0.739 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation Thr526 GEAGGPLtPRRVSSD 9606 7588608 t lperfetto Consistent with the in vivo phosphorylation and inactivation by ras, erf is efficiently phosphorylated in vitro by erk2 and cdc2/cyclin b kinases, at sites similar to those detected in vivo. Furthermore, a single mutation at position 526 results in the loss of a specific phosphopeptide both in in vivo and in vitro (by erk2) labeling. Substitution of thr526 for glutamic acid also decreases the repression ability of erf SIGNOR-29505 0.585 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) smallmolecule CHEBI:60110 ChEBI phosphatidylglycerol(1-) smallmolecule CHEBI:60523 ChEBI up-regulates quantity precursor of 10090 21641550 t lperfetto PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. SIGNOR-267027 0.8 ALG1 protein Q9BT22 UNIPROT alpha-D-Man-(1->2)-alpha-D-Man-(1->2)-alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-alpha-D-GlcNAc(PP-Dol) smallmolecule CHEBI:133994 ChEBI up-regulates quantity chemical modification 9606 28575298 t lperfetto The biosynthesis of eukaryotic lipid-linked oligosaccharides (LLOs) that act as donor substrates in eukaryotic protein N-glycosylation starts on the cytoplasmic side of the endoplasmic reticulum and includes the sequential addition of five mannose units to dolichol-pyrophosphate-GlcNAc2. These reactions are catalyzed by the Alg1, Alg2 and Alg11 gene products and yield Dol-PP-GlcNAc2Man5, an LLO intermediate that is subsequently flipped to the lumen of the endoplasmic reticulum. SIGNOR-260418 0.8 CHEK2 protein O96017 UNIPROT CDC25C protein P30307 UNIPROT down-regulates activity phosphorylation Ser216 SGLYRSPsMPENLNR 9606 12835754 t lperfetto Activated chk2 in turn phosphorylates cdc25c at serine-216 contributing to the g2/m checkpoints. Cds1 phosphorylates and inactivates cdc25 in vitro|CDC25C is phosphorylated on Ser 216 throughout interphase, but not in mitosis. This creates a binding site for 14‐3‐3 proteins | It has been suggested that 14‐3‐3 protein binding is responsible for retaining Cdc25C in the cytoplasm during interphase, thereby contributing to the prevention of premature initiation of mitotic events SIGNOR-102779 0.854 paliperidone chemical CHEBI:82978 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258563 0.8 NFE2 protein Q16621 UNIPROT HBG1 protein P69891 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000426 16287851 f Regulation of expression miannu NF-E2 is a transcription activator for the regulation of a number of erythroid- and megakaryocytic lineage-specific genes. Here we present evidence that the large subunit of mammalian NF-E2, p45, is sumoylated in vivo in human erythroid K562 cells. we demonstrated by stable transfection assay that only the wild-type p45, but not its mutant form p45 (K368R), could efficiently rescue β-globin gene expression in the p45-null, erythroid cell line CB3. These data together point to a model of mammalian β-like globin gene activation by sumoylated p45/NF-E2 in erythroid cells. SIGNOR-251841 0.516 MAPK1 protein P28482 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates phosphorylation Ser643 KILIASPsPTHIHKE 9606 BTO:0000567 18519666 t lperfetto We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_ SIGNOR-178727 0.578 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr980 YASVNPEyFSAADVY -1 7493944 t lperfetto The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinase. We mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain. SIGNOR-246256 0.2 NANOG protein Q9H9S0 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 16153702 f flangone Our results suggest that OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal by activating their own genes and genes encoding components of key signaling pathways and by repressing genes that are key to developmental processes. SIGNOR-242076 0.7 BLOC-1 complex SIGNOR-C381 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 BTO:0000847 22203680 f lperfetto Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes SIGNOR-265939 0.7 LRRK2 protein Q5S007 UNIPROT DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Thr595 NWRGMLKtSKAEELL 9606 BTO:0002181 23813973 t miannu LRRK2 G2019S directly bound to and phosphorylated Drp1 at Threonine595, whereas P110 treatment abolished this phosphorylation.Threonine595 phosphorylation of Drp1 by LRRK2 G2019S is required for Drp1-mediated mitochondrial fragmentation and excessive autophagy SIGNOR-276495 0.579 HDAC4 protein P56524 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 9606 BTO:0000887 10737771 t gcesareni We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2. SIGNOR-76231 0.574 BLOC1S5 protein Q8TDH9 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR form complex binding 9606 22203680 t lperfetto We show that BLOC-1 is an elongated complex that contains one copy each of the eight subunits pallidin, Cappuccino, dysbindin, Snapin, Muted, BLOS1, BLOS2, and BLOS3. The complex appears as a linear chain of eight globular domains, ∼300 A long and ∼30 A in diameter. SIGNOR-265938 0.685 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257966 0.8 ARAP3 protein Q8WWN8 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260457 0.508 UNII-XH2662798I chemical CID:16156006 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 20068082 t gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation, regulated by wee1- and myt1-mediated phosphorylation and cdc25c-mediated dephosphorylation. Cdc25a may also be involved in cdk1 dephosphorylation in the g2/m-phase checkpoint. SIGNOR-163127 0.8 TCF4 protein P15884 UNIPROT SSTR2 protein P30874 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 10207097 t Luana Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain. SIGNOR-261618 0.363 ARAP1 protein Q96P48 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260451 0.44 KLF11 protein O14901 UNIPROT SIN3A protein Q96ST3 UNIPROT up-regulates activity binding 10029 BTO:0000246 11438660 t miannu detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A. SIGNOR-222344 0.495 NARS2 protein Q96I59 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270463 0.8 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates activity dephosphorylation Tyr15 EKIGEGTyGVVYKAR 9606 10454565 t The phosphatase activity of Cdc25A is necessary for Cdk2 activation, most likely due to dephosphorylation on Tyr-15 and Thr-14 of Cdk2. SIGNOR-248482 0.827 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR HDAC1 protein Q13547 UNIPROT up-regulates activity binding 9606 BTO:0000007 28630438 t miannu NUP98-HOXA9 has an activator-repressor role in transcriptional regulation driven by p300 and HDAC1 interactions. The chromosomal translocation t(7;11)(p15, p15), encoding the fusion protein NUP98-HOXA9 (NHA9), is a rare poor risk cytogenetic event in AML associated with a particularly poor prognosis.In summary, NHA9 deregulates the expression of key leukemic genes, including MEIS1-HOXA9-PBX3 complex, through the enhancer binding and the direct interaction of the fusion protein with HDAC and p300 transcriptional regulators. SIGNOR-261498 0.2 RPL27A protein P46776 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262473 0.855 GSK3B protein P49841 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1359 VPRPHVQsVLLTPQD 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276263 0.357 FYN protein P06241 UNIPROT CD79B protein P40259 UNIPROT up-regulates activity phosphorylation Tyr196 GMEEDHTyEGLDIDQ -1 9531288 t CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b SIGNOR-251154 0.664 TNFRSF21 protein O75509 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR down-regulates 9606 32454942 f miannu Further, data from our laboratories indicate that selective agonism of TNFR2 rescues neurons from oxidative stress-induced cell death [160] and excitotoxic cell death [161, 162]. Similarly, TNFR2 activation induces expression of antiapoptotic and detoxifying proteins and protects OPCs against oxidative stress. SIGNOR-263831 0.7 SRC protein P12931 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir. SIGNOR-78706 0.454 DEAF1 protein O75398 UNIPROT RAC3 protein P60763 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001939 18826651 t Gianni Affymetrix gene profiling studies revealed Rac3 as a potential target gene and quantitative RT-PCR analysis confirmed that Rac3 was upregulated by Deaf-1 in immortalized mouse mammary epithelial cells. SIGNOR-269059 0.2 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190206 0.8 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164416 0.632 ACAN protein P16112 UNIPROT A5/b1 integrin complex SIGNOR-C163 SIGNOR up-regulates activity binding 9606 BTO:0003858 16051604 t lperfetto Cartilage Oligomeric Matrix Protein/Thrombospondin 5 Supports Chondrocyte Attachment through Interaction with Integrins|We show that COMP/TSP5 can support chondrocyte attachment and that the RGD sequence in COMP/TSP5 and the integrin receptors alpha5beta1 and alphaVbeta3 on the chondrocytes are involved in mediating this attachment. The interactions of COMP/TSP5 with the integrins are dependent on COMP/TSP5 conformation. SIGNOR-266988 0.323 DUSP26 protein Q9BV47 UNIPROT FADD protein Q13158 UNIPROT down-regulates activity dephosphorylation Ser194 QNRSGAMsPMSWNSD 9606 24548998 t lperfetto This multi-functionality of fadd may depend primarily on its subcellular location. Fadd shuttles between the cytosol and the nucleus and this signal is unclear;however, fadd trafficking requires phosphorylation of the protein on ser194dusp26 suppresses cell proliferation by fadd dephosphorylation SIGNOR-204559 0.372 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates relocalization 10090 BTO:0002572 18423396 t lperfetto Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation SIGNOR-252351 0.2 MYC protein P01106 UNIPROT Enolase proteinfamily SIGNOR-PF74 SIGNOR up-regulates quantity transcriptional regulation 10116 10823814 t inferred from family member miannu C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway. SIGNOR-267785 0.419 PPM1A protein P35813 UNIPROT IKBKE protein Q14164 UNIPROT down-regulates activity dephosphorylation Ser172 DDDEKFVsVYGTEEY 9606 27419230 t miannu PPM1A directly dephosphorylates both MAVS and TBK1 and IKKepsilon.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon. SIGNOR-277072 0.281 BIRC3 protein Q13489 UNIPROT RIPK3 protein Q9Y572 UNIPROT up-regulates activity polyubiquitination 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation. SIGNOR-272714 0.638 HLX protein Q14774 UNIPROT ELK1 protein P19419 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003980 20008130 t Luana In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells. SIGNOR-261622 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation 9606 15632084 t inferred from 70% family members amattioni Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3 SIGNOR-270205 0.2 GFI1B protein Q5VTD9 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 f miannu Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5. SIGNOR-254206 0.285 PPM1D protein O15297 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity dephosphorylation Ser131 DESLANLsEDEYYSE 9606 BTO:0002181 25999347 t miannu We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites. SIGNOR-276904 0.473 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 t Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-122062 0.689 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15498859 t Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. SIGNOR-261517 0.382 AKT proteinfamily SIGNOR-PF24 SIGNOR CHEK1 protein O14757 UNIPROT down-regulates phosphorylation Ser280 AKRPRVTsGGVSESP 9606 15107605 t lperfetto The chk1 protein phosphorylated by pkb on serine 280 does not enter into protein complexes after replication arrest. Moreover, chk1 phosphorylated by pkb fails to undergo activating phosphorylation on serine 345 by atm/atr. Phosphorylation by atm/atr and association with other checkpoint proteins are essential steps in activation of chk1. SIGNOR-244206 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK7 protein Q8WTQ7 UNIPROT up-regulates activity phosphorylation Ser36 ELQRRRRsLALPGLQ 8355 BTO:0001175 18803695 t miannu Recently, we have defined sites of phosphorylation by cAMP-dependent protein kinase (PKA) in the amino termini of both GRK1 and GRK7 in vitro. To determine the conditions under which GRK7 is phosphorylated in vivo, we have generated an antibody that recognizes GRK7 phosphorylated on Ser36, the PKA phosphorylation site. Using this phospho-specific antibody, we have shown that GRK7 is phosphorylated in vivo and is located in the cone inner and outer segments of mammalian, amphibian and fish retinas. The conservation of phosphorylation at Ser36 in GRK7 in these different species (which span a 400 million-year evolutionary period), and its light-dependent regulation, indicates that phosphorylation plays an important role in the function of GRK7 SIGNOR-263152 0.2 PARP1 protein P09874 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR form complex binding 9606 22223884 t alessandro Therefore, we conclude that the endogenous proteins PARP1, p65NF-κB and Snail1 form a ternary complex in the nuclei of cells that are actively expressing fibronectin SIGNOR-254528 0.491 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser621 PKINRSAsEPSLHRA 9606 11971957 t gcesareni We have mapped all camp-induced phosphorylation sites in raf-1, showing that serines 43, 259, and 621 are phosphorylated by pka in vitro and induced by camp in vivo SIGNOR-86137 0.488 CHKA protein P35790 UNIPROT choline smallmolecule CHEBI:15354 ChEBI down-regulates quantity chemical modification 27149373 t lperfetto Choline kinase (CK) phosphorylates choline in the cytidine diphosphate (CDP)-choline pathway for the biosynthesis of phosphatidylcholine (PC), the most abundant class of phospholipids in eukaryotic membranes SIGNOR-275637 0.8 GRPR protein P30550 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257159 0.27 AMOTL2 protein Q9Y2J4 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0001176 21937427 f lperfetto Taking together, our data indicate that Amotl2 plays a pivotal role in polarity, migration and proliferation of angiogenic endothelial cells. SIGNOR-271871 0.7 CSNK2A1 protein P68400 UNIPROT CBX1 protein P83916 UNIPROT down-regulates phosphorylation Thr51 GFSDEDNtWEPEENL 9606 19657222 t lperfetto Two recent papers suggest that hp1 recruitment to damage sites, rather than its rapid mobilization, is the predominant behaviour exhibited by this protein. Our findings reconcile recent findings in a new model, wherein rapid hp1beta mobilization from dsbs is mediated by its phosphorylation on thr51 by ck2 SIGNOR-187450 0.306 EMSY protein Q7Z589 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity binding 9606 BTO:0000567 14651845 t miannu The EMSY protein interacts precisely with a highly conserved transactivating region at the N terminus of the breast cancer protein BRCA2, and has endogenous transcriptional repressor activity when recruited to a high basal promoter. We have suggested that the independent activation domain of BRCA2 within exon 3 might have some role in transcription (Milner et al., 1997). The identification of the repressor protein EMSY, which binds and silences this domain, is consistent with such a function. SIGNOR-263915 0.2 RXRB protein P28702 UNIPROT RARG protein P13631 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16683 0.705 Bombesin smallmolecule CHEBI:80229 ChEBI GRPR protein P30550 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257509 0.8 DEAF1 protein O75398 UNIPROT EN1 protein Q05925 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000375 31145909 t Gianni Deaf1 is the first transcription factor implicated in the regulation of En1, a critical determinant of eccrine fate, within keratinocytes. SIGNOR-269062 0.2 glutamic acid smallmolecule CHEBI:18237 ChEBI GRIK2 protein Q13002 UNIPROT up-regulates activity chemical activation 9606 27586965 t miannu Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its biological activity through a variety of receptors. Glutamate receptors (GluRs) are divided into two major classes on the basis of the mechanism by which they relay their signal: the ionotropic glutamate receptors (iGluRs), which are ligand-gated cation channels, and the metabotropic glutamate receptors (mGluRs) that are G protein-coupled receptors SIGNOR-264471 0.8 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258711 0.8 IRF5 protein Q13568 UNIPROT IL10 protein P22301 UNIPROT down-regulates transcriptional regulation 9606 BTO:0000801 21240265 f The role of IRF5 in inhibiting the transcription of the gene encoding IL-10 that we have identified here is important given its well- documented immunosuppressive activity. SIGNOR-254514 0.432 F2RL3 protein Q96RI0 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257044 0.368 potassium(1+) smallmolecule CHEBI:29103 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 11506885 f miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265590 0.7 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 11689553 t lperfetto Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter. SIGNOR-251494 0.678 CDK5RAP2 protein Q96SN8 UNIPROT WDR62 protein O43379 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271723 0.556 bortezomib chemical CHEBI:52717 ChEBI PSMD1 protein Q99460 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 21504411 t miannu Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. SIGNOR-259312 0.8 SATB1 protein Q01826 UNIPROT HSPA6 protein P17066 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255134 0.2 NFIX protein Q14938 UNIPROT RBFOX3 protein A6NFN3 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268913 0.2 PRKACA protein P17612 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000007 30017192 t miannu In this study, we found that PKCα stabilized and activated PIM-1L by phosphorylation at Ser65. The PIM-1L phosphorylation suppressed sotrastaurin-induced apoptosis. These findings suggest that PKCα promotes cell survival and proliferation by upregulating PIM-1L in acute myeloid leukemia. SIGNOR-259413 0.268 SNAI2 protein O43623 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 21044962 f miannu knockdown of SLUG in SLUG-high breast cancer cells elevated the levels of UbcH5c while decreasing the level of cyclin D1 protein. SLUG is recruited at the E2-box sequence at the UbcH5c gene promoter along with the corepressor CtBP1 and the effector HDAC1 to silence the expression of this gene. SIGNOR-255176 0.467 DNAH10 protein Q8IVF4 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000667 31836722 f miannu Epidermal expression of axonemal dynein heavy chain 10 (DNAH10) was increased 20-fold in samples having had regenerating dermis vs control. Our results associate DNAH10 expression with cell proliferation and inflammation as well as with the epidermal memory resulting from the previous regenerative signals of dermis. SIGNOR-265550 0.7 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC3 protein P33778 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSIYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271983 0.2 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr5 yLDPNLNH 9606 20802513 t llicata In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate fak on tyr194 in the ferm domain collectively, this study provides the first example to explain how fak is activated by receptor tyrosine kinases. SIGNOR-167650 0.586 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser405 VTVSRASsSRSVRTT 9606 BTO:0001271 8034666 t lperfetto Beta II PKC-mediated phosphorylation of lamin B is confined to two sites, Ser395 and Ser405 | Comparative tryptic phosphopeptide mapping demonstrates that the beta II PKC site, Ser405, is a prominent target of mitotic lamin B phosphorylation in vivo. beta II PKC translocates to the nucleus during the G2/M phase of cell cycle concomitant with phosphorylation of Ser405, indicating a physiologic role for nuclear beta II PKC activation in mitotic lamin B phosphorylation in vivo. SIGNOR-248912 0.485 PTPRF protein P10586 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 27225731 f miannu LAR (for leukocyte common antigen-related) is a family of receptor protein tyrosine phosphatases (LAR-RPTPs) with three known members: LAR/PTPRF, PTPδ/PTPRD, and PTPσ/PTPRS. In mammals, LAR-RPTPs have been shown to regulate dendrite and excitatory synapse development and maintenance SIGNOR-264090 0.7 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT up-regulates activity phosphorylation Tyr1333 ARGGQVFyNSEYGEL 9606 BTO:0000394 12881528 t lperfetto Trans-phosphorylation of activated, dimerized receptor tyrosine kinases is known to be critical for the regulation of kinase activity and for receptor interaction with signal transduction molecules. In this study, we have identified five tyrosyl phosphorylation sites in the vegfr-3 carboxyl-terminal tail. SIGNOR-104084 0.2 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys490 QCPRKVIkMESEEGK 9534 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. SIGNOR-261787 0.774 CDK1 protein P06493 UNIPROT TOB2 protein Q14106 UNIPROT up-regulates activity phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 t done miannu Taken together, these observations strongly support the notion that several different CDK-cyclin complexes are involved in the phosphorylation of Tob2 at S254.A more detailed regulatory context of Tob2 phosphorylation at S254 is provided by our findings from mass-spec and in vitro kinase analyses that suggest connections to PP2B and PP2C phosphatases and CDK-cyclin complexes, particularly CDK1, CDK2, and CDK4 (Table 1; Supplemental Table S2).One possibility is that the phosphorylation of S254 helps stabilize the interaction of Tob2 with the Ccr4–Not complex, which could contribute to Tob2's ability to recruit the entire Ccr4–Not complex and thus further enhances deadenylation. SIGNOR-273591 0.2 ASXL1 protein Q8IXJ9 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 22897849 f miannu ASXL1 siRNA in human primary CD34+ cells form cord blood results in upregulation of HOXA5 and HOXA9 with ASXL1 knockdown (KD) as revealed by quantitative real-time PCR SIGNOR-256127 0.442 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 20837657 t lperfetto In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization. SIGNOR-227914 0.705 RNF138 protein Q8WVD3 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 16714285 t miannu Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome. SIGNOR-271593 0.328 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT up-regulates activity binding 9606 9732876 t lperfetto Smad3 and smad4 also act together with c-jun and c-fos to activate transcription in response to tgf-beta, through a tgf-beta-inducible association of c-jun with smad3 and an interaction of smad3 and c-fos SIGNOR-229545 0.706 TIMM9 protein Q9Y5J7 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267702 0.57 BMI1 protein P35226 UNIPROT NDN protein Q99608 UNIPROT down-regulates 9606 BTO:0000007 24392140 f lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin-mediated repression of E2F1-dependent Cdk1 promoter activity. SIGNOR-253386 0.254 PPP2CA protein P67775 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates dephosphorylation 9606 19061640 t gcesareni In the absence of the wt apc protein, phosphorylated beta-catenin is rapidly dephosphorylated by serine/threonine protein phosphatase 2a (pp2a). phosphorylated beta-catenin associated with the wild-type apc protein is recruited to the scf(beta-trcp) complex, ubiquitin conjugated, and degraded. SIGNOR-182637 0.448 ACTL6A protein O96019 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269295 0.643 ATF4 protein P18848 UNIPROT IARS1 protein P41252 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269427 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR THRB protein P10828 UNIPROT down-regulates activity phosphorylation 9606 12809513 t inferred from 70% family members llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-270143 0.2 CDK9 protein P50750 UNIPROT NCOA2 protein Q15596 UNIPROT up-regulates activity phosphorylation Ser469 NYALKMNsPSQSSPG 9606 BTO:0000801 29170386 t Interestingly, GRIP1 is phosphorylated at an N-terminal serine cluster by cyclin-dependent kinase-9 (CDK9), which is recruited into GC-induced GR:GRIP1:CDK9 hetero-complexes, producing distinct GRE-specific GRIP1 phospho-isoforms. Phosphorylation potentiates GRIP1 coactivator but, remarkably, not its corepressor properties. SIGNOR-256096 0.247 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263789 0.8 MAPK3 protein P27361 UNIPROT STAT5A protein P42229 UNIPROT up-regulates phosphorylation Ser780 DSLDSRLsPPAGLFT 9606 BTO:0000975 10194762 t gcesareni Serine 780 is the only substrate in full-length stat5a for active erk SIGNOR-66247 0.699 vasopressin smallmolecule CHEBI:9937 ChEBI AVPR2 protein P30518 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257463 0.8 PTPN9 protein P43378 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 16679294 t gcesareni Ectopic expression of ptp-meg2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while rnai-mediated reduction of ptp-meg2 transcript levels enhanced insulin action SIGNOR-146668 0.262 sirolimus chemical CHEBI:9168 ChEBI AKT1 protein P31749 UNIPROT up-regulates 9606 16452206 f gcesareni We now show that mtor inhibition induces insulin receptor substrate-1 expression and abrogates feedback the pathway, resulting in akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, rad001. SIGNOR-252643 0.8 SELPLG protein Q14242 UNIPROT SELP protein P16109 UNIPROT up-regulates binding 9606 BTO:0000130 23994464 t apalma This steady-state rolling is primarily mediated by the interaction of endothelial P-selectins with their neutrophil glycoprotein counterreceptors, primarily PSGL-1. SIGNOR-255038 0.926 SOD1 protein P00441 UNIPROT ERN1 protein O75460 UNIPROT up-regulates activity binding 10090 BTO:0004488 18519638 t P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction); P00441:p.Ala5Val (mutation causing interaction) SOD1mut-induced ER stress |we first examined whether SOD1mut induces ER stress in NSC34 motor neurons, as assessed by band-shift analyses of the ER transmembrane kinase receptors IRE1 and PERK. Adenovirus (Ad)-mediated expression of ALS-linked SOD1mut (SOD1G93A) was detectable within 48 h of infection (Supplemental Fig. S1A). SOD1mut (SOD1A4V, SOD1G85R, and SOD1G93A) but not wild-type SOD1 (SOD1wt) activated IRE1 and PERK SIGNOR-262786 0.319 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates activity phosphorylation 10090 BTO:0002417 15358865 t gcesareni Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch. SIGNOR-245315 0.648 WNT11 protein O96014 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 23151663 t gcesareni Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase SIGNOR-199641 0.465 ZAP70 protein P43403 UNIPROT DBNL protein Q9UJU6 UNIPROT up-regulates phosphorylation Tyr334 QAEEEAVyEEPPEQE 9606 BTO:0000782 14557276 t lperfetto We found an interaction between the tyrosine kinase zap-70 and hip-55, which was induced by tcr stimulation. Zap-70 phosphorylated hip-55 at tyr-334 and tyr-344, which were shown to be the tyrosine phosphorylation sites of hip-55 in stimulated t cells.Our results demonstrate for the first time that hip-55 is an important adaptor protein for the jnk kinase cascade in tcr signaling. SIGNOR-118691 0.631 MECP2 protein P51608 UNIPROT RELN protein P78509 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19029285 f miannu induction of the reelin and GAD67 mRNAs is accompanied by the dissociation of repressor complexes containing all three DNMTs, MeCP2, and HDAC1 from the corresponding promoters and by increased local histone acetylation. SIGNOR-254578 0.386 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser645 LNEKARLsYSDKNLI 10090 BTO:0000944 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248595 0.302 GABRA1 protein P14867 UNIPROT GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263750 0.646 RUNX1 protein Q01196 UNIPROT ANKRD26 protein Q9UPS8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000843 24430186 t lperfetto In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs. SIGNOR-266069 0.2 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258992 0.745 Melanin-concentrating hormone smallmolecule CHEBI:80254 ChEBI MCHR2 protein Q969V1 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257541 0.8 Immune_response phenotype SIGNOR-PH17 SIGNOR ARDS phenotype SIGNOR-PH128 SIGNOR up-regulates 9606 32446778 f miannu The presence of SARS-CoV-2 in the lung induces an uncontrolled generalized immune response. Several immune cells (like T-lymphocytes, macrophages and dendritic cells) sustain the impressive secretion of cytokines and chemokines ultimately leading to acute respiratory distress syndrome. These data clearly indicate that, in SARS-CoV in-fection, ARDS is the ultimate result of a cytokine storm. SIGNOR-261035 0.7 F2RL2 protein O00254 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256904 0.2 MK-2461 chemical CID:44137946 PUBCHEM MST1R protein Q04912 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194387 0.8 OTX1 protein P32242 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation -1 18849347 f miannu Three OTX family proteins - OTX1, OTX2 and CRX - bound to both Sites 1 and 2 in vitro, and all of them increased BEST1 promoter activity. SIGNOR-254887 0.311 PRKCD protein Q05655 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 BTO:0000222 BTO:0000887;BTO:0001103 16611834 t gcesareni Here we show in various cell models that the adipose hormone leptin, a putative mediator in obesity-related insulin resistance, promotes phosphorylation of ser-318 in irs1 by a janus kinase 2, irs2, and pkc-dependent pathway. we observed that insulin stimulates phosphorylation of ser(318) in irs-1, which is mediated, at least partially, by pkc-zeta. SIGNOR-146105 0.637 OPRM1 protein P35372 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256990 0.631 CDK9 protein P50750 UNIPROT XRN2 protein Q9H0D6 UNIPROT up-regulates activity phosphorylation Thr439 FTPSGILtPHALGSR -1 26728557 t miannu Among the RNA processing factors phosphorylated by Cdk9 was the 5'-to-3' "torpedo" exoribonuclease Xrn2, required in transcription termination by Pol II, which we validated as a bona fide P-TEFb substrate in vivo and in vitro. Phosphorylation by Cdk9 or phosphomimetic substitution of its target residue, Thr439, enhanced enzymatic activity of Xrn2 on synthetic substrates in vitro.  SIGNOR-277194 0.281 MAPK9 protein P45984 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu we have identified serine 321 as the major site of phosphorylation by both SAPK3 and JNK2. SAPK3 but not JNK2 also phosphorylates serine 391 SIGNOR-250142 0.374 PARP1 protein P09874 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates activity relocalization 9606 33859667 t SaraGualdi The mechanism of KDM5B recruitment is quite specific and requires the presence of nucleosomes containing histone variant MacroH2A1.1 and PARylation by PARP1. SIGNOR-271574 0.36 CDK2 protein P24941 UNIPROT UHRF1 protein Q96T88 UNIPROT down-regulates quantity by destabilization phosphorylation Ser675 KTKVEPYsLTAQQSS -1 26727879 t miannu UHRF1 is phosphorylated by CDK2/cyclin A. In vitro kinase assay was performed with CDK2/cyclin A using recombinant wild-type UHRF1 or UHRF1-S674A mutant  SIGNOR-277192 0.306 BMP7 protein P18075 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates binding 9606 9748228 t acerquone We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes. SIGNOR-60240 0.555 ERBB2 protein P04626 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 8816440 t gcesareni Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3. SIGNOR-147838 0.602 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1132 TLPHGPRsASVSSIS 9534 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-235742 0.707 LRRK2 protein Q5S007 UNIPROT CADPS2 protein Q86UW7 UNIPROT up-regulates quantity transcriptional regulation 9606 28647363 f gianni This approach enabled us to disclose a differential effect of high levels of LRRK2 and aSyn on CADPS2 promoter activity. Specifically, CADPS2 transcriptional activity was enhanced by high cellular levels of LRRK2 and reduced by overexpression of aSyn. Consistently, CADPS2 mRNA levels were diminished in aSyn overexpressing cells. SIGNOR-268928 0.296 F2 protein P00734 UNIPROT F7 protein P08709 UNIPROT up-regulates activity 9606 BTO:0000131 29880919 t lperfetto Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind SIGNOR-263529 0.304 MTHFD1 protein P11586 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI up-regulates quantity chemical modification -1 18767138 t lperfetto Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis.|The Arg653Gln substitution is located in the synthetase domain, which catalyzes the magnesium adenosine triphosphate (MgATP)-dependent production of formylTHF from THF and formate SIGNOR-268250 0.8 CSNK2A2 protein P19784 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates activity phosphorylation Thr523 AGSTDENtDSEEHQE 9606 BTO:0000567 15367657 t llicata XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain | In addition, we present data to show that the acute loss of aprataxin by small interfering RNA (siRNA) renders HeLa cells sensitive to MMS through a mechanism that destabilizes XRCC1. SIGNOR-251052 0.468 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser251 GKLGGQDsFESIESY 9606 BTO:0000782 12475968 t lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition SIGNOR-96330 0.311 FOXA1 protein P55317 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 19486887 f miannu The results showed overexpression of Foxa1 promoted the expression of HSP72, while Foxa1 depletion, induced by antisense oligonucleotides, decreased the expression of HSP72 in MCF-7 cells under normal and heat stress condition. SIGNOR-254165 0.2 SATB1 protein Q01826 UNIPROT NUMB protein P49757 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000725 23563689 f miannu Satb1 simultaneously repressed sets of genes encoding molecules involved in HSC activation and cellular polarity, including Numb and Myc SIGNOR-224835 0.341 MTOR protein P42345 UNIPROT EIF4EBP3 protein O60516 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase. SIGNOR-122035 0.363 UNG protein P13051 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275711 0.7 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr504 AEPLPPSyVACS 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251355 0.808 PRKCG protein P05129 UNIPROT GRIN1 protein Q05586 UNIPROT up-regulates activity phosphorylation Ser890 ITSTLASsFKRRRSS 10116 BTO:0000938 15936117 t miannu Serines 890 and 896 of the NMDA receptor subunit NR1 are differentially phosphorylated by protein kinase C isoforms. The results show that PKC alpha phosphorylates preferentially S896 and PKC gamma preferentially S890. SIGNOR-263176 0.355 PREX2 protein Q70Z35 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260572 0.43 HTR1D protein P28221 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257000 0.365 MAPK8 protein P45983 UNIPROT ITCH protein Q96J02 UNIPROT up-regulates phosphorylation 9606 16469705 t gcesareni Here we show that tnfalpha-mediated jnk activation accelerates turnover of the nf-kappab-induced antiapoptotic protein c-flip, an inhibitor of caspase-8. This is not due to direct c-flip phosphorylation but depends on jnk-mediated phosphorylation and activation of the e3 ubiquitin ligase itch, which specifically ubiquitinates c-flip and induces its proteasomal degradation. SIGNOR-144456 0.648 PLK1 protein P53350 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates quantity by destabilization phosphorylation Ser170 KTCRYIPsLPDRILD -1 23643811 t miannu Plk1 directly bound to Cdc20 and phosphorylates it on serine-170 located in CRY-box. Whereas wild-type Cdc20 was degraded according to progress cell cycle beyond mitosis, the phosphorylation-defective mutant, which serine-170 was changed into alanine, was not destroyed in early G1 phase.  SIGNOR-276493 0.977 RHOA protein P61586 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 11102529 t gcesareni Our results demonstrate that direct stimulation of pld1 in vivo by rhoa SIGNOR-84953 0.69 zotepine chemical CHEBI:32316 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 20223878 t Luana These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. SIGNOR-257829 0.8 SYVN1 protein Q86TM6 UNIPROT SERPINI1 protein Q99574 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21507957 t miannu In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. SIGNOR-272757 0.2 RAB7A protein P51149 UNIPROT Late macropinosomes phenotype SIGNOR-PH229 SIGNOR up-regulates 9606 19693279 f miannu Rab7 is localized on later macropinosomes. Rab21 is localized on macropinosomes at an intermediate stage partially overlapping with Rab5 and Rab7, and then dissociates from the macropinosomes prior to Lamp1 acquisition by fusing with lysosomes. SIGNOR-277779 0.7 SOD1 protein P00441 UNIPROT BCL2 protein P10415 UNIPROT up-regulates activity binding 9606 BTO:0001279 15233914 t P00441:p.Gly94Ala (mutation disrupting interaction) Familial amyotrophic lateral sclerosis (ALS)-linked mutations in the copper-zinc superoxide dismutase (SOD1) gene cause motor neuron death in about 3% of ALS cases. While the wild-type (wt) protein is anti-apoptotic, mutant SOD1 promotes apoptosis.|We now demonstrate that both wt and mutant SOD1 bind the anti-apoptotic protein Bcl-2, providing evidence of a direct link between SOD1 and an apoptotic pathway. This interaction is evident in vitro and in vivo in mouse and human spinal cord.|These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein. SIGNOR-262799 0.495 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 8846788 t gcesareni However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity. SIGNOR-44356 0.501 DTX1 protein Q86Y01 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates activity ubiquitination 7227 22162134 t lperfetto The expression of dx, which physically interacts with notch, favors a mono-ubiquitinated state of the receptor, which leads to a ligand-independent intracellular activation of notch SIGNOR-254317 0.776 FBXW7 protein Q969H0 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0002572 22388891 t miannu Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α SIGNOR-272907 0.401 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9973379 t CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4. SIGNOR-251161 0.765 IKBKE protein Q14164 UNIPROT TANK protein Q92844 UNIPROT down-regulates activity phosphorylation Ser228 EEDTSFEsLSKFNVK 9534 BTO:0000298 10759890 t miannu IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex SIGNOR-262718 0.738 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Ser539 SLFNVSPsCSSFNSP 9606 BTO:0000887;BTO:0001103 17609368 t lperfetto Ampk phosphorylates pgc-1alpha directly both in vitro and in cells. These direct phosphorylations of the pgc-1alpha protein at threonine-177 and serine-538. SIGNOR-216647 0.491 FBXW11 protein Q9UKB1 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 10074433 t gcesareni We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct. SIGNOR-65429 0.739 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-233435 0.619 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89272 0.399 FOXO proteinfamily SIGNOR-PF27 SIGNOR IGFBP1 protein P08833 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10358076 f miannu Reporter gene studies in hepg2 hepatoma cells show that fkhr stimulates insulin-like growth factor-binding protein-1 promoter activity through an irs SIGNOR-252925 0.2 PPP6C protein O00743 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity dephosphorylation Ser828 EHDSAEGsHTSGQSN 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276517 0.332 IGF1R protein P08069 UNIPROT FBN1 protein P35555 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0000951 17200203 f Indirect:regulation of expression miannu Decorin and IGF-I induce fibrillin-1 protein synthesis in normal rat kidney fibroblasts SIGNOR-251863 0.297 Nucleosome_H2A.Z.1 variant complex SIGNOR-C322 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 24311584 f miannu In the nucleosome, two of each of the histones H2A, H2B, H3 and H4 form the histone octamer and about 145–147 base pairs of DNA are wrapped around it . The histone H2A.Z variant is widely conserved among eukaryotes. Two isoforms, H2A.Z.1 and H2A.Z.2, have been identified in vertebrates and may have distinct functions in cell growth and gene expression. SIGNOR-263713 0.7 ITCH protein Q96J02 UNIPROT H1-2 protein P16403 UNIPROT up-regulates activity polyubiquitination Lys46 PVSELITkAVAASKE 9606 BTO:0000815 30517763 t miannu ITCH interacts with and ubiquitinates linker histone H1.2 at K46. ITCH biochemically competes with RNF168 and RNF8 to polyubiquitinate histone H1.2. The results indicated that ITCH-mediated K46-Ubn is essential for the binding of histone H1.2 to chromatin. SIGNOR-272926 0.2 CSNK2A1 protein P68400 UNIPROT MYH9 protein P35579 UNIPROT up-regulates phosphorylation Ser1943 RKGAGDGsDEEVDGK 9606 22123909 t gcesareni In egf-stimulated cells, the myosin-iia heavy chain is phosphorylated on the casein kinase 2 site (s1943) SIGNOR-177818 0.344 MMP3 protein P08254 UNIPROT ACAN protein P16112 UNIPROT down-regulates quantity by destabilization cleavage Asn360 DFVDIPEnFFGVGGE 9606 BTO:0000206 9202061 t lperfetto Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374 SIGNOR-266986 0.732 CDC20 protein Q12834 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000567 11285280 t miannu These results suggested that cyclin A is a target of the Cdc20-associated APC/C in human cells. SIGNOR-272578 0.966 MAPK9 protein P45984 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates activity phosphorylation Thr103 LIDATGDtPGAEDDE 9606 BTO:0000298 12756254 t lperfetto Recruitment of jnk to jip1 and jnk-dependent jip1 phosphorylation regulates jnk module dynamics and activation it was observed that phosphorylation by jnk of jip1 on thr-103 and not other phosphorylated jip1 residues is necessary for the regulation of dlk association with jip1, dlk activation, and subsequent module activation. SIGNOR-101201 0.767 TP53 protein P04637 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR down-regulates quantity by repression transcriptional regulation 9606 27692180 t inferred from family member miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-270272 0.419 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys21 EGPRDGLkKERLLDD 9606 9990853 t gcesareni We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. SIGNOR-64317 0.529 SRPK2 protein P78362 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19592491 f lperfetto Compared with control, srpk2 wild type evidently elevated cyclin d1 transcription, and the catalytic activity was lost in srpk2 kd, suggesting that kinase activity of srpk2 is required for this effect. SIGNOR-186763 0.2 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT unknown phosphorylation Tyr8 MEELQDDyEDMMEEN -1 10942405 t The primary phosphorylation of band 3 catalyzed by p72syk generates the SH2 binding motifs that are a prerequisite for the following recruitment of Lyn. p72syk as the most likely candidate to perform this task and indicates Y8 and Y21. Syk and Lyn phosphorylate band 3 at both cytosolic and membrane domains, Y-phosphorylation/dephosphorylation is likely involved in the regulation of several erythrocyte functions (ie, glycolysis, cell shape, cytoskeleton SIGNOR-251413 0.458 MUC12 protein Q9UKN1 UNIPROT JUN protein P05412 UNIPROT up-regulates activity binding 9606 BTO:0000037 32596961 t miannu MUC12 promoted the recruitment of c-Jun on the promoter of TGF-β1, leading to its transcription. SIGNOR-265474 0.258 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser330 MEEDSYDsFGEPSYP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250801 0.368 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR JUN protein P05412 UNIPROT down-regulates activity 9606 BTO:0000801 10973958 f lperfetto NF-kB-, AP-1-, and Smad3-driven promoters all require p300/CREB-binding protein for their transactivation. Previous studies have suggested that NF-kB- and AP-1-driven promoters can be inhibited by competitive recruitment of coactivators such as p300/CPB to other unrelated promoters. We hypothesized that NF-kB and AP-1 compete with Smad3 for limiting quantities of p300. This hypothesis predicts that added p300 should alleviate TGF-b1/Smad3-mediated inhibition of inflammatory genes. Conversely, increasing doses of TGF-b1/Smad3 would compete away even overexpressed p300 from NF-kB/AP- 1-driven promoters. SIGNOR-249557 0.706 dabrafenib chemical CHEBI:75045 ChEBI LIMK1 protein P53667 UNIPROT down-regulates activity chemical inhibition -1 24720932 t miannu Dabrafenib is known to inhibit V600E, V600K and V600D BRAF enzymes with in vitro IC50 values of 0.65, 0.5 and 1.84 nM, respectively. Dabrafenib can inhibit wild-type BRAF and CRAF kinases with IC50 values of 3.2 and 5.0 nM. Other kinases (SIK1, NEK111 and LIMK1) can be inhibited by dabrafenib when administered in high concentrations SIGNOR-259216 0.8 ETV4 protein P43268 UNIPROT VIM protein P08670 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093;BTO:0000815 8895512 f miannu Our results suggest that PEA3 specifically transactivates vimentin promoter through PEA3 site. Among members of the ETS transcription factor family only Erg showed ability to transactivate vimentin promoter besides PEA3. SIGNOR-254070 0.2 DSCAM protein O60469 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264277 0.2 SLC12A3 protein P55017 UNIPROT chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity phosphorylation 21613606 t lperfetto Eukaryotic cells regulate their volume in the long term through the coordinated function of the Na+-coupled chloride (NKCC1/2 and NCC) and K+-coupled chloride (KCC1–4) cotransporters, which encompass two branches of the SLC12|The K+-Cl− cotransporters move chloride outside the cell, are inhibited by phosphorylation, and are activated by dephosphorylation. In contrast, the Na+-K+-2Cl− cotransporters introduce chloride into the cell, are inhibited by dephosphorylation, and are activated by phosphorylation gene family of solute transporters (12).  SIGNOR-264633 0.8 MRPS7 protein Q9Y2R9 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-267730 0.757 PRKCZ protein Q05513 UNIPROT ADD1 protein P35611 UNIPROT up-regulates phosphorylation Ser726 KKKFRTPsFLKKSKK 9606 BTO:0000938 BTO:0000671 9679146 t gcesareni These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc. SIGNOR-59303 0.2 MYC protein P01106 UNIPROT HECTD4 protein Q9Y4D8 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267144 0.2 CHRM3 protein P20309 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256882 0.2 FRG1 protein Q14331 UNIPROT KMT5B protein Q4FZB7 UNIPROT down-regulates activity binding 10090 BTO:0000165 23720823 t miannu Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. SIGNOR-266639 0.2 GCM2 protein O75603 UNIPROT PTH protein P01270 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004712 20558332 f miannu We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription. SIGNOR-254200 0.415 POLR2G protein P62487 UNIPROT RNA Polymerase II complex SIGNOR-C391 SIGNOR form complex binding 9606 BTO:0000567 9852112 t lperfetto Pol II is composed of 10–12 polypeptides ranging in size from 220 to 7 kDa, depending on the source of purification (11, 12, 13). The subunits of human pol II (or RNA polymerase B) have been defined as RPB1 (220 kDa), RPB2 (140 kDa), RPB3 (33 kDa), RPB4 (18 kDa), RPB5 (28 kDa), RPB6 (19 kDa), RPB7 (27 kDa), RPB8 (17 kDa), RPB9 (14.5 kDa), RPB10alpha (or RPB12, 7.0 kDa), RPB10beta (or RPB10, 7.6 kDa), and RPB11 (14 kDa) (3,11, 12, 13). RPB5, RPB6, RPB8, RPB10alpha, and RPB10beta are shared by all three eukaryotic RNA polymerases, whereas the rest of the RPB components are unique to pol II SIGNOR-266165 0.868 MTHFR protein P42898 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 BTO:0000567 24769206 f miannu MTHFR promotes heterochromatin maintenance at the centromeric region. SIGNOR-263889 0.7 POU5F1 protein Q01860 UNIPROT TDGF1 protein P13385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001086 17068183 f miannu To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1,000 genes, including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1, and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury [T], DKK1, HLX1, GATA6, ID2, and DLX5), as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. SIGNOR-254943 0.681 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser77 YEPEGSAsPTPPYLK 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248552 0.336 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Ser227 DHEKKAYsFCGTVEY 9606 10980595 t lperfetto We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway SIGNOR-244692 0.2 LCK protein P06239 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 17998336 t inferred from 70% of family members gcesareni The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1. SIGNOR-269921 0.576 UBE2I protein P63279 UNIPROT ZHX1 protein Q9UKY1 UNIPROT up-regulates quantity by stabilization sumoylation Lys454 VPTSQSVkHETALVN 9606 BTO:0000007 23686912 t miannu Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. The sumoylation of zinc‐fingers and homeoboxes 1 (ZHX1) by ubc9 regulates its stability and transcriptional repression activity. However, in the current work, we demonstrated that ZHX1 was only SUMOylated by SUMO1. SIGNOR-263900 0.46 MAPK3 protein P27361 UNIPROT SOX9 protein P48436 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20457810 f fspada Soluble pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (erk/mapk) and the subsequent upregulation of sox9 expression. SIGNOR-165353 0.387 GLI3 protein P10071 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity transcriptional regulation 10090 12435361 t Gianni Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH SIGNOR-268949 0.453 DUSP6 protein Q16828 UNIPROT FOXO1 protein Q12778 UNIPROT up-regulates activity dephosphorylation Ser256 SPRRRAAsMDNNSKF 9606 22848439 t lperfetto It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref . SIGNOR-276983 0.436 UBE2I protein P63279 UNIPROT FOS protein P01100 UNIPROT down-regulates activity sumoylation Lys265 SISSMELkTEPFDDF 9606 SIGNOR-C154 16055711 t lperfetto We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity. SIGNOR-263013 0.37 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr156 ADEDEDDyHNPGYLV 9606 BTO:0000782 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247018 0.765 YEATS4 protein O95619 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269302 0.764 pemetrexed disodium chemical CHEBI:63722 ChEBI GART protein P22102 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 14596699 t miannu Thymidylate synthase, the primary target of pemetrexed,9 is a fo-late-dependent enzyme that catalyzes the transformation of deoxyuri-dine monophosphate to deoxythymidine monophosphate. Inhibi-tion of TS results in decreased levels of thymidine, which is necessary for DNA synthesis. In addition to TS, pemetrexed inhibits DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), and glycinamide ribonucleotide formyltransferase (GARFT). SIGNOR-259291 0.8 NCBP2 protein P52298 UNIPROT Cap-binding complex complex SIGNOR-C440 SIGNOR form complex binding 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268358 0.969 RAB32 protein Q13637 UNIPROT AP-1 complex complex SIGNOR-C248 SIGNOR up-regulates activity relocalization 9606 23247405 t lperfetto Rab32 and Rab38 interact physically and colocalize with BLOC-2, AP-1 and AP-3|These results indicate that Rab32 and Rab38 operate in the same pathways previously defined for AP-1, AP-3 and BLOC-2 and suggest they are the specific proteins that divert AP-1, AP-3 and BLOC-2-dependent cargoes to maturing melanosomes and away from lysosomes. SIGNOR-260700 0.2 CDK7 protein P50613 UNIPROT NR5A1 protein Q13285 UNIPROT up-regulates phosphorylation Ser203 EYPEPYAsPPQPGLP 9606 17901130 t llicata In conclusion, our results indicate that cdk7, as part of the cak complex and tfiih, phosphorylates sf1 at s203 followed by increased transcriptional activity of sf1 SIGNOR-157952 0.372 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1365 TKTSPKLsNKELKPQ 9606 BTO:0003492 21254166 t miannu  This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361. SIGNOR-276300 0.606 RUNX2 protein Q13950 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 20551513 t gcesareni Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphory-lated runx2, promoting its association with the coac-tivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs. SIGNOR-166170 0.412 DOK3 protein Q7L591 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling. SIGNOR-268448 0.565 RNF111 protein Q6ZNA4 UNIPROT AP2M1 protein Q96CW1 UNIPROT up-regulates ubiquitination 9606 20965945 t gcesareni Arkadia ubiquitylated the _?2 Subunit at lys130. In addition, arkadia interacted with the ap2 complex, and modified endocytosis of epidermal growth factor receptor (egfr) induced by egf. Arkadia thus appears to regulate egf signalling by modulating endocytosis of egfr through interaction with ap2 complex. SIGNOR-168931 0.2 ZDHHC9 protein Q9Y397 UNIPROT HRAS protein P01112 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 t miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. SIGNOR-261352 0.443 SCF-betaTRCP complex SIGNOR-C5 SIGNOR NFKB2 protein Q00653 UNIPROT up-regulates activity ubiquitination 9606 BTO:0000567 14676825 t lperfetto Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase. SIGNOR-217175 0.541 MAPK9 protein P45984 UNIPROT MYC protein P01106 UNIPROT up-regulates phosphorylation Ser62 LLPTPPLsPSRRSGL 9606 10551811 t gcesareni The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71. SIGNOR-72104 0.364 Caspase 3 complex complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp242 VRQKSEVdIVVSEDL 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-256441 0.37 AKT1 protein P31749 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Thr90 EARHRVPtTELCRPP 9606 BTO:0000782;BTO:0001271 15930267 t miannu Akt phosphorylates tal1 oncoprotein and inhibits its repressor activity. / our results show that akt specifically phosphorylates thr90 of the tal1 protein within its transactivation domain in vitro and in vivo. SIGNOR-252479 0.38 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 1303753 t gcesareni Lar ptpase shows strong preference for dephosphorylation first at py5 (at tri-, di-, and monophosphotyrosyl levels). Initially this regioselectivity gives the y5(py9)(py10) diphospho regioisomer, followed by equal dephosphorylation at py9 or py10 to give the corresponding monophosphoryl species on the way to fully dephosphorylated product. SIGNOR-16247 0.568 RPGRIP1L protein Q68CZ1 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates demethylation 9606 20080798 t lperfetto Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-217412 0.2 HEXIM1 protein O94992 UNIPROT KDM5B protein Q9UGL1 UNIPROT up-regulates activity relocalization 9606 BTO:0000815 31776402 t lperfetto We previously reported that the tumor suppressor HEXIM1 is a mediator of KDM5B recruitment to its target genes, and HEXIM1 is required for the inhibition of nuclear hormone receptor activity by KDM5B.  SIGNOR-273439 0.2 DMTF1 protein Q9Y222 UNIPROT JUNB protein P17275 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004532 19816943 t Luana  Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.  SIGNOR-261585 0.267 ATM protein Q13315 UNIPROT TDP1 protein Q9NUW8 UNIPROT up-regulates phosphorylation Ser81 PKRQKSGsQEDLGWC 9606 19851285 t lperfetto Optimal function of the dna repair enzyme tdp1 requires its phosphorylation by atm and/or dna-pk. Here we show that top1-associated dna double-stranded breaks (dsbs) induce the phosphorylation of tdp1 at s81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (atm) and dna-dependent protein kinase (dna-pk) SIGNOR-188772 0.553 ethanol chemical CHEBI:16236 ChEBI GlyR proteinfamily SIGNOR-PF62 SIGNOR up-regulates activity chemical activation 8355 BTO:0000964 8700149 t inferred from family member miannu Pharmacologically relevant concentrations of ethanol (10-200 mM) reversibly potentiated the glycine receptor function in all receptors. Ethanol potentiation depended on the glycine concentration used, with decreased potentiation observed at higher glycine concentrations. SIGNOR-270260 0.8 DLG3 protein Q92796 UNIPROT NMDA receptor_2C complex SIGNOR-C349 SIGNOR up-regulates activity relocalization BTO:0000227 32904533 t lperfetto DLG3 plays a critical role in clustering of NMDA receptors at excitatory synapses. SIGNOR-266008 0.675 LLGL1 protein Q15334 UNIPROT Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270907 0.55 CTDSPL protein O15194 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity dephosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0000007 17035229 t Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity SIGNOR-248307 0.408 KDM4C protein Q9H3R0 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates activity binding 9606 29207681 t miannu In hypoxia, HIF-1α dimerizes with HIF-1β to form active HIF-1 complex. JMJD2C interacts with HIF-1α and promotes the transcriptional activation of HIF-1 targeting genes via demethylating di- and trimethylated H3K9. SIGNOR-263873 0.2 NUP98-HOXA9 fusion protein SIGNOR-FP15 SIGNOR CEBPA protein P49715 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17442773 f miannu Over 102 cytoplasmic mRNAs were significantly altered in K562 myeloid leukemic cells transduced with NUP98‐HOXA9, 92 being increased and only 10 decreased. The transcription factor CCAAT enhancer binding protein‐α (C/EBPα), a tumor suppressor gene and a crucial regulator of granulopoiesis through inhibition of c‐JUN, was downmodulated by NUP98‐HOXA9 SIGNOR-261501 0.2 wortmannin chemical CHEBI:52289 ChEBI MYLK protein Q15746 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207791 0.8 SF3B5 protein Q9BWJ5 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270673 0.762 FABP2 protein P12104 UNIPROT Fatty acid stimulus SIGNOR-ST19 SIGNOR up-regulates quantity relocalization 9606 28457600 t miannu Astrocytes and endothelial cells, two major components of the blood brain barrier, are the major contributors to the transportation of PUFAs from the circulation to brain. There are four classes of lipid transportation proteins involved in lipid synthesis and transportation in adult brain, including fatty acid translocase (FAT/CD36), caveolin-1, fatty acid binding proteins (FABPs) long chain acyl-coA synthase (ACS) and fatty acid transportation proteins (FATPs). SIGNOR-264456 0.7 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT unknown phosphorylation Ser70 EAMNYEGsPIKVTLA 9606 19933706 t gcesareni Simultaneous inactivation of two cdk phosphorylation sites at ser10 and ser70 (npm-aa) induced g(2)/m cell cycle arrest, phosphorylation of cdk1 at tyr15 (cdc2(tyr15)) and increased cytoplasmic accumulation of cdc25c. SIGNOR-161801 0.528 PLK1 protein P53350 UNIPROT TNKS protein O95271 UNIPROT up-regulates quantity by stabilization phosphorylation Thr982 SLISPAStPSCLSAA 9606 BTO:0000567 21818122 t miannu Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.  SIGNOR-276241 0.434 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser118 GEAAEPGsPTAAEGE -1 8034575 t lperfetto Of the 7 phosphorylated serine residues identified by Edman degradation, only 1 was within the known phosphorylation domain by protein kinase C. All the other phosphorylated serine residues originated from the N-terminal half of the molecule and were immediately followed by proline. | We conclude that the primary phosphorylation site is Ser116 | SIGNOR-248907 0.724 PTK2 protein Q05397 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr905 DVYEEDSyVKRSQGR 9606 21454698 t llicata Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed. SIGNOR-173009 0.628 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30017632 f miannu Smad4 interacted withSmad2/3 and participated in the transcription of downstream pro-fi-brotic target genes SIGNOR-260440 0.7 RNF8 protein O76064 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18001824 t gcesareni Rnf8 can ubiquitylate histone h2a and h2ax, SIGNOR-159309 0.2 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser492 MTLTKSRsFTSSYAI 9606 19261611 t llicata Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding. SIGNOR-184464 0.2 AKT1 protein P31749 UNIPROT MAP3K8 protein P41279 UNIPROT up-regulates activity phosphorylation Ser413 LERKRLLsRKELELP 9606 BTO:0000007 12138205 t Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator. SIGNOR-252572 0.546 citrate(3-) smallmolecule CHEBI:16947 ChEBI ACACA protein Q13085 UNIPROT up-regulates activity binding 9606 6138356 t miannu Citrate, an allosteric activator of acetyl-CoA carboxylase, induces polymerization of an inactive protomeric form of the enzyme into an active filamentous form composed of 10-20 protomers.  SIGNOR-267104 0.8 CDK1 protein P06493 UNIPROT KDM5B protein Q9UGL1 UNIPROT down-regulates activity phosphorylation Ser1456 FKLERERsYELVRSA 9606 BTO:0000815 31776402 t lperfetto Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. SIGNOR-273435 0.26 8-oxo-7-[(6-sulfo-2-naphthalenyl)hydrazinylidene]-5-quinolinesulfonic acid chemical CHEBI:95064 ChEBI PTPN6 protein P29350 UNIPROT down-regulates activity chemical inhibition 9606 20337577 t NSC-87877 (1, Fig. (7)) was identified as a Shp2 PTP inhibitor with an IC50 of 0.33 μM [83]. NSC-87877 inhibits Shp1 with the same potency. SIGNOR-261913 0.8 CASP6 protein P55212 UNIPROT Caspase 6 complex complex SIGNOR-C228 SIGNOR form complex binding cleavage:Asp193 DTNITEVdAASVYTL 21621544 t lperfetto It is generally recognized that effector caspases undergo proteolytic cleavage of the inactive zymogen at a specific aspartate residue, resulting in a large N-terminal p20 polypeptide chain and a small C-terminal p10 polypeptide chain, leading to a p202/p102 tetramer. SIGNOR-256392 0.2 PLK1 protein P53350 UNIPROT CENPU protein Q71F23 UNIPROT down-regulates phosphorylation Ser77 TFDPPLHsTAIYADE 9606 17081991 t lperfetto S77 and t78 of pbip1 are important for plk1-dependent pbip1 phosphorylation and degradation. Here, we demonstrate that a pbd-binding protein, pbip1, is crucial for recruiting plk1 to the interphase and mitotic kinetochores. Unprecedentedly, plk1 phosphorylated pbip1 at t78. Later in mitosis, plk1 also induced pbip1 degradation in a t78-dependent manner, thereby enabling itself to interact with other components critical for proper kinetochore functions SIGNOR-150453 0.735 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 t lperfetto Plk1 interacts with BRCA2 in vivo, and mutation of Ser193, Ser205/206, and Thr203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. SIGNOR-249217 0.549 ABL1 protein P00519 UNIPROT LASP1 protein Q14847 UNIPROT up-regulates phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000150 15138294 t llicata C-abl activation by apoptotic agents specifically promotes phosphorylation of lasp-1 at tyrosine 171, which is associated with the loss of lasp-1 localization to focal adhesions and induction of cell death. Thus, lasp-1 is a dynamic focal adhesion protein necessary for cell migration and survival in response to growth factors and ecm proteins. SIGNOR-124719 0.348 CDC25A protein P30304 UNIPROT RAF1 protein P04049 UNIPROT down-regulates dephosphorylation 9606 7744247 t gcesareni Cdc25a can act on substrates other than cdks, since it dephosphorylates the homeodomain transcription factor cut and interacts with and dephosphorylates the proto-oncogene raf-1, resulting in a significant decrease in raf-1 kinase activity SIGNOR-32548 0.4 ZNF224 protein Q9NZL3 UNIPROT ALDOA protein P04075 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17900823 f miannu We previously reported that ZNF224, a novel Krüppel-associated box-containing zinc-finger protein, represses aldolase A gene transcription by interacting with the KAP-1 co-repressor. SIGNOR-255627 0.499 IMPDH2 protein P12268 UNIPROT 5'-xanthylic acid smallmolecule CHEBI:15652 ChEBI up-regulates quantity chemical modification 9606 19480389 t miannu IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. The IMPDH-catalyzed conversion of IMP to XMP is the first committed and rate-limiting step in guanine nucleotide biosynthesis. XMP is subsequently converted to GMP by the action of GMP synthetase (GMPS). SIGNOR-267335 0.8 MAP3K8 protein P41279 UNIPROT MAP3K14 protein Q99558 UNIPROT up-regulates activity phosphorylation Thr559 TGDYIPGtETHMAPE 9606 9742107 t lperfetto In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha SIGNOR-249387 0.546 PPP1CA protein P62136 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser75 LGYEPEGsASPTPPY 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248551 0.336 APLNR protein P35414 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256960 0.254 GADD45A protein P24522 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates binding 9606 20626350 t gcesareni Gadd45alfa appears to act as an endogenous inhibitor of the alternative p38alfa-activation pathway in t-cell, by binding to p38alfa and preventing tyr323 phosphorilation SIGNOR-166584 0.469 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 10428798 t lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-217288 0.426 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-181195 0.2 CCL5 protein P13501 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates 9606 BTO:0000584 38339310 f miannu This suggests CCL5 not only remodels the PDAC TME to benefit tumor cells, but can also enhance the tumor cell’s metastatic potential. SIGNOR-277729 0.7 SGK1 protein O00141 UNIPROT FBXW7 protein Q969H0 UNIPROT up-regulates phosphorylation Ser227 QQRRRITsVQPPTGL 9606 BTO:0001271 21147854 t lperfetto Here, we report that the serum- and glucocorticoid-inducible protein kinase sgk1 remarkably reduced the protein stability of the active form of notch1 through fbw7activated sgk1 phosphorylated fbw7 at serine 227 SIGNOR-170404 0.294 AKT1 protein P31749 UNIPROT WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 t llicata Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt. SIGNOR-252481 0.399 CBX5 protein P45973 UNIPROT H3-3A protein P84243 UNIPROT up-regulates activity binding 9606 methylation:Lys10 RTKQTARkSTGGKAP 19111658 t miannu A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing. SIGNOR-264488 0.2 SMARCC2 protein Q8TAQ2 UNIPROT Neural progenitor-specific SWI/SNF complex SIGNOR-C477 SIGNOR form complex binding 9606 25195934 t miannu The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation.  SIGNOR-270616 0.825 FOXO6 protein A8MYZ6 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 25648147 t miannu We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH. SIGNOR-260103 0.2 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser325 SSNASTIsGRLSPIM -1 11980723 t llicata Phosphorylation of Ser319 forms a consensus sequence for phosphorylation by CK1, allowing it to phosphorylate Ser322, which in turn primes the CK1-catalysed phosphorylation of Ser325 | Multisite phosphorylation of the region containing Ser319, Ser322, Ser325 and Ser329 provides a signal for the nuclear exclusion of FKHR SIGNOR-252902 0.48 GP1BB protein P13224 UNIPROT GPIb-IX-V complex complex SIGNOR-C270 SIGNOR form complex binding 9606 BTO:0000132 16293600 t lperfetto The GPIb-V-IX receptor consists of 4 transmembrane subunits: GPIbα, disulfide-linked to GPIbβ, and the noncovalently associated GPIX and GPV components, in ratios of 2:2:2:1. SIGNOR-261850 0.647 STAT6 protein P42226 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20508200 f lperfetto Phosphorylated STAT6 dimerizes and translocates to the nucleus where it induces the expression of its target genes, including markers (Arg1, Chi3l3, Mrc1, Mgl1, and Retnla) and regulators (Pparalpha, Ppargamma and PGC-1?) of alternative activation. SIGNOR-249538 0.258 MLNR protein O43193 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257016 0.419 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser416 GFPSKTDsPSCEYSR 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262979 0.315 ACD protein Q96AP0 UNIPROT TERT protein O14746 UNIPROT up-regulates binding 9606 17237768 t miannu We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme. SIGNOR-152321 0.555 MAPK11 protein Q15759 UNIPROT HBA1 protein P69905 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20162623 f Indirect:regulation miannu Our results demonstrate that activin A induced Hb synthesis and promoter activation of the specific erythroid gene, ζ-globin, through p38α and p38β isoforms and their activator, MKK6 (mitogen-activated protein kinase kinase 6). SIGNOR-251834 0.2 PRLR protein P16471 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 17975019 f miannu We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. SIGNOR-254187 0.2 MAPK14 protein Q16539 UNIPROT BAZ1B protein Q9UIG0 UNIPROT up-regulates phosphorylation Ser158 KSDGACDsPSSDKEN 9606 19776015 t gcesareni Moreover, this region (wac domain) was also phosphorylated by recombinant proteins of p38_? And jnk2_? But not by akt1 SIGNOR-188160 0.2 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser203 PRLQHSFsFAGFPSA 9606 18326031 t lperfetto Mk2-mediated inhibition of brf1 requires phosphorylation at s54, s92, and s203. Phosphorylation of brf1 by mk2 does not appear to alter its ability to interact with ares or to associate with mrna decay enzymes. Thus, mk2 inhibits brf1-dependent amd through direct phosphorylation. SIGNOR-161270 0.611 ELP2 protein Q6IA86 UNIPROT Elongator complex complex SIGNOR-C466 SIGNOR form complex binding 9606 28601220 t miannu Elongator is a highly conserved eukaryotic protein complex consisting of two sets of six Elp proteins, while homologues of its catalytic subunit Elp3 are found in all the kingdoms of life. Although it was originally described as a transcription elongation factor, cumulating evidence suggests that its primary function is catalyzing tRNA modifications. In humans, defects in Elongator subunits are associated with neurological disorders and cancer. SIGNOR-269709 0.778 MRPL15 protein Q9P015 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262378 0.692 Vincristine sulfate chemical CHEBI:79401 ChEBI TUBB protein P07437 UNIPROT down-regulates activity chemical inhibition 9606 30599272 t miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. SIGNOR-259251 0.8 PRKG1 protein Q13976 UNIPROT TNNI3 protein P19429 UNIPROT up-regulates activity phosphorylation Ser23 PAPIRRRsSNYRAYA 9606 15769444 t lperfetto Phosphorylation at ser 23/24 (e.g., by pka or pkg) results in reduction in myofilament ca2+ sensitivity and an increase in crossbridge cycling rate, leading to acceleration of relaxation and an increase in power output but a reduced economy of contraction. Conversely, phosphorylation at ser 43/45 (by pkc) is associated with reduced maximum ca2+-activated force and decreased crossbridge cycling rates, which are likely to reduce power output and delay relaxation, with an increased economy of contraction. SIGNOR-134640 0.363 M2_polarization phenotype SIGNOR-PH55 SIGNOR IL4 protein P05112 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. M2 polarized cells express a variety of anti-inflammatory mediators, such as IL-4, IL-10, and transforming growth factor-β (TGF-β), and contribute to immunoregulation SIGNOR-263822 0.7 MTMR2 protein Q13614 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI up-regulates quantity chemical modification 9606 18429927 t miannu PtdIns(3,5)P2 can be dephosphorylated by the 3-phosphatase myotubularins (MTMs), leading to the production of PtdIns5P. Myotubularins also dephosphorylate PtdIns3P into PtdIns SIGNOR-269808 0.8 Phenelzine chemical CHEBI:8060 ChEBI SLC6A2 protein P23975 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu At the human norepinephrine transporter, among the antidepressants desipramine was the most potent with a KD=0.83±0.05 nM. All the tetracyclic antidepressants, except mirtazapine, which is a structural analog of mianserin, were more potent at the norepinephrine transporter than at the serotonin transporter. Tomoxetine, considered from animal data to be very selective for the norepinephrine transporter, had high affinity for the human norepinephrine transporter (KD=2.03±0.06 nM). However, at the human serotonin transporter, tomoxetine was nearly as potent and close to that for dothiepin and venlafaxine. Venlafaxine, considered a serotonin and norepinephrine re-uptake inhibitor based on animal data, was very weak at the human norepinephrine transporter. Its KD value was 5× less that than for norepinephrine. All of the serotonin selective re-uptake inhibitors, with the exception of paroxetine, were also weak at the human norepinephrine transporter.  SIGNOR-258743 0.8 ACTB protein P60709 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity binding 9606 28233384 t lperfetto Here, we report the highest resolution, cryo-EM structures of actin filaments with bound ATP analog β,γ-imidoadenosine 5′-triphosphate (AMPPNP) (3.1 Å) and ADP with inorganic phosphate (ADP-Pi) (3.1 Å) as well as a 3.6-Å resolution structure of the ADP filament. These structures of the three well-characterized nucleotide states of actin monomers and filaments SIGNOR-261879 0.7 ibrutinib chemical CHEBI:76612 ChEBI BTK protein Q06187 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189641 0.8 CCT137690 chemical CID:25154041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190898 0.8 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity phosphorylation Tyr315 MPMDTSVyESPYSDP 9606 BTO:0000661 11828374 t lperfetto We show here that Tyr315 and Tyr319 in the interdomain B of ZAP-70 are autophosphorylated in vitro and become phosphorylated in vivo upon TCR triggering. Moreover, by mutational analysis, we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function. SIGNOR-247048 0.2 PIM proteinfamily SIGNOR-PF34 SIGNOR Histone H3 proteinfamily SIGNOR-PF69 SIGNOR down-regulates activity phosphorylation 9606 17643117 t gcesareni Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation. SIGNOR-265365 0.2 TRIM3 protein O75382 UNIPROT GKAP1 protein Q5VSY0 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 20352094 t miannu Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites. SIGNOR-271959 0.249 PRKCA protein P17252 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Ser12 KSKPKDAsQRRRSLE -1 2996780 t lperfetto We propose that protein kinase C is responsible for this modification based on the following evidence. First, the tumor promoters, 12-O-tetradecanoylphorbol-13-acetate and teleocidin, and synthetic diacylglycerol, known activators of protein kinase C in vivo, cause nearly complete phosphorylation of pp60src at serine 12. Second, among five purified serine/threonine-specific protein kinases tested, only protein kinase C phosphorylates pp60c-src and pp60v-src in vitro at serine 12. Third, purified protein kinase C phosphorylates a synthetic peptide corresponding to the N-terminal 20 amino acids of pp60c-src at serine 12. The physiological significance of this novel phosphorylation is discussed. SIGNOR-248893 0.589 TBX2 protein Q13207 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249594 0.51 HOXD3 protein P31249 UNIPROT ITGA5 protein P08648 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14610084 t Luana The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis. SIGNOR-261649 0.252 DNAAF10 protein Q96MX6 UNIPROT PAQosome co-chaperone complex complex SIGNOR-C516 SIGNOR form complex binding 9606 30484152 t miannu The PAQosome (Particle for Arrangement of Quaternary structure) is a large multisubunit chaperone complex that is essential for the assembly and stabilization of other macromolecular complexes. It also interacts with several chaperones including Hsp90, Hsp70, and CCT. The PAQosome is comprised of the R2TP complex, the URI1 prefoldin complex (also known as the non-canonical prefoldin-like complex), the RNA polymerase subunit RPB5, and the WD40 repeat protein WDR92.  SIGNOR-270921 0.2 DYRK3 protein O43781 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates activity phosphorylation Ser1330 PAFGRVSsPPNAMMS 9606 BTO:0000578 31066068 t miannu Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. SIGNOR-275451 0.2 STAT1 protein P42224 UNIPROT IRF2 protein P14316 UNIPROT up-regulates activity binding 9606 15778351 t miannu We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2. SIGNOR-254532 0.558 MAPK9 protein P45984 UNIPROT BAX protein Q07812 UNIPROT up-regulates 9606 15071501 f JNK-mediated phosphorylation of 14-3-3 at Ser184 reduces its affinity for Bax. gcesareni Demonstrate that jnk-mediated phosphorylation of 14-3-3 induces the release of bax from 14-3-3 and triggers its translocation to the mitochondria;these results strongly indicate that jnk regulates the activity of bax by phosphorylating 14-3-3 proteins. SIGNOR-124023 0.301 ELOVL6 protein Q9H5J4 UNIPROT palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI down-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267887 0.8 N(2)-formyl-N(1)-(5-phospho-beta-D-ribosyl)glycinamide(2-) smallmolecule CHEBI:147286 ChEBI 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267307 0.8 RAB5B protein P61020 UNIPROT Early Endosome complex SIGNOR-C246 SIGNOR form complex binding 9606 19924646 t lperfetto The Rab proteins primarily localized to the EE include Rab5 and Rab4, which regulate distinct early endocytic events. In addition to these two Rab proteins, some of the other less well-characterized Rabs at the EE include Rab10 , Rab14 , Rab21 and Rab22 SIGNOR-276874 0.469 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-219312 0.752 PRKCA protein P17252 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser190 RGAPKRGsGKDSHHP -1 2413024 t lperfetto MBP was phosphorylated by either protein kinase A or C | Subsequent amino acid analysis and/or sequential Edman degradation of the purified phosphopeptides, together with the known primary sequence of this protein, revealed that Ser-46 and Ser-151 were specifically phosphorylated by protein kinase C, whereas Thr-34 and Ser-115 were phosphorylated preferentially by protein kinase A. Both kinases reacted with Ser-8, Ser-11, Ser-55, Ser-110, Ser-132, and Ser-161 at various reaction velocities. SIGNOR-248871 0.498 Caspase-2 PIDDosome complex SIGNOR-C292 SIGNOR BID protein P55957 UNIPROT up-regulates activity cleavage 9606 20158568 t miannu Inactive caspase-2 monomers are recruited to the PIDDosome in response to certain cellular stresses. This results in dimerization and activation of caspase-2. Caspase-2 cleaves and activates Bid to induce MOMP eventually resulting in activation of executioner caspases by caspase-9-mediated cleavage. SIGNOR-262644 0.56 RAB23 protein Q9ULC3 UNIPROT GLIS2 protein Q9BZE0 UNIPROT down-regulates 9606 16364285 f gcesareni Based on su(fu) function, we predict that rab23 can interact with all gli1 molecules including gli1, gli2 and gli3, and inhibit their transcriptional activities and nuclear localization. SIGNOR-143163 0.2 SKIL protein P12757 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12419246 t lperfetto Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad7 SIGNOR-217703 0.686 MAPK3 protein P27361 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser789 QSVDKVTsPTKV 9606 BTO:0001260 10514499 t lperfetto Extracellular signal-regulated kinases (erks) phosphorylate the high molecular mass isoform of the actin-binding protein caldesmon (h-cad) at two sites (ser(759) and ser(789)) during smooth muscle stimulation. Nmr spectroscopy shows that the actin binding properties of the minimal inhibitory region of caldesmon, residues 750-779, alter upon map kinase phosphorylation of ser-759, a residue not involved in actin binding. This phosphorylation leads to markedly diminished actin affinity as a result of the loss of interaction at one of the two sites that bind to f-actin. SIGNOR-71045 0.467 MAPK1 protein P28482 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates activity phosphorylation Ser376 EKLFQGYsFVAPSIL 15568999 t lperfetto In the present study, we show that, in addition to being phosphorylated on Thr-581 and Ser-360 by ERK1/2 or p38, MSK1 can autophosphorylate on at least six sites: Ser-212, Ser-376, Ser-381, Ser-750, Ser-752 and Ser-758. Of these sites, the N-terminal T-loop residue Ser-212 and the 'hydrophobic motif' Ser-376 are phosphorylated by the C-terminal kinase domain of MSK1, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain of MSK1 SIGNOR-249445 0.606 TRIM38 protein O00635 UNIPROT TRIM38 protein O00635 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21306652 t miannu Our study shows that, similar to other TRIM family members, TRIM38 is localized in the cytoplasm. TRIM38 increases ubiquitination of other cellular proteins and catalyzes self-ubiquitination. TRIM38 also promotes K63- and K48-linked ubiquitination of cellular proteins. An intact RING domain is important for the functions of TRIM38. In addition, enterovirus 71 infection induces TRIM38 degradation. SIGNOR-271906 0.2 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser299 SQPPGEDsDTDVDDD 9606 18678890 t gcesareni The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites. SIGNOR-179875 0.35 ATF4 protein P18848 UNIPROT NARS1 protein O43776 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269422 0.2 spiperone chemical CHEBI:9233 ChEBI HTR2B protein P41595 UNIPROT down-regulates activity chemical inhibition 10036 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258692 0.8 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248327 0.755 DYRK2 protein Q92630 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser321 QSLSLASsPKGTIEN 9606 BTO:0002181 34363019 t miannu Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.  SIGNOR-276735 0.2 MED25 protein Q71SY5 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266681 0.581 FERMT3 protein Q86UX7 UNIPROT ITGB3 protein P05106 UNIPROT up-regulates activity binding 10090 BTO:0000132;BTO:0003292 18278053 t lperfetto Mechanistically, Kindlin-3 can directly bind to regions of beta-integrin tails distinct from those of Talin and trigger integrin activation. We have therefore identified Kindlin-3 as a novel and essential element for platelet integrin activation in hemostasis and thrombosis|Kindlin-3 was also able to interact with the wild-type beta1 and beta3 integrin tails (Fig. 3c), in the presence and absence of Talin1 (Supplementary Fig. 3 online), and the F3 subdomain of Kindlin-3 was sufficient for this interaction and this interaction occurred in a direct manner SIGNOR-266066 0.644 WT1 protein P19544 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23042785 t irozzo Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. SIGNOR-255904 0.386 KAT2B protein Q92831 UNIPROT H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269625 0.2 PHKG1 protein Q16816 UNIPROT PHKG1 protein Q16816 UNIPROT unknown phosphorylation Ser31 EILGRGVsSVVRRCI -1 7935360 t miannu Phosphopeptides correspond to sequences occurring in the gamma-subunit of phosphorylase kinase […] undergoes autophosphorylation. phosphorylation occurs primarily at Ser30 while in the latter an additional reaction takes place at Ser81. SIGNOR-250388 0.2 WNT10B protein O00744 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 12055200 t fspada Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6 SIGNOR-89134 0.657 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A1 protein P11166 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8940145 f gcesareni The constitutively active akt also increased the synthesis of the ubiquitously expressed glucose transporter 1. The increased glucose influx in the 3t3-l1 adipocytes directed lipid but not glycogen synthesis SIGNOR-45064 0.2 ELK4 protein P28324 UNIPROT INSIG2 protein Q9Y5U4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 20145255 t Luana Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter. SIGNOR-261592 0.2 CDK14 protein O94921 UNIPROT CCNY protein Q8ND76 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 RASTIFLsKSQTDVR 9606 BTO:0000599 24794231 t lperfetto Phosphorylation of cyclin Y by CDK14 induces its ubiquitination and degradation|Phosphorylation of CCNY at Serines 71 and 73 creates a putative phospho-degron that controls its association with an SCF complex SIGNOR-273008 0.826 STK38 protein Q15208 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 BTO:0000007 21262772 t no lperfetto More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. | SIGNOR-272961 0.2 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 19162178 t gcesareni The hgf-induced wave2 transport, lamellipodia formation, stathmin/op18 phosphorylation at ser38 and binding to kinesin-wave2 complex, but not stathmin/op18 phosphorylation at ser25 and microtubule growth, were abrogated by pak1 inhibitor ipa-3 SIGNOR-183503 0.38 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT down-regulates activity phosphorylation Ser14 PFSFGTLsSWELEAW 9606 BTO:0000567 12876286 t llicata CHOP transcription factor phosphorylation by casein kinase 2 inhibits transcriptional activation. | The serine to alanine substituted site CHOP mutant was not phosphorylated by CK2, indicating that serines 14–15 and 30–31 of CHOP are the CK2 phosphoacceptor sites SIGNOR-250850 0.348 RABGGTA protein Q92696 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity lipidation 9606 BTO:0000007 18532927 t miannu Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional SIGNOR-265572 0.614 PPP1CA protein P62136 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000599;BTO:0001594 19440292 t Avicins dephosphorylate Stat3 in a variety of human tumor cell lines, leading to a decrease in the transcriptional activity of Stat3.| However, PD98059, an inhibitor of MEK1/2, had no significant effects on avicin-induced dephosphorylation of Stat3 (Ser 727) SIGNOR-248563 0.332 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser379 DLILNRCsESTKRKL 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89288 0.399 neratinib chemical CHEBI:61397 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 23632474 t Neratinib (HKI-272) is a tyrosine kinase inhibitor, under investigation for the treatment breast cancer and other solid tumours. gcesareni Ineratinib is a potent irreversible pan-erbb tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (her)-2-positive breast cancer and other solid tumours. SIGNOR-202015 0.8 succinate(2-) smallmolecule CHEBI:30031 ChEBI fumarate(2-) smallmolecule CHEBI:29806 ChEBI up-regulates quantity precursor of 9606 16143825 t miannu Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. The SDH enzyme, also known as respiratory chain complex II, faces the mitochondrial matrix and is bound to the inner membrane. The human enzyme readily oxidizes succinate to fumarate, while the reverse reaction is hardly detectable in most human cells and tissues under standard conditions. SIGNOR-266275 0.8 SRC protein P12931 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates phosphorylation Tyr736 FGMSRNLySGDYYRI 9606 16186108 t gcesareni Here, using baculoviral co-expression of the ddr2 cytosolic domain and src, we show that src targets three tyrosine residues (tyr-736, tyr-740, and tyr-741) in the activation loop of ddr2 for phosphorylation. This phosphorylation by src stimulates ddr2 cis-autophosphorylation of additional tyrosine residues. SIGNOR-140728 0.385 N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:17311 ChEBI 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI up-regulates quantity precursor of 9606 11431483 t miannu Epsilon-N-Trimethyllysine hydroxylase (EC ) is the first enzyme in the biosynthetic pathway of l-carnitine and catalyzes the formation of beta-hydroxy-N-epsilon-trimethyllysine from epsilon-N-trimethyllysine, a reaction dependent on alpha-ketoglutarate, Fe(2+), and oxygen. SIGNOR-269685 0.8 MAPK1 protein P28482 UNIPROT MCRIP1 protein C9JLW8 UNIPROT down-regulates activity phosphorylation Thr30 PSSSEIFtPAHEENV 9606 25728771 t lperfetto When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation SIGNOR-264774 0.2 DOK1 protein Q99704 UNIPROT Av/b3 integrin complex SIGNOR-C177 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257688 0.338 CDK16 protein Q00536 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization phosphorylation Ser10 NVRVSNGsPSLERMD 9606 BTO:0000567 25205104 t lperfetto In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells.|Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target. SIGNOR-273016 0.336 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser105 KKEESEEsDDDMGFG 9606 12379128 t gcesareni The phosphorylation sites in grk2-phosphorylated p2 are identified (s102 and s105) and are identical to the sites known to regulate p2 activity. SIGNOR-94258 0.2 Nalorphine chemical CHEBI:7458 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9262330 t miannu We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. SIGNOR-258664 0.8 ERG protein P11308 UNIPROT WNT3A protein P56704 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001321 23913826 t Luana Interestingly, our data showed that ERG drastically induced Wnt ligand gene expression. SIGNOR-261598 0.2 CUDC-101 chemical CID:24756910 PUBCHEM HDAC10 protein Q969S8 UNIPROT down-regulates activity chemical inhibition -1 20143778 t miannu By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. SIGNOR-262257 0.8 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr806 PLLLIVEyAKYGSLR 9606 14711813 t llicata Mass spectrometric analysis revealed that ret tyr(806), tyr(809), tyr(900), tyr(905), tyr(981), tyr(1062), tyr(1090), and tyr(1096) were autophosphorylation sites. these facts suggest that tyr806 and tyr809, located in this unique position, play a novel supplemental role for the activation loop upon phosphorylation. SIGNOR-121153 0.2 TRIM59 protein Q8IWR1 UNIPROT IRF7 protein Q92985 UNIPROT down-regulates activity 9606 BTO:0000567; BTO:0002181 22588174 f Giorgia TRIM59 also inhibited the phosphorylation of IRF3 and IRF7, which induces dimerization, suggesting that TRIM59 negatively regulates kinases for IRF3/7 (IKKe/TBK1) or their upstream signal SIGNOR-260374 0.26 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258897 0.8 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI (6S)-5-methyltetrahydrofolate(2-) smallmolecule CHEBI:18608 ChEBI up-regulates quantity precursor of 9606 10720211 t lperfetto Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and contributes to the metabolism of the amino acid homocysteine. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus generating the active form of folate required for remethylation of homocysteine to methionine. SIGNOR-268230 0.8 MRAP2 protein Q96G30 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000246 19329486 t miannu We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor. SIGNOR-252361 0.547 ENO3 protein P13929 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI up-regulates quantity chemical modification 9606 29767008 t miannu Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. Subsequent studies have shown that three types of enolase isoenzymes exist in mammals: Œ±-enolase (ENO1) is present in almost all mature tissues; Œ≤-enolase (ENO3) exists primarily in muscle tissues; and Œ≥-enolase (ENO2) occurs mainly in nervous and neuroendocrine tissues. All enolases are composed of two identical subunits. SIGNOR-266526 0.8 Loratadine chemical CHEBI:6538 ChEBI SLC6A15 protein Q9H2J7 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 25318072 t Simone Vumbaca Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2. Our studies provide thefirst chemical tool for B0AT2. SIGNOR-261092 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser324 RDLELPLsPSLLGGP 9606 7889942 t gcesareni Erki phosphorylates five c-terminal sites in elk-i (s324, t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-252085 0.2 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR PAX7 protein P23759 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001103;BTO:0002314 22493066 t lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells NICD regulates Pax7 through interaction with RBP-J_, which binds to two consensus sites upstream of the Pax7 gene. SIGNOR-219365 0.383 spermine smallmolecule CHEBI:15746 ChEBI Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 14617280 f apalma Cell proliferation is highly dependent on the synthesis of polyamines, which are derived from arginine metabolism SIGNOR-255552 0.7 CBP/p300 complex SIGNOR-C6 SIGNOR ALOX15 protein P16050 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000018 12517954 f lperfetto IL-4 has been shown to up-regulate 15-lipoxygenase and produce 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) in A549 cells via the Janus kinase/STAT6 pathway under coactivation of CREB binding protein/p300. SIGNOR-254100 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR IDH2 protein P48735 UNIPROT down-regulates quantity by destabilization phosphorylation Thr197 GTFKMVFtPKDGSGV 34929314 t lperfetto During the cell cycle S phase, Cyclin A-CDK2 phosphorylates IDH1 on its Threonine 157 residue (Threonine 197 in IDH2) to facilitate its recognition and ubiquitination by Skp2 E3 ubiquitin, followed by degradation through 26S proteasome SIGNOR-267622 0.267 PINK1 protein Q9BXM7 UNIPROT PRKN protein O60260 UNIPROT up-regulates phosphorylation Ser65 NCDLDQQsIVHIVQR 9606 22724072 t llicata We show that human pink1 is specifically activated by mitochondrial membrane potential (??m) depolarization, enabling it to phosphorylate parkin at ser(65). We further show that phosphorylation of parkin at ser(65) leads to marked activation of its e3 ligase activity that is prevented by mutation of ser(65) or inactivation of pink1. SIGNOR-197976 0.2 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr234 SFKKQEKtPKTPKGP 10090 SIGNOR-C16 11278991 t lperfetto We have recently found that nucleophosmin (npm/b23), a phosphoprotein primarily found in nucleolus, associates with unduplicated centrosomes and is a direct substrate of cdk2-cyclin e in centrosome duplication. Upon phosphorylation by CDK2-cyclin E, NPM/B23 dissociates from centrosomes, which is a prerequisite step for centrosomes to initiate duplication. SIGNOR-235725 0.572 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 BTO:0000763;BTO:0000149 10197981 t llicata Oncogenically activated ras inhibits the tgfbeta-induced nuclear accumulation of smad2 and smad3 and smad-dependent transcription. Ras acting via erk map kinases causes phosphorylation of smad2 and smad3 at specific sites in the region linking the dna-binding domain and the transcriptional activation domain. SIGNOR-66742 0.74 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI L-asparagine zwitterion smallmolecule CHEBI:58048 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268071 0.8 SHANK2 protein Q9UPX8 UNIPROT ACTN1 protein P12814 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264584 0.3 PTK6 protein Q13882 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Tyr315 TFCGTPEyLAPEVLE 9606 BTO:0000150 BTO:0001129 20606012 t gcesareni Here we demonstrate that AKT is a direct substrate of PTK6 and that AKT tyrosine residues 315 and 326 are phosphorylated by PTK6. SIGNOR-252618 0.463 ATM protein Q13315 UNIPROT RNF20 protein Q5VTR2 UNIPROT up-regulates phosphorylation 9606 21763684 t gcesareni E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm. SIGNOR-174949 0.531 TCF3 protein P15923 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 23684607 f miannu The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. SIGNOR-255385 0.318 TLN1 protein Q9Y490 UNIPROT ITGB2 protein P05107 UNIPROT up-regulates activity binding 10090 BTO:0000132 19118207 t miannu Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails. SIGNOR-257618 0.711 BTRC protein Q9Y297 UNIPROT GLI2 protein P10070 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0002572 16611981 t The interaction between BTRC and Gli2 occur whne Gli2 is phosphorilated. lperfetto The phosphorylated gli2 protein interacts with beta-trcp, and is ubiquitinated and degraded by the proteasome SIGNOR-146109 0.642 SNTB1 protein Q13884 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255992 0.5 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression 9606 17909097 f inferred from family member gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-267789 0.8 TFG protein Q92734 UNIPROT SEC16A protein O15027 UNIPROT up-regulates binding 9606 21478858 t miannu We identify tfg-1, a new conserved regulator of protein secretion that interacts directly with sec-16 and controls the export of cargoes from the endoplasmic reticulum in caenorhabditis elegans. Hydrodynamic studies indicate that tfg-1 forms hexamers that facilitate the co-assembly of sec-16 with copii subunits. SIGNOR-173242 0.635 DUSP1 protein P28562 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates dephosphorylation 9606 10617468 t inferred from 70% of family members gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. SIGNOR-269930 0.83 PAN2-PAN3 deadenylation complex complex SIGNOR-C553 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI down-regulates quantity by destabilization chemical modification 9606 34280615 t miannu There are two major deadenylase complexes, Ccr4-Not and Pan2-Pan3, which shorten the 3′ poly(A) tail of mRNA and are conserved from yeast to human.The Ccr4-Not complex has two catalytic subunits including the Ccr4 (Carbon catabolite repressor 4) and Pop2 (PGK promoter directed overproduction). The Pan2-Pan3 complex comprises the catalytic subunit Pan2, a member of the RNase D family, and the regulatory subunit Pan3. Degradation of mRNA begins with either shortening of the poly(A) tail by deadenylases or removal of 5′ cap structure by the decapping enzyme Dcp1-Dcp2. SIGNOR-273872 0.8 adenosine smallmolecule CHEBI:16335 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI up-regulates quantity precursor of 9606 33961946 t miannu Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5‚Ä≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). SIGNOR-267836 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Thr92 EVPDVTAtPARLLFF 9606 18676833 t gcesareni Mcl-1 is phosphorylated at two sites in mitosis, ser64 and thr92. Phosphorylation of thr92 by cyclin-dependent kinase 1 (cdk1)-cyclin b1 initiates degradation of mcl-1 in cells arrested in mitosis by microtubule poisons. SIGNOR-216900 0.427 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr325 TELEPLCtPVVTCTP 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-252357 0.787 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1654 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269338 0.721 LYN protein P07948 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr759 LYDVSRMyVDPSEIN -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249384 0.609 TBP protein P20226 UNIPROT SL1 complex complex SIGNOR-C464 SIGNOR form complex binding 9606 30693017 t lperfetto SL1 comprises TBP, TAF1A (also known as TAFI48), TAF1B (also known as TAFI63), TAF1C (also known as TAFI110), and TAF1D (also known as TAFI41) and recruits the RNAP1 complex to induce PIC formation. SIGNOR-269562 0.743 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser910 KALGERVsIL 9606 BTO:0000776 10473617 t llicata Activation of the serine kinase protein kinase d (pkd)/pkcmicro is controlled by the phosphorylation of two serine residues within its activation loop via a pkc-dependent signaling cascade. In this study we have identified the c-terminal serine 916 residue as an in vivo phosphorylation site within active pkd/pkcmu. moreover, using different mutants of pkd/pkcmu, we show that serine 916 is not trans-phosphorylated by an upstream kinase but is rather an autophosphorylation event that occurs following activation of pkd/pkcmu. SIGNOR-70525 0.2 RAB6C protein Q9H0N0 UNIPROT VPS13B protein Q7Z7G8 UNIPROT down-regulates activity binding 9606 BTO:0000007 25492866 t miannu Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 Golgi Localization Is Mediated by Active RAB6 . COH1 Interacts with All Three Mammalian RAB6 Homologues SIGNOR-269204 0.2 axitinib chemical CHEBI:66910 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 21297102 t gcesareni Axitinib , a highly selective inhibitor of vascular endothelial growth factor receptors taken orally, is approved for second-line treatment of advanced renal cell carcinoma (rcc) after failure of prior treatment with sunitinib or a cytokine. SIGNOR-171863 0.8 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RARG protein P13631 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256196 0.8 TBX5 protein Q99593 UNIPROT FGF10 protein O15520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18451335 f miannu TBX5 is expressed, among others, in the embryonic heart and forelimbs.8 In the heart, it regulates transcription of downstream genes such as the atrial natriuretic factor (NPPA) and fibroblast growth factor 10 (FGF10) by the binding to T-box binding elements (TBEs),11 often in combination with the NKX2-5 transcription factor. SIGNOR-255383 0.455 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr243 ARRLCDLyYINSPEL 9606 22195962 t llicata Mitochondrial pdhk1 is tyrosine phosphorylated and activated by fgfr1 in cancer cells further mass spectrometric analysis identified three tyrosine residues of pdhk1, including y136, y243 and y244, that are phosphorylated by fgfr1 SIGNOR-191723 0.352 HOXD12 protein P35452 UNIPROT MAFG protein O15525 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221958 0.38 WNT5A protein P41221 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates binding 9606 2808370 t gcesareni Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway. SIGNOR-23441 0.761 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr387 LMRTLCGtPTYLAPE 9606 BTO:0000007 11901158 t gcesareni Phosphorylation of thr-68 by the ataxia telangiectasia-mutated is necessary for efficient activation of chk2 when cells are exposed to ionizing radiation. By an unknown mechanism, this initial event promotes additional autophosphorylation events including modifications of thr-383 and thr-387 SIGNOR-116131 0.2 ADP chemical CHEBI:16761 ChEBI PRKAG1 protein P54619 UNIPROT up-regulates chemical activation 9606 SIGNOR-C15 21399626 t gcesareni Amp binding to the gamma-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation.Adp also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. Atp promotes dephosphorylation of catalytic subunit, rendering the ampk enzyme inactive. SIGNOR-172813 0.8 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 9727491 t gcesareni Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them. SIGNOR-256459 0.734 CARD8 protein Q9Y2G2 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 16678772 t amattioni Tucan is a recently identified card-containing protein that can complex with caspase-9 and prevent cytochrome c-induced caspase activation. SIGNOR-146663 0.432 CTSL protein P07711 UNIPROT BGLAP protein P02818 UNIPROT down-regulates quantity by destabilization cleavage Gly58 RYLYQWLgAPVPYPD -1 9076588 t miannu This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. SIGNOR-256321 0.2 WNK3 protein Q9BYP7 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation 21613606 t lperfetto We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs SIGNOR-264626 0.508 NARS2 protein Q96I59 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270465 0.8 EXOSC7 protein Q15024 UNIPROT Exosome_Complex complex SIGNOR-C255 SIGNOR form complex binding -1 24189234 t miannu The RNA exosome is an evolutionarily conserved multi-protein complex involved in the 3' degradation of a variety of RNA transcripts. In the nucleus, the exosome participates in the maturation of structured RNAs, in the surveillance of pre-mRNAs and in the decay of a variety of noncoding transcripts. In the cytoplasm, the exosome degrades mRNAs in constitutive and regulated turnover pathways. The eukaryotic exosome, however, is composed of nine different subunits that are still somewhat related in sequence to the archaeal Rrp41-like subunits (Rrp41, Rrp46 and Mtr3), the archaeal Rrp42-like subunits (Rrp45, Rrp43 and Rrp42) and the cap proteins (Rrp4, Csl4 and Rrp40). SIGNOR-261386 0.919 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT up-regulates activity phosphorylation Tyr448 GDDSDEDyEKVPLPN 9534 BTO:0004055 12709437 t lperfetto By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk. SIGNOR-246596 0.563 DICER1 protein Q9UPY3 UNIPROT RISC(DICER1/AGO2/TARBP2) complex SIGNOR-C32 SIGNOR form complex binding 9606 16142218 t lperfetto Dicer and trbp interact in vivo and in vitro /our data indicate that trbp is primarily required for the assembly and/or functioning of si_ or mi_riscs in mammalian cells, but it may also facilitate the cleavage of pre_mirnas by dicer. SIGNOR-140223 0.94 SMURF2 protein Q9HAU4 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0001538 11158580 t miannu Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3.  SIGNOR-272936 0.718 FLI1 protein Q01543 UNIPROT HOXA10 protein P31260 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001549 17688409 f miannu Transcription factors GATA-1 and Fli-1 regulate human HOXA10 expression in megakaryocytic cells. Mutation of the GATA-1 and the Ets-1 motifs amplified the expression of HOXA10 in HEL and K562 cells, confirming the importance of these cis-acting elements in regulating HOXA10 expression in megakaryocytic cells. Chromatin immunoprecipitation (ChIP) and chloramphenicol acetyl transferase (CAT) assays confirm that HOXA11 binds to the putative binding site, resulting in repression of HOXA10 expression. SIGNOR-254471 0.2 PAK3 protein O75914 UNIPROT MYO6 protein Q9UM54 UNIPROT up-regulates activity phosphorylation Thr405 TAGGTKGtVIKVPLK -1 11517222 t miannu P21-activated kinase 3 phosphorylated myosin VI, and the site was identified as Thr(406). The phosphorylation of myosin VI significantly facilitated the actin-translocating activity of myosin VI.  SIGNOR-250244 0.339 PRKAB1 protein Q9Y478 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition SIGNOR-173044 0.524 PBRM1 protein Q86U86 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18339845 f miannu Endogenous wild-type baf180 bound to the p21 promoter and was required for proper p21 expression and g(1) arrest after transforming growth factor-beta and gamma-radiation treatment. SIGNOR-178022 0.265 UCHL3 protein P15374 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity deubiquitination Lys57 EAVAYAPkKELINIK 27941124 t lperfetto Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. | UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.|Our results suggested that three lysine sites (56, 57, and 63) on RAD51 that are close to E59 are deubiquitinated by UCHL3. SIGNOR-275907 0.328 KAT6A protein Q92794 UNIPROT KAT6A/KAT6B complex SIGNOR-C54 SIGNOR form complex binding 9606 BTO:0001271 17694082 t miannu Like gcn5/pcaf and p300/cbp, moz and morf are transcriptional co-activators with intrinsic hat activity. SIGNOR-157304 0.4 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207209 0.8 CSNK2A1 protein P68400 UNIPROT MRE11 protein P49959 UNIPROT up-regulates activity phosphorylation Ser561 MANDSDDsISAATNK -1 28436950 t miannu Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689. SIGNOR-265894 0.2 STAT5A protein P42229 UNIPROT IGF1 protein P05019 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 10050749 t lperfetto Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α SIGNOR-251743 0.441 FGFR4 protein P22455 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates phosphorylation Tyr642 RGVHHIDyYKKTSNG 9606 BTO:0001130 18670643 t lperfetto Binding of fgf to fgf receptors leads to receptor dimerization and subsequent tyrosine autophosphorylation and phosphorylation of target substrates. Autophosphorylation on tyrosine is considered to have at least two functions. One such function is the stimulation of the intrinsic protein tyrosine kinase activity by an allosteric mechanismthis antibody specifically recognizes tyr642/643 in fgfr-4. SIGNOR-179776 0.2 mTORC1 complex SIGNOR-C3 SIGNOR ISCU protein Q9H1K1 UNIPROT up-regulates phosphorylation Ser14 FRLRRAAsALLLRSP 9606 23508953 t lperfetto Here, we demonstrate that mtorc1 associates with iscu and phosphorylates iscu at serine 14. This phosphorylation stabilized iscu protein. SIGNOR-217082 0.2 PIK3CA protein P42336 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242649 0.7 KRAS protein P01116 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k SIGNOR-175210 0.625 BDNF protein P23560 UNIPROT NTRK2 protein Q16620 UNIPROT up-regulates binding 9606 7679912 t gcesareni Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb SIGNOR-31597 0.813 1-(6,8-difluoro-2-methyl-4-quinolinyl)-3-[4-(dimethylamino)phenyl]urea chemical CHEBI:92941 ChEBI HCRTR1 protein O43613 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206733 0.8 CDC25A protein P30304 UNIPROT CCNA2 protein P20248 UNIPROT up-regulates activity dephosphorylation 9606 16682204 t miannu Cdc25A dephosphorylates and activates CyclinE\u2013Cdk2, CyclinA\u2013Cdk2 and CyclinB\u2013Cdk1, whereas Cdc25B and Cdc25C primarily target CyclinB\u2013Cdk1  [4,5] . SIGNOR-277136 0.684 DUOX2 protein Q9NRD8 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264720 0.7 2'-deoxycytidine smallmolecule CHEBI:15698 ChEBI 2'-deoxycytosine 5'-monophosphate(2-) smallmolecule CHEBI:57566 ChEBI up-regulates quantity precursor of 20637175 t lperfetto Human deoxycytidine kinase (dCK4; EC 2.7.1.74) catalyzes the phosphorylation of 2′-deoxycytidine (dCyd), 2′-deoxyadenosine and 2′-deoxyguanosine to their corresponding monophosphate forms, using ATP or UTP as phosphoryl donors. This reaction is the first and rate-limiting step of the deoxyribonucleoside salvage pathway, which provides deoxynucleoside triphosphates for DNA replication and repair as an alternative to de novo nucleotide synthesis SIGNOR-275810 0.8 E2F1 protein Q01094 UNIPROT HIC1 protein Q14526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19491197 f miannu expression of E2F1 in the p53(-/-) hepatocellular carcinoma cell line Hep3B led to an increase of endogenous HIC1 mRNA, although bisulfite genomic sequencing of the HIC1 promoter revealed that the region bearing the two E2F1 binding sites is hypermethylated. In addition, endogenous E2F1 induced by etoposide treatment bound to the HIC1 promoter. Moreover, inhibition of E2F1 strongly reduced the expression of etoposide-induced HIC1. SIGNOR-253844 0.291 GRIK1 protein P39086 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. This is widely acknowledged for NMDARs, which have a high Ca2+ conductance, but Ca2+ flux through AMPARs and KARs can still be substantial. SIGNOR-264942 0.8 PRKACA protein P17612 UNIPROT GLI3 protein P10071 UNIPROT down-regulates quantity phosphorylation Ser1006 GHGVRRAsDPVRTGS 9606 10693759 t lperfetto Ci/gli zinc finger proteins mediate the transcriptional effects of hedgehog protein signals. In drosophila, ci action as transcriptional repressor or activator is contingent upon hedgehog-regulated, pka-dependent proteolytic processingall six pka phosphorylation sites are required for processing of gli3. SIGNOR-75339 0.454 NOTCH proteinfamily SIGNOR-PF30 SIGNOR IL7R protein P16871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 22577461 f lperfetto Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells SIGNOR-254345 0.2 TBK1 protein Q9UHD2 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates phosphorylation Ser403 ESLSQMLsMGFSDEG 9606 BTO:0000801 22921120 t llicata Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance. SIGNOR-191944 0.705 TFEB protein P19484 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes; SIGNOR-276559 0.397 AKT proteinfamily SIGNOR-PF24 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 11108261 t lperfetto Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt. SIGNOR-244243 0.2 SCF-FBW7 complex SIGNOR-C135 SIGNOR DEK protein P35659 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0002181 21282377 t miannu  These data suggest that the E3 ligase SCFFbxw7-α degrades p-DEK in a GSK-3β–dependent manner.Therefore, the phosphorylation of DEK by GSK-3β is a crucial step to mediate Tpm RNA splicing. SIGNOR-276304 0.292 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity by destabilization ubiquitination Lys569 DLHVVRPkLPKPPTD 10090 35670107 t lperfetto TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels SIGNOR-272540 0.2 RIPK1 protein Q13546 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity phosphorylation Ser14 LNVIKMKsSDFLESA -1 18408713 t miannu These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1) SIGNOR-276161 0.2 NKD1 protein Q969G9 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates binding 9606 BTO:0000671 15064403 t gcesareni Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation SIGNOR-123695 0.699 PTCH1 protein Q13635 UNIPROT SMO protein Q99835 UNIPROT down-regulates activity binding 9606 BTO:0001757;BTO:0001298 12192414 t lperfetto We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. SIGNOR-91709 0.782 MC2R protein Q01718 UNIPROT cortisol smallmolecule CHEBI:17650 ChEBI up-regulates quantity 9606 BTO:0000047 20371771 f lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). SIGNOR-268621 0.8 ATG16L1 protein Q676U5 UNIPROT CLTCL1 protein P53675 UNIPROT up-regulates binding 9606 20639872 t gcesareni Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors SIGNOR-166705 0.308 PTPRC protein P08575 UNIPROT TYK2 protein P29597 UNIPROT down-regulates activity dephosphorylation Tyr1054 AVPEGHEyYRVREDG 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248357 0.412 RRAGD protein Q9NQL2 UNIPROT RAGBD complex SIGNOR-C116 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228182 0.774 PPP1CA protein P62136 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity dephosphorylation Ser259 SQRQRSTsTPNVHMV 9606 16630891 t We have identified a complex comprised of Shoc2/Sur-8 and the catalytic subunit of protein phosphatase 1 (PP1c) as a highly specific M-Ras effector. M-Ras targets Shoc2-PP1c to stimulate Raf activity by dephosphorylating the S259 inhibitory site of Raf proteins SIGNOR-251649 0.273 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SNAI2 protein O43623 UNIPROT down-regulates quantity by destabilization phosphorylation Ser104 KDHSGSEsPISDEEE 9606 24662826 t miannu At G1/S transition, cyclin E-cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. SIGNOR-276629 0.29 SLBP protein Q14493 UNIPROT H2BC20P protein Q6DN03 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265382 0.2 PHA-680632 chemical CID:11249084 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206103 0.8 TTL protein Q8NG68 UNIPROT TUBA4A protein P68366 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176927 0.288 DOCK10 protein Q96BY6 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260549 0.509 SNTG2 protein Q9NY99 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255995 0.525 DLGAP5 protein Q15398 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264600 0.2 SGK1 protein O00141 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000007 11154281 t lperfetto We show here that sgk1, like akt, promotes cell survival and that it does so in part by phosphorylating and inactivating fkhrl1. However, sgk and akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on fkhrl1. While both kinases can phosphorylate thr-32, sgk displays a marked preference for ser-315 whereas akt favors ser-253. SIGNOR-252989 0.79 vatalanib chemical CHEBI:90620 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258309 0.8 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260577 0.744 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Thr205 PLKTGEQtPPHEHIC 9534 BTO:0000298 12756254 t miannu After mapping JNK-dependent JIP1 phosphorylation sites and testing their functional significance, it was observed that phosphorylation by JNK of JIP1 on Thr-103 and not other phosphorylated JIP1 residues is necessary for the regulation of DLK association with JIP1, DLK activation, and subsequent module activation. The data presented corroborates our previous observations using endogenous proteins, demonstrates that JNK binding to JIP1 is necessary for module activation, and shows that activation of JIP1-JNK module dynamics requires phosphorylation of JIP1 on Thr-103 by JNK. and Thr-205 are phosphorylated directly by JNK after JNK binds to JIP1. SIGNOR-250127 0.879 CSNK2A1 protein P68400 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser149 RRGASDLsSEEGWRL -1 8954982 t llicata Casein kinase 2 phosphorylates recombinant human spermidine/spermine N1-acetyltransferase on both serine and threonine residues. | suggesting that the Ser-phosphorylated residues are located in the C-terminus of the protein, probably Ser 146 and 149. SIGNOR-250950 0.328 Host translation inhibitor nsp1 protein P0DTD1-PRO_0000449619 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0002552 33188728 f miannu We present here data demonstrating that among all viral proteins, Nsp1 causes the most severe viability reduction in the cells of human lung origin. We found that introduction of Nsp1, but not other viral proteins, induced apoptosis in H1299 cells SIGNOR-262506 0.7 AMPK complex SIGNOR-C15 SIGNOR SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser122 YRNTGSIsGPKVNRP 10090 BTO:0003946 17341212 t miannu In the present study, we demonstrate that the metabolic sensing kinase AMPK (AMP-activated protein kinase) phosphorylates NKCC2 on Ser126 in vitro. Activation of AMPK in the MMDD1 (mouse macula densa-derived 1) cell line resulted in an increase in Ser126 phosphorylation in situ, suggesting that AMPK may phosphorylate NKCC2 in vivo. The functional significance of Ser126 phosphorylation was examined by mutating the serine residue to an alanine residue resulting in a marked reduction in co-transporter activity when exogenously expressed in Xenopus laevis oocytes under isotonic conditions. SIGNOR-263103 0.2 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260583 0.755 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser26 GTASRPSsSRSYVTT -1 11895474 t miannu In vitro analyses revealed that vimentin served as an excellent substrate for PAK. This phosphorylated vimentin lost the potential to form 10 nm filaments. We identified Ser25, Ser38, Ser50, Ser65 and Ser72 in the amino-terminal head domain as the major phosphorylation sites on vimentin for PAK.  SIGNOR-250237 0.309 UQCRFS1 protein P47985 UNIPROT Mitochondrial respiratory chain complex III complex SIGNOR-C279 SIGNOR form complex binding 30030361 t lperfetto Complex III (EC 1.10.2.2) or quinol-cytochrome c reductase performs electron transfer coupled to proton pumping using the ‘Q-cycle’ mechanism [79,80]. Structurally, it is a tightly bound symmetrical dimer (cIII2), being each ‘monomer’ composed of three catalytic core (MT-CYB, CYC1 and UQCRFS1) and seven supernumerary subunits SIGNOR-262190 0.934 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser203 PTETGESsQAEENIE -1 1828073 t llicata Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin.| SIGNOR-250867 0.309 CYC-116 chemical CID:6420138 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191224 0.8 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Thr14 IEKIGEGtYGVVYKG 9606 19574738 t gcesareni Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c SIGNOR-186617 0.855 PTPN1 protein P18031 UNIPROT PITX1 protein P78337 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr179 EDVYAAGySYNNWAA 9606 27752061 t lperfetto PTP1B dephosphorylates PITX-1 at Y160, 175 and Y179.|Through directly dephosphorylating PITX-1 at Y160, Y175 and Y179, PTP1B promoted proteasomal degradation of PITX-1, thus leaded in downregulating p120RasGAP and CRC cell survival. SIGNOR-276973 0.359 MAPK14 protein Q16539 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Thr568 SPGVPMQtPCFTLQY 9606 BTO:0000567 10806207 t llicata Rskb, a 90-kda ribosomal s6 protein kinase family (rsk) member with two complete catalytic domains connected by a linker, is activated through p38- and erk-mitogen-activated protein kinases. unlike other rsks, the activation loop phosphorylation sites of both catalytic domains of rskb, ser(196) and thr(568), were required for activity. Rskb activation depended on phosphorylation of linker ser(343) and ser(360) and associated with phosphorylation of nonconserved ser(347), but ser(347)-deficient rskb retained partial activity. SIGNOR-77220 0.593 PIK3R4 protein Q99570 UNIPROT PIK3C3 protein Q8NEB9 UNIPROT up-regulates activity binding 10090 27411398 t lperfetto Vps34 PI 3-kinase activity18 is stimulated by complex formation with the protein kinase Vps15|Rab5GTP binds Vps15, enhancing Vps34 activity SIGNOR-260709 0.939 dehydroepiandrosterone chemical CHEBI:28689 ChEBI androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI up-regulates quantity precursor of 9606 BTO:0000056 2139411 t lperfetto The isolation, cloning, and expression of a cDNA insert complementary to mRNA encoding human 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase is reported. |The expressed protein was similar in size to human placental microsomal 3 beta-hydroxysteroid dehydrogenase/delta 5----4isomerase, as detected by immunoblot analysis, and catalyzed the conversion of 17 alpha-hydroxypregnenolone to 17 alpha-hydroxyprogesterone, pregnenolone to progesterone, and dehydroepiandrosterone to androstenedione. SIGNOR-268641 0.8 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1696 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269342 0.721 DUSP9 protein Q99956 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates binding 9606 21908610 t gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-176589 0.696 CDK5 protein Q00535 UNIPROT EPRS1 protein P07814 UNIPROT down-regulates phosphorylation Ser886 LSQSSDSsPTRNSEP 9606 19647514 t lperfetto Ser(886) phosphorylation is required for the interaction of nsap1, which blocks eprs binding to target mrnas. The same phosphorylation event induces subsequent binding of ribosomal protein l13a and gapdh and restores mrna binding. Ifn-_ activates cdk5 to phosphorylate ser(886) in the linker domain of glutamyl-prolyl trna synthetase (eprs), the initial event in assembly of the gait complex. Cdk5/p35 also induces, albeit indirectly via a distinct kinase, phosphorylation of ser(999), the second essential event in gait pathway activation SIGNOR-187383 0.2 SP3 protein Q02447 UNIPROT CYP27A1 protein Q02318 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11867220 f miannu Therefore, Sp1, Sp3 and HNF4 co-operate in the expression of the human CYP27 gene in HepG2 cells. SIGNOR-255197 0.2 HTR1E protein P28566 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256984 0.368 ACTN1 protein P12814 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates quantity by stabilization binding 9606 27871158 t lperfetto Actin exists in polymer where filamin and α-actinin act as cross-linkers with approximately 1:10 ratios SIGNOR-261852 0.7 CTDSP1 protein Q9GZU7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser195 PNSSYPNsPGSSSST 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248799 0.484 EFNA2 protein O43921 UNIPROT EPHA6 protein Q9UF33 UNIPROT up-regulates binding 9606 10072375 t tpavlidou Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8) SIGNOR-65419 0.745 TEK protein Q02763 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252728 0.491 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258296 0.8 PRKCD protein Q05655 UNIPROT HAX1 protein O00165 UNIPROT down-regulates quantity by destabilization phosphorylation Ser210 QPKSYFKsISVTKIT 10090 BTO:0002572 25419709 t lperfetto FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells, SIGNOR-275562 0.2 CDK1 protein P06493 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser807 PGGNIYIsPLKSPYK 9606 1756735 t lperfetto The retinoblastoma gene product (prb) is a nuclear phosphoprotein that is thought to play a key role in the negative regulation of cellular proliferation. The active form of prb is underphosphorylated. Using synthetic peptides corresponding to potential cdc2 phosphorylation sites, we have developed a strategy which has allowed the identification of five sites. S249, t252, t373, s807 and s811 are phosphorylated in vivo, and in each case these sites correspond closely to the consensus sequence for phosphorylation by p34cdc2. SIGNOR-21552 0.68 HTR2C protein P28335 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256734 0.296 EGFR protein P00533 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr155 LNDSAAYyLNDLDRI -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277226 0.449 MAP3K5 protein Q99683 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates activity phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17937911 t lperfetto Reporter gene assays showed that all three identified in vitro autophosphorylation sites (thr813, thr838, thr842) regulate ask1 signalingmutation of thr838 drastically reduced reporter gene activity when compared to unstimulated control levels. Interestingly, mutation of the other two sites also provided a significant reduction in ask1 function (figure 6a), suggesting that autophosphorylation at the residues thr842 and thr813 regulates ask1 signaling. SIGNOR-158427 0.2 GCG protein P01275 UNIPROT GCGR protein P47871 UNIPROT up-regulates binding 9606 12529935 t fspada Mutation of a highly conserved d64 residue in the n-terminal portion of the rat glucagon receptor completely eliminates glucagon binding. This residue corresponds to a mutated asp residue at amino acid 60 in the growth hormone releasing hormone receptor that gives rise to the little mouse phenotype (lin et al.1993). Antisera directed against amino acid sequences 126_137 of the n-terminal region, and agai residues 206_219 of the first extracellular loop block [125i]-glucagon binding and interfere with glucagon-induced adenylyl cyclase generation in rat liver membranes. SIGNOR-97338 0.772 sorafenib tosylate chemical CHEBI:50928 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 16757355 t miannu Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis. The in vitro and cellular profile of sorafenib is summarized in Table I. SIGNOR-259225 0.8 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT up-regulates sumoylation Lys160 EAHQWFLkHEARPLA 9534 9756909 t lperfetto We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation. SIGNOR-261786 0.774 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr228 GPSSSLNtPGSFRRG 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274085 0.533 diisononyl phthalate chemical CHEBI:35459 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). SIGNOR-268775 0.8 UPF1 protein Q92900 UNIPROT Upf-EJC complex SIGNOR-C367 SIGNOR form complex binding 9606 BTO:0000567 17803942 t miannu The three Up-frameshift (Upf) proteins, Upf1, Upf2, and Upf3 that together form the Upf complex, constitute the conserved core of NMD from yeast to humans. hUpf3b Forms Multiple Contacts with the EJC and Depends on hUpf2 for Complex Formation with hUpf1 SIGNOR-265237 0.968 PKC proteinfamily SIGNOR-PF53 SIGNOR SLITRK1 protein Q96PX8 UNIPROT up-regulates activity phosphorylation Ser695 DCGSHSLsD -1 19640509 t miannu In our studies, SICD was phosphorylated by PKA, PKC, and CK2, and association of SLITRK1 with 14-3-3 was regulated by phosphorylation at Ser695. Co-precipitation experiments demonstrated much greater recovery of 14-3-3 in SLITRK1 precipitates when wild-type or S695E was used, as compared with S695A, consistent with the results with purified peptides. SIGNOR-273635 0.2 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 12361602 t apalma Notch is cleaved and translocates to the nucleus, where it activates a family of transcription factors, exemplified by Suppressor of Hairless and CBF/RJBk SIGNOR-255380 0.95 SOSTDC1 protein Q6X4U4 UNIPROT WNT4 protein P56705 UNIPROT down-regulates activity 10090 22829579 f lperfetto Our laboratory identified an almost twofold upregulation of sclerostin domain-containing 1 (Sostdc1; also referred to as WISE, USAG-1, ectodin), a dual Bmp/Wnt inhibitor, in postnatal day (P)1 pancreata from transgenic mice misexpressing hepatocyte nuclear factor (Hnf)6 in islet endocrine cells. SIGNOR-242707 0.281 GDNF protein P39905 UNIPROT NRG1 protein Q02297 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252182 0.369 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNK9 protein Q9NPC2 UNIPROT down-regulates activity phosphorylation Thr341 IEEISPStLKNSLFP 9606 BTO:0004232 17374744 t miannu PKC acts directly on hTASK3 channels to phosphorylate an identified amino acid in the C terminus region (Thr341), thereby reducing channel current.  SIGNOR-276059 0.2 PIK3C3 protein Q8NEB9 UNIPROT Vps34 Complex I complex SIGNOR-C242 SIGNOR form complex binding -1 30397185 t lperfetto PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. |Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. SIGNOR-260316 0.918 P2RY1 protein P47900 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257442 0.2 XAV939 chemical CHEBI:62878 ChEBI TNKS2 protein Q9H2K2 UNIPROT down-regulates chemical inhibition 9606 19759537 t gcesareni Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2. SIGNOR-188057 0.8 MBD2 protein Q9UBB5 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 f Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. SIGNOR-254026 0.2 PRKCB protein P05771 UNIPROT ANXA2 protein P07355 UNIPROT unknown phosphorylation Ser2 sTVHEILC -1 8898866 t lperfetto A comparison of the phosphorylation patterns obtained identified Ser-II as the protein kinase C site responsible for regulating the annexin II-p11 interaction. Ser-II lies within the sequence mediating p11 binding, i.e. amino-acid residues 1 to 14 of annexin II, and phosphorylation at this site most likely leads to a direct spatial interference with p11 binding. SIGNOR-248956 0.335 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI corticosterone smallmolecule CHEBI:16827 ChEBI up-regulates quantity precursor of 9606 BTO:0000048 33117906 t lperfetto The zona glomerulosa lacks the 17alpha-hydroxylase enzyme, committing pregnenolone to the exclusive production of aldosterone.|In the adrenal steroidogenic pathway, 21-hydroxylase (P450c21) catalyzes the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol to form cortisol and the conversion of progesterone to 11-deoxycorticosterone to form aldosterone SIGNOR-268673 0.8 TRIM62 protein Q9BVG3 UNIPROT TRIM62 protein Q9BVG3 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23402750 t miannu A ubiquitination assay performed in HEK293T cells further confirmed the E3 ubiquitin ligase activity and self-ubiquitination activity of TRIM62 and the requirement of the RING finger domain. Importantly, the treatment of HEK293T cells with a proteasome inhibitor stabilized poly-ubiquitinated TRIM62, indicating that self-ubiquitination promoted the proteasomal degradation of TRIM62.  SIGNOR-272102 0.2 MTOR protein P42345 UNIPROT MTOR protein P42345 UNIPROT up-regulates activity phosphorylation Ser2481 TVPESIHsFIGDGLV 10090 BTO:0000944 SIGNOR-C2 SIGNOR-C2 20022946 t lperfetto We have found that in HEK293 cells and 3T3-L1 adipocytes, insulin promotes both raptor- and rictor-associated mTOR Ser(P)-2481 in a wortmannin-sensitive manner. Thus, insulin signals via PI3K to promote both mTORC1- and mTORC2-associated mTOR Ser-2481 autophosphorylation. SIGNOR-235427 0.2 USP13 protein Q92995 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization deubiquitination 9606 BTO:0006155 27923907 t done miannu  In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation. SIGNOR-274124 0.358 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 9346241 t lperfetto We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation SIGNOR-216389 0.886 IFNGR1 protein P15260 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR form complex binding 9606 BTO:0000801 19041276 t lperfetto The activation of this signaling pathway involves the binding of IFN-g to two IFN-g receptor (IFN-gR) subunits, made up of respective IFNgR1:IFNgR2 pairs, which dimerize upon IFN-g binding to form the IFN-gR complex. Two JAKs, JAK1and JAK2,which bind to each IFN-gR subunits, respectively through their N-terminal domains, both become activated by tyrosine phosphorylation in a JAK2-dependent process. SIGNOR-249485 0.737 RPS6KB1 protein P23443 UNIPROT IRS1 protein P35568 UNIPROT down-regulates quantity by destabilization phosphorylation Ser639 YMPMSPKsVSAPQQI 10090 BTO:0002572 18498745 t lperfetto In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8 SIGNOR-236599 0.784 phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI up-regulates quantity precursor of 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266538 0.8 ZNRF3 protein Q9ULT6 UNIPROT FZD6 protein O60353 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22575959 t Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. SIGNOR-260114 0.604 PIK3CD protein O00329 UNIPROT PIK3CD protein O00329 UNIPROT down-regulates phosphorylation Ser1039 NWLAHNVsKDNRQ 9606 10064595 t gcesareni Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo in vitro autophosphorylation of p110delta completely down-regulates its lipid kinase activity. SIGNOR-65186 0.2 Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 28347630 f miannu Microtubules are essential for the generation, migration and differentiation of neurons. Within dendrites microtubules have also been implicated in the formation and plasticity of spines. For instance, the treatment of hippocampal neurons with low doses of the microtubule destabilizing drug Nocodazole impairs BDNF induced dendritic spine formation SIGNOR-266829 0.7 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni In the absence of hedgehog signaling, gli1 is transcriptionally repressed, gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation, and gli3 is processed to a cleaved repressor. SIGNOR-154222 0.556 GNE protein Q9Y223 UNIPROT N-acyl-D-mannosamine 6-phosphate(2-) smallmolecule CHEBI:57666 ChEBI up-regulates quantity chemical modification 10745088 t lperfetto UDP-GlcNAc 2-epimerase is a bifunctional enzyme and catalyzes the first two steps of neuraminic acid synthesis in the cytosol, the conversion of UDP-N-acetylglucosamine to ManAc and the phosphorylation to ManAc-6-phosphate. SIGNOR-266074 0.8 MAP2K4 protein P45985 UNIPROT MAP2K4 protein P45985 UNIPROT up-regulates activity phosphorylation Thr261 LVDSIAKtRDAGCRP -1 9162092 t Ser221 and, to a lesser extent, Thr225 in MKK4 as necessary sites for basal and MEKK-induced autophosphorylation and activation of MKK4. SIGNOR-251421 0.2 PRKCB protein P05771 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1303 NKLRRQHsYDTFVDL -1 11306676 t lperfetto These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels. SIGNOR-249084 0.368 PRKACA protein P17612 UNIPROT NEFL protein P07196 UNIPROT down-regulates activity phosphorylation 9606 8019002 t miannu Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L. SIGNOR-252401 0.2 EEF1A1P5 protein Q5VTE0 UNIPROT Cys-tRNA(Cys) smallmolecule CHEBI:29152 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269548 0.8 PPP2CA protein P67775 UNIPROT PREX2 protein Q70Z35 UNIPROT up-regulates activity dephosphorylation Ser1107 DTISNRDsYSDCNSN 9606 BTO:0000007 26438819 t miannu PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ. SIGNOR-277184 0.2 CYP24A1 protein Q07973 UNIPROT calcitriol smallmolecule CHEBI:17823 ChEBI down-regulates quantity chemical modification 30080183 t lperfetto Homozygous mutations in the vitamin D 24-hydroxylase CYP24A1, the major enzyme responsible for inactivation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, lead to idiopathic infantile hypercalcemia (IIH). SIGNOR-270572 0.8 LYL1 protein P12980 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 f miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. SIGNOR-198276 0.2 PRKDC protein P78527 UNIPROT GOLPH3 protein Q9H4A6 UNIPROT up-regulates activity phosphorylation Thr143 ALKHVKEtQPPETVQ -1 BTO:0000567 24485452 t In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents SIGNOR-253557 0.321 AKT proteinfamily SIGNOR-PF24 SIGNOR MAP2K4 protein P45985 UNIPROT down-regulates activity phosphorylation Ser80 IERLRTHsIESSGKL 9606 BTO:0002181 11707464 t miannu Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation. In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition.  SIGNOR-275980 0.2 CREB5 protein Q02930 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002818 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253811 0.2 PAK1 protein Q13153 UNIPROT PGAM1 protein P18669 UNIPROT down-regulates phosphorylation Ser118 QVKIWRRsYDVPPPP 9606 BTO:0000130 12189148 t Activated pak1 gcesareni Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity. SIGNOR-91594 0.2 GLI3 protein P10071 UNIPROT MYCN protein P04198 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17419683 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. .Hedgehog Signals induce cellular proliferation through upregulation of n-myc, cyclin d/e, and foxm1. SIGNOR-154237 0.362 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr107 AYPATGPyGAPAGPL 9606 20600357 t llicata In this report we have identified novel tyrosine phosphorylation sites in galectin-3 as well as the kinase responsible for its phosphorylation. Our results demonstrate that tyrosines at positions 79, 107 and 118 can be phosphorylated in vitro and in vivo by c-abl kinase. our results demonstrate that cells expressing galectin-3 y107f variant showed reduced migration in wound healing assay ( fig. 5). This result confirms the role of galectin-3 tyrosine phosphorylation in cell motility. SIGNOR-166493 0.361 KNSTRN protein Q9Y448 UNIPROT KIF2B protein Q8N4N8 UNIPROT down-regulates activity relocalization 9606 BTO:0001938 22535524 t lperfetto The protein astrin has been shown to remove Kif2b from kinetochores in metaphase through competitive binding of CLASP1 (Manning et al., 2010 blue right-pointing triangle). During prometaphase, Aurora B kinase activity prevents astrin from localizing to kinetochores (Manning et al., 2010 blue right-pointing triangle; Schmidt et al., 2010 blue right-pointing triangle). This permits Kif2b to localize to kinetochores to destabilize k-MT attachments to execute error correction through Plk1-dependent recruitment and activation. SIGNOR-252053 0.414 LYN protein P07948 UNIPROT FCGR2B protein P31994 UNIPROT up-regulates activity phosphorylation Tyr292 GAENTITySLLMHPD -1 8756631 t lperfetto Therefore, we conclude that FcgammaRIIb1 phosphorylation upon BCR-FcgammaR coligation is most likely due to BCR-associated Lyn SIGNOR-249380 0.436 PAX7 protein P23759 UNIPROT MLL2 complex complex SIGNOR-C88 SIGNOR up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103 22863532 t lperfetto Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-217712 0.308 GF proteinfamily SIGNOR-PF39 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR up-regulates activity binding 9606 17306385 t miannu Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. SIGNOR-256163 0.2 PRKDC protein P78527 UNIPROT DNA-PK complex SIGNOR-C107 SIGNOR form complex binding 9606 17308091 t miannu Complexes formed by interactions between Ku70, Ku80, and DNA-PKcs were well-established SIGNOR-226026 0.934 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT up-regulates activity phosphorylation Tyr340 RGQRDSSyYWEIEAS 10090 BTO:0001482 8876196 t  JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process. SIGNOR-251361 0.607 TIMM50 protein Q3ZCQ8 UNIPROT TIM23 complex complex SIGNOR-C423 SIGNOR form complex binding 32074073 t lperfetto The human TIM23 complex is formed by the core components TIM50 (50), TIM23 (23) and TIM17A/B (17A/B). The sorting elements are TIM21 (21) and ROMO1, and the motor elements include TIM44 (44), PAM18 (18; DNAJC15 and DNAJC19), PAM16 (16; MAGMAS), mtHSP70 (Mortalin) and GrpE. SIGNOR-267696 0.644 CDK5 protein Q00535 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates activity phosphorylation Ser1123 RSRSRSRsPRPRGDS 10116 BTO:0004102 12824184 t llicata We demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival.  SIGNOR-250663 0.344 MAPK3 protein P27361 UNIPROT BRD4 protein O60885 UNIPROT down-regulates activity 9606 32482868 t lperfetto The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity. SIGNOR-262048 0.315 CABLES1 protein Q8TDN4 UNIPROT CDK2 protein P24941 UNIPROT down-regulates activity binding -1 25361894 t miannu Our study also showed that Cables1 increases the level of p21 and decreases the level of pRb, but does not affect the other cell cycle-related proteins we studied. Induction of apoptosis by Cables1, which occurs partially through inhibiting Cdk2 activity and upregulating p21, is prevented by Akt phosphorylation and 14-3-3 binding. SIGNOR-276759 0.481 PTPN11 protein Q06124 UNIPROT PTK2B protein Q14289 UNIPROT down-regulates activity dephosphorylation Tyr906 CQLPPEGyVVVVKNV 9606 10880513 t miannu We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. |We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM..... 1) RAFTK is a substrate of SHP2 in vitro and 2) dephosphorylation of RAFTK by SHP2 inhibits its kinase activity. SIGNOR-277084 0.718 CCKAR protein P32238 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257410 0.471 PAK2 protein Q13177 UNIPROT CASP7 protein P55210 UNIPROT down-regulates phosphorylation Ser30 DAKPDRSsFVPSLFS 9606 BTO:0000150 21555521 t gcesareni Pak2 can bind with caspase-7 and phosphorylate caspase-7 at the ser-30, thr-173, and ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. SIGNOR-173659 0.355 PAK5 protein Q9P286 UNIPROT PAK5 protein Q9P286 UNIPROT up-regulates activity phosphorylation His19 SGPSNFEhRVHTGFD -1 12860998 t miannu Active form of Cdc42, but not Rac1 and Rho, protein was able to activate the purified GST-Pak5 autophosphorylation and kinase activity. Mutations of Pak5, which disrupted the interaction of Cdc42 and Pak5, also abolished the induction of autophosphorylation.  The H19L/H22L mutant of Pak5 was insensitive to the Cdc42-induced autophosphorylation. SIGNOR-250248 0.2 MIB1 protein Q86YT6 UNIPROT RYK protein P34925 UNIPROT down-regulates ubiquitination 9606 21875946 t gcesareni We discovered that ryk both physically and functionally interacts with the e3 ubiquitin ligase mind bomb 1 (mib1).We Found that overexpressed ryk and mib1 colocalized and that the overexpression of mib1 leads to the loss of surface ryk expression. In addition, biochemical studies revealed that mib1 promotes the ubiquitination and degradation of ryk. Endogenous ryk and mib1 were required for the wnt-dependent activation of wnt/ctnnb1 signaling SIGNOR-176282 0.331 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-269967 0.2 SEM1 protein P60896 UNIPROT 26S Proteasome complex SIGNOR-C307 SIGNOR form complex binding 9606 BTO:0000007 29636472 t lperfetto Here, we report near-atomic resolution cryo-EM structures of the activated human proteasome|The proteasome is composed of a 28-subunit barrel-shaped core particle (CP) and two 19- subunit regulatory particles (RP)5–8 capped at both sides of the CP|Human proteasomes were purified through affinity chromatography on a large scale from a stable HEK293 cell line SIGNOR-263343 0.2 BCL2 protein P10415 UNIPROT CYCS protein P99999 UNIPROT down-regulates activity 9606 BTO:0000567 12624108 f lperfetto Bcl-2 blocked the release of mitochondrial cytochrome c SIGNOR-99063 0.636 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21798082 t lperfetto Akt inactivates protein degradation by phosphorylating and thus repressing the transcription factors of the foxo family, and stimulates protein synthesis via the mammalian target of rapamycin (mtor) and glycogen synthase kinase 3b (gsk3b). SIGNOR-252820 0.909 LSM-1231 chemical CHEBI:91471 ChEBI NTRK2 protein Q16620 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259759 0.8 SPTB protein P11277 UNIPROT Erythrocytic spectrin complex SIGNOR-C384 SIGNOR form complex binding 9606 BTO:0000424 24302288 t lperfetto Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of alpha and beta subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell SIGNOR-266024 0.734 NEDD1 protein Q8NHV4 UNIPROT g-TuRC complex complex SIGNOR-C282 SIGNOR up-regulates activity binding 9606 19029337 t miannu It has been reported that NEDD1 directly interacts with and recruits the gamma-tubulin ring complex to centrosomes and to spindle MTs to promote MT nucleation and spindle assembly SIGNOR-261422 0.761 ARNT protein P27540 UNIPROT CA9 protein Q16790 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22387692 f lperfetto The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. SIGNOR-253706 0.512 PAX7 protein P23759 UNIPROT KMT2A protein Q03164 UNIPROT up-regulates binding 9606 SIGNOR-C89 22863532 t miannu Carm1 specifically methylates multiple arginines in the n-terminus of pax7. Methylated pax7 directly binds the c-terminal cleavage forms of the trithorax proteins mll1/2 resulting in the recruitment of the ash2l:mll1/2:wdr5:rbbp5 histone h3k4 methyltransferase complex to regulatory enhancers and the proximal promoter of myf5. SIGNOR-198626 0.2 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT up-regulates phosphorylation Ser49 IEGMILLsELSRRRI 9606 3352609 t lperfetto The wild-type and ser-48 mutant proteins became extensively phosphorylated by eif-2 kinases present in the reticulocyte lysate. These findings support the hypothesis that the serine 48 residue is required for high-affinity interaction between eif2 alpha(p) and eif2b. SIGNOR-24539 0.888 SLIT2 protein O94813 UNIPROT ROBO3 protein Q96MS0 UNIPROT up-regulates activity binding -1 16226035 t miannu This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation. SIGNOR-268381 0.638 TRIB3 protein Q96RU7 UNIPROT ACACB protein O00763 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 16794074 t miannu TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1.  Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D). SIGNOR-271601 0.26 MRPL19 protein P49406 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262375 0.712 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1270 SDLPVPRtPGSGAGE 9606 10995387 t llicata Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter. SIGNOR-82137 0.454 NUMA1 protein Q14980 UNIPROT TUBA4A protein P68366 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116788 0.502 RPL37A protein P61513 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262462 0.82 RPS6KA3 protein P51812 UNIPROT HMGN1 protein P05114 UNIPROT unknown phosphorylation Ser7 sSAEGAAK 10090 12773393 t lperfetto The results presented here show that MSK2 and, to a lesser extent, MSK1 are the major protein kinases required for the phosphorylation of histone H3 at both Ser10 and Ser28 and HMG-14 at Ser6 after stimulation of primary embryonic fibroblasts by TPA or anisomycin. SIGNOR-249215 0.368 VAPB-PTPIP51 complex complex SIGNOR-C275 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 10116 BTO:0000142 30841933 f lperfetto Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. SIGNOR-262120 0.7 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 22890322 t lperfetto Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8 SIGNOR-191781 0.787 MDH1 protein P40925 UNIPROT NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Malate is dehydrogenated to produce oxaloacetate by the enzyme Malate Dehydrogenase. In this reaction NAD is converted to NADH2. Oxaloacetate formed in this reaction reacts with acetyl-CoA to form citrate in order to start another round of the citric acid cycle SIGNOR-266287 0.8 SIX1 protein Q15475 UNIPROT EZR protein P15311 UNIPROT up-regulates quantity transcriptional regulation 9606 16488997 t We now show that the gene encoding Ezrin is a direct transcriptional target of Six1. SIGNOR-259374 0.348 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI sedoheptulose 7-phosphate smallmolecule CHEBI:15721 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268140 0.8 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 15774499 t gcesareni The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. SIGNOR-134658 0.585 TJP2 protein Q9UDY2 UNIPROT YAP1 protein P46937 UNIPROT down-regulates binding 9606 23829894 t milica The Crumbs complex component AMOT co-localizes with MST1_ 2, LATS1_ 2 and YAP in a complex at the tight junction to control cell growth. Zona occludens-2 (ZO-2) in the tight junction, and a-catenin, b-catenin, or PTPN14 in the adherence junction, also bind to YAP_TAZ. SIGNOR-230754 0.507 hexestrol chemical CHEBI:31669 ChEBI AKR1C1 protein Q04828 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193230 0.8 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity phosphorylation Ser335 YDSFGEPsYPEVFEP -1 9558331 t llicata In vitro the large hydrophilic loop of PS-2 between transmembrane domains 6 and 7 can be phosphorylated by casein kinase-1 (CK-1) and CK-2, but not by PKA or PKC. Quantitative analysis of in vitro phosphorylation demonstrates the presence of two phosphorylation sites for CK-1 and a single site for CK-2. A deletion analysis revealed that the CTF of PS-2 is phosphorylated in vivo within an acidic sequence containing three potential phosphorylation sites for CKs (serines 327, 330, and 335). These data suggest that CK type protein kinases phosphorylate the CTF of PS-2 within its hydrophilic loop domain in vivo. Interestingly, the potential phosphorylation sites are located directly adjacent to the recently identified caspase cleavage sites. SIGNOR-250802 0.368 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates activity phosphorylation Ser642 NACTLTTsPRLPVF 10090 BTO:0000944 15664191 t lperfetto Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2 SIGNOR-249444 0.622 MAPK9 protein P45984 UNIPROT KLF13 protein Q9Y2Y9 UNIPROT down-regulates quantity by destabilization phosphorylation Ser123 APPSPAWsEPEPEAG 10090 37029927 t miannu TGF-β-mediated downregulation of KLF13 by HDAC-mediated epigenetic silencing and JNK-induced phosphorylation abrogates the latter’s inhibitory effect on TGF-β signaling. SIGNOR-277809 0.2 452342-67-5 chemical CID:10202642 PUBCHEM TGFBR1 protein P36897 UNIPROT down-regulates chemical inhibition 9606 BTO:0000671 18075500 t gcesareni Gw788388 is a new tgf-beta type i receptor inhibitor with a much improved pharmacokinetic profile compared with sb431542. SIGNOR-159863 0.8 CNOT6 protein Q9ULM6 UNIPROT CCR4-NOT complex complex SIGNOR-C439 SIGNOR form complex binding 9606 19558367 t lperfetto In the present study, we examine the composition of the human Ccr4-Not complex in an in-depth proteomic approach using stable cell lines expressing tagged CNOT proteins. We find at least four different variants of the human complex, consisting of seven stable core proteins and mutually exclusive associated mRNA deadenylase subunits. Interestingly, human CNOT4 is in a separate approximately 200 kDa complex. Furthermore, analyses of associated proteins indicate involvement of Ccr4-Not complexes in splicing, transport and localization of RNA molecules. SIGNOR-268309 0.814 ceramide smallmolecule CHEBI:17761 ChEBI ceramide 1-phosphate(2-) smallmolecule CHEBI:84404 ChEBI up-regulates quantity precursor of 9606 34202192 t miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). SIGNOR-268501 0.8 KAT2B protein Q92831 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269621 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD83 protein Q01151 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 f miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. SIGNOR-254781 0.261 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT up-regulates activity binding 9606 BTO:0000007 19535918 t miannu UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex.  SIGNOR-265180 0.806 NEK9 protein Q8TD19 UNIPROT NEDD1 protein Q8NHV4 UNIPROT up-regulates activity phosphorylation Ser377 EKAGLPRsINTDTLS -1 22818914 t miannu Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells. SIGNOR-263016 0.434 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr1229 SSEDLSAyASISFQK 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236752 0.913 MYC protein P01106 UNIPROT HLA-C protein P10321 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000848 8206526 f miannu In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. SIGNOR-254602 0.258 MAP3K7 protein O43318 UNIPROT IKBKG protein Q9Y6K9 UNIPROT up-regulates activity binding 9606 SIGNOR-C14 20038579 t lperfetto This result suggests that ikkgamma/nemo binds to the polyubiquitinated tak1. SIGNOR-162634 0.81 MAPK14 protein Q16539 UNIPROT TP63 protein Q9H3D4 UNIPROT down-regulates quantity by destabilization phosphorylation Ser301 S-->T -1 30301786 t miannu P38α phosphorylates and destabilizes p63. SIGNOR-277414 0.311 DPF2 protein Q92785 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates activity binding 9606 BTO:0000007 20460684 t miannu REQ is required for the oncogenic activity induced by RelB/p52. . Through in vitro binding experiments, REQ was found to bind to several SWI/SNF complex subunits and also to the p52 NF-κB subunit through its nuclear localization signal containing the N-terminal region. In this study, we present evidence that REQ is a specific adaptor protein that links RelB/p52 with Brm-type SWI/SNF complexes and thereby plays pivotal roles at the most downstream stages of the noncanonical NF-κB pathway. We further show that REQ is required for oncogenesis in several human tumor cell lines in which the noncanonical NF-κB pathway is aberrantly regulated.REQ and Brm specifically promote RelB/p52-dependent transcriptional activity. SIGNOR-261964 0.305 PRKCA protein P17252 UNIPROT CLIP1 protein P30622 UNIPROT down-regulates phosphorylation Ser312 ASLKRSPsASSLSSM 9606 20519438 t lperfetto Furthermore, by using phosphoproteomic analysis, we determined that s309 and s311 of clip-170 are phosphorylated in cells and mapped s311 as a protein kinase a (pka) phosphorylation site.phosphorylation of s311 may be critical for establishing the ?folded Back? Conformation of clip-170clip-170 open and folded back conformations represent active and inactive modes of the protein, respectively SIGNOR-165857 0.2 caesium(1+) chemical CHEBI:49547 ChEBI KCNJ13 protein O60928 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9620703 t miannu Figure 4 shows the response of Kir7.1 to increasing [Ba2+]o. The EC50 for Ba2+ block was 1 mM (Figure 4C), independent of the type of cell in which the channel was expressed. Other known inward rectifier K+ channels are sensitive to inhibition at much lower concentrations SIGNOR-258926 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UNG protein P13051 UNIPROT up-regulates activity phosphorylation Ser23 ARKRHAPsPEPAVQG 9606 BTO:0000567 18079698 t miannu We investigated the ability of four active CDK/cyclin pairs to phosphorylate UNG2 in vitro.When UNG2 was subjected to in vitro phosphorylation by either of these sets of CDK/cyclins, multiple phosphorylated forms of UNG2 were observed (Figure 5B). Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases.Mass spectrometry analyses revealed that the ‘early' CDK4/cyclin D and CDK2/cyclin E kinases were able to phosphorylate all three UNG2 Ser/Thr residues observed in vivo (only CDK2/cyclin E shown). Of these, only S64 was phosphorylated by the ‘late' CDK2/cyclin A and CDK1/cyclin B kinases (Figure 5B, upper panels) in agreement with the accumulation of this phosphorylation in G2 (Figure 3B). In addition, (unspecific) phosphorylation by all kinases was observed at S12 and S14. SIGNOR-276088 0.291 NBEA protein Q8NFP9 UNIPROT DLG3 protein Q92796 UNIPROT up-regulates activity binding BTO:0000227 23277425 t lperfetto Interestingly, a recent proteomic analysis (Lauks et al., 2012) revealed that Nbea binds SAP102, which interacts with glutamate receptors early in the biosynthetic route and regulates their targeting. This finding, along with the interaction of Nbea with the glycine receptor beta subunit (del Pino et al., 2011), further strengthens the notion that Nbea targets neurotransmitter receptors to synapses. SIGNOR-266004 0.427 AMPK complex SIGNOR-C15 SIGNOR EPM2A protein O95278 UNIPROT up-regulates activity phosphorylation -1 18029386 t miannu Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro. SIGNOR-271730 0.354 PPM1B protein O75688 UNIPROT PPARG protein P37231 UNIPROT up-regulates activity dephosphorylation 9606 23320500 t miannu Furthermore we show that PPM1B can directly dephosphorylate PPARgamma, both in intact cells and in vitro.|In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112).|The serine/threonine phosphatase PPM1B (PP2Cbeta) selectively modulates PPARgamma activity. SIGNOR-277073 0.376 PTPN11 protein Q06124 UNIPROT JAK2 protein O60674 UNIPROT up-regulates quantity by stabilization dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 14522994 t We report that SHP-2 dephosphorylates tyrosine (Tyr-1007) of Jak2 kinase, a critical recruitment site for the ubiquitin ligase-associated inhibitory protein suppressor of cytokine signaling-1 (SOCS-1), thereby contributing to Jak2 stability. Inactivation of SHP-2 function by blocking receptor/SHP-2 association or by using a catalytically inactive mutant of SHP-2 led to a marked increase in Jak2 ubiquitination/degradation, Jak2 phosphorylation on Tyr-1007, and Jak2/SOCS-1 association SIGNOR-248665 0.789 CEBPA protein P49715 UNIPROT Granulocyte_differentiation phenotype SIGNOR-PH102 SIGNOR up-regulates 9606 11283671 f apalma We previously reported that the transcription factor C/EBPα is sufficient to induce granulocytic differentiation in multipotential precursor cells, and that Cebpa -knockout mice have a selective block in granulocyte maturation SIGNOR-255674 0.7 BDKRB1 protein P46663 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257411 0.434 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT down-regulates activity cleavage Ala92 PAFISEDaSGYLTSS -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site. SIGNOR-263576 0.426 ATM protein Q13315 UNIPROT AVEN protein Q9NQS1 UNIPROT up-regulates activity phosphorylation Ser308 NILPDQTsQDLKSKE -1 18571408 t miannu Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site). SIGNOR-262637 0.388 PPP3CB protein P16298 UNIPROT IL6 protein P05231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 18177723 f lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy SIGNOR-251734 0.2 CUX2 protein O14529 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 10090 26221032 f miannu Genetic inactivation in mouse embryo fibroblasts or CUX2 knockdown in HCC38 cells delayed DNA repair and increased DNA damage. These results demonstrate that CUX2 functions as an accessory factor that stimulates the repair of oxidative DNA damage SIGNOR-263958 0.7 NKX3-1 protein Q99801 UNIPROT HDAC1 protein Q13547 UNIPROT down-regulates activity binding 9606 16697957 t miannu NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity. SIGNOR-251549 0.374 AURKB protein Q96GD4 UNIPROT NDC80 protein O14777 UNIPROT down-regulates phosphorylation Ser15 SGGAGRLsMQELRSQ 9606 20471944 t lperfetto To determine whether the combinatorial regulation of the kmn network by aurora b observed in vitro is critical to controlling kinetochore-microtubule attachments in vivo, we next investigated the effect of the phosphomimetic (to aspartate) and nonphosphorylatable (to alanine) mutants of dsn1, knl1, and ndc80 in vertebrate cells. We predicted that both types of mutations in critical phosphorylation sites would affect chromosome segregation, since preventing the inactivation of inappropriately attached kinetochores by aurora b (in the nonphosphorylatable mutant) or constitutively inactivating this attachment (in the phosphomimetic mutant). SIGNOR-165554 0.845 ATM protein Q13315 UNIPROT AATF protein Q9NY61 UNIPROT up-regulates quantity by stabilization phosphorylation Ser189 EGDDAEDsQGESEED 9606 BTO:0001109 17157788 t lperfetto The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. |DNA damage stabilizes Che-1 protein|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site. SIGNOR-264415 0.359 PRKACA protein P17612 UNIPROT TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 22310283 t gcesareni Thus, our data revealed a novel interplay between pka phosphorylation and tal1-mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis. SIGNOR-195987 0.2 SPOP protein O43791 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 25278611 t miannu Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. Up-regulation of DEK, TRIM24 and NCOA3 is a feature of prostate cancer SPOP mutations. SIGNOR-272827 0.488 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR THBD protein P07204 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15677570 f miannu We further show evidence suggesting that NF-κB inhibits TM expression indirectly by competition for the coactivator p300/CBP. SIGNOR-253909 0.2 HLA-G protein P17693 UNIPROT LILRB1 protein Q8NHL6 UNIPROT up-regulates binding 9606 15718280 t gcesareni Hla-g binds a limited repertoire of peptides and interacts with the inhibitory leukocyte ig-like receptors lir-1 and lir-2 SIGNOR-134180 0.766 CASP3 protein P42574 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp345 EEWEAQRdSHLGPHR -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261756 0.461 NMDA proteinfamily SIGNOR-PF56 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264801 0.2 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT down-regulates phosphorylation 9606 12832520 t gcesareni Cprk displays catalytic activity in in vitro kinase assays and is itself phosphorylated by cdk5/p35. Cdk5/p35 inhibits cprk activity. SIGNOR-102652 0.506 PAF1C complex SIGNOR-C471 SIGNOR TCEA1 protein P23193 UNIPROT up-regulates activity binding 9606 BTO:0000567 20178742 t miannu HPAF1C Independently and Cooperatively (with SII) Stimulates Transcription Elongation. Direct Interactions of hPAF1C with Pol II and SII Are Required for Its Intrinsic and Synergistic Effects on Chromatin Transcription. SIGNOR-269838 0.625 HDLBP protein Q00341 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 33941620 f miannu Vigilin (Vgl1) is essential for heterochromatin formation, chromosome segregation, and mRNA stability and is associated with autism spectrum disorders and cancer: vigilin, for example, can suppress proto-oncogene c-fms expression in breast cancer. SIGNOR-266694 0.7 bafilomycin A1 chemical CHEBI:22689 ChEBI ATP6V1A protein P38606 UNIPROT down-regulates activity chemical inhibition 9606 9572882 t Simone Vumbaca The macrolide antibiotic bafilomycin A1 is a very potent and specific inhibitor of V-ATPases. SIGNOR-261084 0.8 RHOA protein P61586 UNIPROT FHL2 protein Q14192 UNIPROT up-regulates relocalization 9606 11847121 t gcesareni Here, we show that stimulation of the rho pathway induces translocation of the transcriptional lim-only coactivator fhl2 to the nucleus and subsequent activation of fhl2- and androgen receptor-dependent genes. SIGNOR-114071 0.352 EEF1A1P5 protein Q5VTE0 UNIPROT Tyr-tRNA(Tyr) smallmolecule CHEBI:29161 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269558 0.8 ACP1 protein P24666 UNIPROT EPHA2 protein P29317 UNIPROT down-regulates activity dephosphorylation Tyr772 EDDPEATyTTSGGKI -1 21538645 t gcesareni The SAM domain tyrosine Y960 which has been implicated in downstream PI3K signaling is dephosphorylated exclusively by HCPTP-B. The activation loop tyrosine (Y772) which directly controls kinase activity is dephosphorylated about six times faster by HCPTP-A. In contrast, the juxtamembrane tyrosines (Y575, Y588 and Y594) which are implicated in both control of kinase activity and downstream signaling are dephosphorylated by both variants with similar rates SIGNOR-246027 0.652 WNT5A protein P41221 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131841 0.753 OTULIN protein Q96BN8 UNIPROT UBC protein P0CG48 UNIPROT up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270820 0.709 SMO protein Q99835 UNIPROT FYN protein P06241 UNIPROT up-regulates phosphorylation 9606 23074268 t gcesareni Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion. SIGNOR-199156 0.412 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249347 0.733 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-249682 0.403 A4/b1 integrin complex SIGNOR-C162 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269011 0.7 CXCL12 protein P48061 UNIPROT ACKR3 protein P25106 UNIPROT up-regulates binding 9606 BTO:0000782 16107333 t gcesareni Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1. SIGNOR-139709 0.715 ERBB2 protein P04626 UNIPROT DOCK7 protein Q96N67 UNIPROT up-regulates phosphorylation Tyr1257 METVPQLyDFTETHN 9606 18426980 t llicata We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family. SIGNOR-178348 0.519 HSD17B1 protein P14061 UNIPROT 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity chemical modification -1 8994190 t Luana Human 17 beta-hydroxysteroid dehydrogenase (17-HSD) type 1 catalyzes the conversion of the low activity estrogen, estrone, into highly active estradiol, both in the gonads and in target tissues.  SIGNOR-269760 0.8 PBK protein Q96KB5 UNIPROT PRDX1 protein Q06830 UNIPROT up-regulates phosphorylation Ser32 QFKDISLsDYKGKYV 9606 BTO:0000782;BTO:0000848;BTO:0001286 20647304 t lperfetto We report that prx1 is newly discovered direct target of topk. Our results demonstrate that topk phosphorylation of prx1 at ser-32 inhibits uvb-induced apoptosis in rpmi7951 melanoma cells by increasing prx1 peroxidase activity and decreasing the intracellular accumulation of h2o2. SIGNOR-166901 0.262 ZNF165 protein P49910 UNIPROT PMEPA1 protein Q969W9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000356 26567849 t Luana ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1. SIGNOR-266094 0.274 TOMM70 protein O94826 UNIPROT HSPA1A protein P0DMV8 UNIPROT up-regulates activity binding 9534 12526792 t miannu The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting. SIGNOR-261380 0.2 UBE2D2 protein P62837 UNIPROT TRIM22 protein Q8IYM9 UNIPROT up-regulates activity binding 9606 BTO:0000007 18656448 t miannu  It was found that TRIM22 underwent self-ubiquitylation in vitro in combination with the E2 enzyme UbcH5B and the ubiquitylation was dependent on its RING finger domain. Further evidences showed that TRIM22 could also be self-ubiquitylated in vivo. Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase. SIGNOR-271779 0.304 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 15895091 t gcesareni We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. SIGNOR-137236 0.917 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL4 protein P05112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 15048722 f We demonstrate that NF-kappa B binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappa B nuclear translocation in living cells blocked binding of NF-kappa B to the IL-4 promoter. The data provide first evidence that NF-kappa B is directly involved in IL-4 transcription SIGNOR-254497 0.421 SP1 protein P08047 UNIPROT HGF protein P14210 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9223667 t lperfetto Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. SIGNOR-251739 0.2 CDK1 protein P06493 UNIPROT HASPIN protein Q8TF76 UNIPROT up-regulates activity phosphorylation Thr128 RPPQKCStPCGPLRL 9606 BTO:0000567 24413556 t miannu Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis. SIGNOR-275419 0.2 CEBPD protein P49716 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000011 10649448 f gcesareni We conclude that glucocorticoid-induced adipogenesis from bone marrow stromal cells is mediated through a reaction cascade in which dexamethasone transcriptionally activates C/EBPdelta; C/EBPdelta then binds to PPARgamma2 promoter and transactivates PPARgamma2 gene expression. SIGNOR-253062 0.585 F2RL1 protein P55085 UNIPROT SERPINB2 protein P05120 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 21072196 f miannu PAR-2 activation up-regulated four genes more than 5 fold (DUSP6, WWOX, AREG, SERPINB2) and down-regulated another six genes more than 3 fold (TXNIP, RARG, ITGB4, CTSD, MSC and TM4SF15). SIGNOR-254856 0.2 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-268094 0.8 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity dephosphorylation Ser37 NVLSPLPsQAMDDLM 9606 16501611 t Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway. SIGNOR-248500 0.321 ALDH5A1 protein P51649 UNIPROT succinate(2-) smallmolecule CHEBI:30031 ChEBI up-regulates quantity chemical modification 9606 19300440 t miannu Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. SIGNOR-266617 0.8 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81153 0.418 RF-C complex complex SIGNOR-C375 SIGNOR PCNA protein P12004 UNIPROT up-regulates activity binding 9534 BTO:0004055 12930972 t lperfetto Replication factor C (RF-C) complex binds to DNA primers and loads PCNA onto DNA, thereby increasing the processivity of DNA polymerases. SIGNOR-265510 0.812 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-119996 0.784 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser36 AQQVSSLsESEESQD 9606 20730097 t lperfetto Although the functional impact of ck-mediated atf1 phosphorylation is still unclear, we found that mutation of ser-36 and ser-41 increased cbp kix domain binding by up to four fold (fig. 2g). This result is consistent with the negative impact of ck-mediated phosphorylation on cbp binding affinity of creb that we previously reported SIGNOR-167544 0.298 PPP3CA protein Q08209 UNIPROT FLNA protein P21333 UNIPROT down-regulates dephosphorylation Ser2152 TRRRRAPsVANVGSH 9606 16442073 t gcesareni We report that a purified c-terminal recombinant region of filamin is a suitable substrate for calcineurin in vitro. Furthermore, 1 microm cyclosporin a (csa), a specific calcineurin inhibitor, reduced the dephosphorylation of the recombinant fragment in 293ft cells SIGNOR-143979 0.261 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr120 HKFNVTGtPEQYVPY 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275596 0.2 CDK2 protein P24941 UNIPROT CCDC6 protein Q16204 UNIPROT up-regulates phosphorylation Ser244 QPVSAPPsPRDISME 9606 14712216 t amattioni Serine 244 phosphorylation is required for h4 apoptotic function. SIGNOR-121198 0.2 MAPK9 protein P45984 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates phosphorylation Ser319 NSKYNAEsTERESQD 9606 18667537 t llicata This jnk phosphorylation of ps1 at ser(319)thr(320) enhances the stability of the ps1 c-terminal fragment that is necessary for gamma-secretase activity. SIGNOR-179676 0.38 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates activity phosphorylation Tyr514 TFCGTPDyIAPEILQ 9534 BTO:0000298 11381116 t The tyrosine phosphorylation sites of PKC delta in the H(2)O(2)-treated cells were identified as Tyr-311, Tyr-332, and Tyr-512 by mass spectrometric analysis with the use of the precursor-scan method and by immunoblot analysis with the use of phosphorylation site-specific antibodies. Tyr-311 was the predominant modification site among them. In an in vitro study, phosphorylation at this site by Lck, a non-receptor-type tyrosine kinase, enhanced the basal enzymatic activity and elevated its maximal velocity in the presence of diacylglycerol. phosphorylation at Tyr-311 between the regulatory and catalytic domains is a critical step for generation of the active PKC delta in response to H(2)O(2). SIGNOR-251386 0.513 MYC protein P01106 UNIPROT SURF1 protein Q15526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10858544 f miannu We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response. SIGNOR-254615 0.2 BAZ1B protein Q9UIG0 UNIPROT B-WICH complex complex SIGNOR-C447 SIGNOR form complex binding 9606 21559432 t miannu The B-WICH complex is an extended form of WICH [26], and is involved in both RNA pol I and RNA pol III transcription [20], [21]. In addition to the three core proteins, WSTF, SNF2h, and nuclear myosin (NM1); the myb binding protein 1b, RNA helicase II/DXX21, and SAP155 all also associate via RNA species [21]. The subunit SNF2h is an ISWI ATPase, which slides nucleosomes in an ATP-dependent manner [27]. WSTF is a component of several complexes: two SNF2h complexes, B-WICH [21] and WICH [26], and one SWI/SNF type of chromatin remodelling complex, the WINAC complex, which is involved in vitamin D-mediated RNA pol II transcription SIGNOR-268826 0.556 SOD1 protein P00441 UNIPROT hydrogen peroxide smallmolecule CHEBI:16240 ChEBI up-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272287 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Ser364 FGQRDRSsSAPNVHI 9606 10869359 t lperfetto We show that phosphorylation of b-raf by akt occurs at multiple residues within its amino terminal regulatory domain, at both the conserved and unique phosphorylation sites. Akt phosphorylated b-raf on s364 and s428 to inactivate its kinase activity b-raf contains three akt consensus sites, table i. One site, ser364 is conserved with c-raf;however, two sites, ser428 and thr439, are unique to b-raf SIGNOR-244152 0.2 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser93 ARMMSTEsANSFTLI 9606 BTO:0002552 32187724 t lperfetto We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration SIGNOR-264556 0.302 GNA11 protein P29992 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 27515033 t scontino TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C. SIGNOR-267203 0.613 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT up-regulates activity binding 10116 9428795 t We have shown that one of the functions of the GR to activate transcription of the AGP gene is to recruit C/EBPbeta and to maintain it bound at its target DNA sequences (SRU) SIGNOR-251655 0.467 AKT1 protein P31749 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 18483217 f PDGF signaling has been implicated in several fibrotic conditions and is assumed to play a role in driving proliferation of cells with a myofibroblast phenotype. SIGNOR-254371 0.7 INSIG1 protein O15503 UNIPROT SCAP protein Q12770 UNIPROT down-regulates activity binding 10029 BTO:0000246 12202038 t Using coimmunoprecipitation and tandem mass spectrometry, we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER. SIGNOR-267495 0.762 JAK2 protein O60674 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Tyr333 QRYRLVPyGNHSYLE 9606 BTO:0001535 34131122 t miannu Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. SIGNOR-277567 0.301 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258289 0.8 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 8266078 t gcesareni Il-2r gamma was demonstrated to be a component of the il-4 receptor on the basis of chemical cross-linking data, the ability of il-2r gamma to augment il-4 binding affinity, and the requirement for il-2r gamma in il-4-mediated phosphorylation of insulin receptor substrate-1. SIGNOR-37362 0.826 MAP3K2 protein Q9Y2U5 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 11343802 t lperfetto Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation SIGNOR-244888 0.42 ATP smallmolecule CHEBI:15422 ChEBI PRKAG1 protein P54619 UNIPROT down-regulates chemical inhibition 9606 SIGNOR-C15 21680840 t gcesareni AMPK is an ___ heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations. SIGNOR-228607 0.8 (-)-selegiline chemical CHEBI:9086 ChEBI MAOB protein P27338 UNIPROT down-regulates activity chemical inhibition -1 21377879 t Luana All the compounds were found as extremely potent and selective towards MAO-B, (Table 2) with at least 100 times more potent than the positive control selegiline.  SIGNOR-258136 0.8 TRAF6 protein Q9Y4K3 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates activity binding 9606 25290089 t lperfetto The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex. SIGNOR-205458 0.932 MYOD1 protein P15172 UNIPROT MYH7 protein P12883 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165 17111365 f Regulation miannu Transient transfection assays demonstrated that the calcineurin/NFATc1 signaling pathway is essential for MyHCbeta promoter activation during transformation of C2C12 myotubes but is not sufficient for complete fast MyHCIId/x promoter inhibition. Along with NFATc1, myocyte enhancer factor-2D (MEF-2D) and the myogenic transcription factor MyoD transactivated the MyHCbeta promoter in calcium-ionophore-treated myotubes in a calcineurin-dependent manner. SIGNOR-251958 0.393 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation 9606 19237534 t inferred from 70% family members lperfetto We previously established that phosphorylation of lsf in early g1 at ser-291 and ser-309 inhibits its transcriptional activity and that dephosphorylation later in g1 is required for its reactivation. At the peak activities of erk and cyclin c/cdk2 in early g1, lsf is efficiently phosphorylated on ser-291 and ser-309. SIGNOR-270201 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NME1 protein P15531 UNIPROT up-regulates phosphorylation Ser120 GRNIIHGsDSVESAE 9606 18234856 t lperfetto Application of this approach to the discovery of cdk1-cyclin b substrates yielded identification of >70 substrates and phosphorylation sites. Many of these sites are known to be phosphorylated in vivo, but most of the proteins have not been characterized as cdk1-cyclin b substrates. SIGNOR-216825 0.274 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates activity ubiquitination 9606 19917253 t lperfetto Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation SIGNOR-232104 0.799 superoxide smallmolecule CHEBI:18421 ChEBI Oxidative_stress phenotype SIGNOR-PH215 SIGNOR up-regulates 9606 29301787 f lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272276 0.7 PHF2 protein O75151 UNIPROT ARID5B protein Q14865 UNIPROT up-regulates activity binding 9606 BTO:0000007 21532585 t miannu We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity. SIGNOR-264514 0.55 MAPK14 protein Q16539 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT up-regulates phosphorylation Thr263 TTLSLPLtPESPNDP 9606 BTO:0000887 11741533 t gcesareni Cytokine stimulation of energy expenditure through p38 map kinase activation of ppargamma coactivator-1we show here that many cytokines activate the transcriptional ppar gamma coactivator-1 (pgc-1) through phosphorylation by p38 kinase, resulting in stabilization and activation of pgc-1 proteinp38 mapk directly phosphorylates pgc-1 on residues threonine 262, serine 265, and threonine 298 SIGNOR-112770 0.575 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1074 QRGSSGHtPPPSGPP 26190112 t Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-253543 0.299 GNB1 protein P62873 UNIPROT PLCB1 protein Q9NQ66 UNIPROT down-regulates binding 9606 8870665 t gcesareni These results indicate that g-protein beta gamma subunits constitute a mechanism by which g-protein mediate a rapid and transient plc- beta 1. SIGNOR-44369 0.47 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu Both isoforms [GOT! AND GOT2] catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and √鬱-ketoglutarate. SIGNOR-266921 0.8 SRC protein P12931 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Tyr326 EVLEDNDyGRAVDWW 9534 BTO:0004055 11445557 t lperfetto Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity. SIGNOR-252623 0.668 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr163 FDAILYYyQSGGRIR 9606 BTO:0000938 BTO:0000671 19166614 t gcesareni Previously we have shown that acute brain-derived neurotrophic factor (bdnf) activation of neurotrophin receptor tyrosine kinase b (trkb) suppresses the shaker voltage-gated potassium channel (kv1.3) via phosphorylation of multiple tyrosine residues in the n and c terminal aspects of the channel protein. SIGNOR-183523 0.383 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates activity dephosphorylation Tyr204 HTGFLTEyVATRWYR -1 19494114 t Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases|Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. SIGNOR-248707 0.466 CSAD protein Q9Y600 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267548 0.8 FOXO proteinfamily SIGNOR-PF27 SIGNOR CITED2 protein Q99967 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150 18158893 f gcesareni Foxo3a induces expression of cited2 SIGNOR-252933 0.2 XPA protein P23025 UNIPROT Nucleotide-excision_repair phenotype SIGNOR-PH209 SIGNOR up-regulates 24086043 f lperfetto The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275704 0.7 bilirubin(2-) smallmolecule CHEBI:57977 ChEBI biliverdin(2-) smallmolecule CHEBI:57991 ChEBI up-regulates quantity precursor of 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275522 0.8 PPP3CB protein P16298 UNIPROT TFEB protein P19484 UNIPROT up-regulates activity dephosphorylation Ser142 AGNSAPNsPMAMLHI 9606 BTO:0000007 26000950 t Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation. SIGNOR-255307 0.381 RPS6KB1 protein P23443 UNIPROT GLI1 protein P08151 UNIPROT up-regulates phosphorylation Ser84 LTKKRALsISPLSDA 9606 22439934 t gcesareni In this study, we found that an activated mtor/s6k1 pathway promotes gli1 transcriptional activity and oncogenic function through s6k1-mediated gli1 phosphorylation at ser84, which releases gli1 from its endogenous inhibitor, sufu. SIGNOR-196756 0.533 GCK protein P35557 UNIPROT alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI up-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266448 0.8 PRKAR2A protein P13861 UNIPROT PRKACB protein P22694 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258757 0.893 FUS protein P35637 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates quantity by repression post transcriptional regulation 10090 BTO:0001279 28515487 f This conclusion is also supported by the analysis of alternative splicing events in hFUS+/+; Smn+/− mice. As shown in Fig. 6b, the splicing of Dusp22, Mphosph9, Adarb1, hnRNP A2/B1, Gria4, Vps16, Atxn2 and Agrin, which are significantly affected in hFUS+/+ mice, is not further modified by SMN decrease SIGNOR-262805 0.256 LRIG1 protein Q96JA1 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates 9606 23723069 f miannu Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including erbb and met receptors, and promotes receptor degradation. SIGNOR-202143 0.409 CDK2 protein P24941 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1497 EPGVERSsPSKCPSL 9606 BTO:0000551 19683496 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-187607 0.669 EGR1 protein P18146 UNIPROT COL4A2 protein P08572 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21931594 f Regulation miannu Egr-1 induced a time-dependent ECM gene expression program, with the number of ECM genes increasing >2.5-fold (from 16 to 41) between 24 and 48 h. Genes in this group include those coding for multiple collagens (COL4A1, COL4A2, COL11A1, COL7A1, COL10A1) SIGNOR-251918 0.2 NOTCH1 protein P46531 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 11404076 t gcesareni Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip. SIGNOR-86125 0.591 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser35 SQGSSSQsQGISSSS 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81403 0.832 PP1 proteinfamily SIGNOR-PF54 SIGNOR CFTR protein P13569 UNIPROT up-regulates activity dephosphorylation 10090 BTO:0000988 21317537 t lperfetto WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression. IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, SIGNOR-264646 0.2 TRIM27 protein P14373 UNIPROT WASHC1 protein A8K0Z3 UNIPROT up-regulates activity ubiquitination Lys220 DAPLSISkREQLEQQ 9606 23452853 t miannu Our mechanistic studies uncovered that K63-linked ubiquitination of WASH K220 by MAGE-L2-TRIM27 is required for endosomal F-actin nucleation and retrograde transport. These results suggest that K63-linked ubiquitination of WASH K220 by TRIM27 is required for WASH function in retrograde transport. SIGNOR-253514 0.2 DLGAP1 protein O14490 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264588 0.2 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 t lperfetto Vav interacts with the tyrosine kinase syk SIGNOR-107049 0.919 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000552 14744793 t gcesareni We showed that perifosine activates the mitogen-activated protein/extracellular signal-regulated kinase pathway, and this activation promotes the phosphorylation of sp1 in known mitogen-activated protein kinase residues (threonine 453 and 739), thereby leading to increased sp1 binding and enhanced p21(waf1/cip1) transcription. SIGNOR-248062 0.644 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DNM1L protein O00429 UNIPROT up-regulates activity phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 BTO:0000007 25658205 t Barakat Here, we show that expression of oncogenic Ras or direct activation of the MAPK pathway leads to increased mitochondrial fragmentation and that blocking this phenotype, through knockdown of the mitochondrial fission-mediating GTPase Drp1, inhibits tumor growth. This fission is driven by Erk2-mediated phosphorylation of Drp1 on Serine 616, and both this phosphorylation and mitochondrial fragmentation are increased in human pancreatic cancer. SIGNOR-275407 0.2 SRT1720 chemical CID:25232708 PUBCHEM SIRT1 protein Q96EB6 UNIPROT up-regulates activity chemical activation 9606 18046409 t Selleck gcesareni Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. SIGNOR-207114 0.8 beta-carboline chemical CHEBI:109895 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 BTO:0000227 18790874 t brain lperfetto The BZ-sensitive GABAA-Rs can be further subdivided, in that receptors containing the alpha1 subunit have a higher sensitivity to a subpopulation of BZ site ligands, the benzodiazepines quazepam and cinolazepam (Sieghart, 1989) or nonbenzodiazepines such as zolpidem (an imidazopyridine) and a few others, including CL218-872 (triazolopyridazine), zaleplon, and indiplon, and abecarnil (β-carboline), (Olsen and Gordey, 2000; Korpi et al., 2002; Sieghart and Ernst, 2005). SIGNOR-263805 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR DIAPH1 protein O60610 UNIPROT up-regulates quantity by stabilization phosphorylation Thr768 PVLPFGLtPKKLYKP 9606 BTO:0002588 23325789 t miannu  DIAPH1 is phosphorylated in response to dibutyryl cAMP (Bt2cAMP) at Thr-759 via a pathway that requires extracellular signal-related kinase (ERK).We also show that Bt2cAMP promotes the PKA- and ERK-dependent phosphorylation of DIAPH1 at T759 and that mutation of this site alters the stability of the protein and the rate of cAMP-stimulated mitochondrial movement. SIGNOR-276483 0.2 TFEB protein P19484 UNIPROT IL6R protein P08887 UNIPROT up-regulates quantity by expression transcriptional regulation 30145926 f lperfetto Inhibition of DNM or dynein-mediated endocytic trafficking for up to 1 h resulted in translocation of TFEB-GFP to the nucleus in P8B11-HeLa cells (Figure 5(a-c) and a correlated increase in transcription of TFEB-target genes, including MAP1LC3/LC3, SQSTM1, MCOLN1, CTSB, CTSF, and TFEB SIGNOR-276798 0.2 MC3R protein P41968 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257142 0.251 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr472 KLAEGSAyEEVPTSM 9606 BTO:0000142 1689310 t llicata We have identified the sites phosphorylated in vitro by epidermal growth factor (egf) receptor kinase in bovine brain phospholipase c-gamma (plc-gamma). They are tyrosine residues 472, 771, 783, and 1254. we propose, therefore, that the phosphorylation of plc-gamma by egf receptor kinase alters its interaction with putative inhibitory proteins and leads to its activation. SIGNOR-20980 0.837 ROBO proteinfamily SIGNOR-PF14 SIGNOR CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser216 SGLYRSPsMPENLNR 9606 BTO:0000567;BTO:0000938 BTO:0000142 15150265 t lperfetto P38 binds and phosphorylates cdc25-b and -c at serines 309 and 361 and at serine 216, respectively, and phosphorylation of these residues is required for binding to 14-3-3 proteinsphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3 SIGNOR-124851 0.2 DHODH protein Q02127 UNIPROT (S)-dihydroorotate smallmolecule CHEBI:30864 ChEBI down-regulates quantity chemical modification 9606 30449682 t miannu OXPHOS directly drives the respiration-coupled mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) that converts dihydroorotate (DHO) to orotate in the de novo pyrimidine synthesis pathway SIGNOR-267430 0.8 CSNK2A1 protein P68400 UNIPROT HSPH1 protein Q92598 UNIPROT down-regulates activity phosphorylation Ser509 PTEENEMsSEADMEC -1 12558502 t llicata Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function. | the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro. SIGNOR-250901 0.331 biphenyl-4,4'-diol chemical CHEBI:34367 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation -1 9751507 t miannu Bisphenol A is an equally strong agonist for ERα as for ERβ, and the same is true for 4,4′-biphenol, which differs from bisphenol A in that it lacks the propane group between the phenolic rings. SIGNOR-268740 0.8 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1016 DVVDADEyLIPQQGF 9606 BTO:0000567 10653583 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto After binding of epidermal growth factor (EGF), the EGF receptor (EGFR) becomes autophosphorylated via tyrosine. SIGNOR-236475 0.2 CCR4-NOT complex complex SIGNOR-C439 SIGNOR NANOS3 protein P60323 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268350 0.339 PHLPP1 protein O60346 UNIPROT PRKCA protein P17252 UNIPROT down-regulates quantity dephosphorylation Ser657 QSDFEGFsYVNPQFV 9606 BTO:0000067 18162466 t gcesareni In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha SIGNOR-237043 0.252 HSBP1 protein O75506 UNIPROT HSF1 protein Q00613 UNIPROT down-regulates activity binding 9606 BTO:0000567 9649501 t Monia HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein. SIGNOR-261181 0.691 NR0B2 protein Q15466 UNIPROT NR1I2 protein O75469 UNIPROT down-regulates binding 9606 12805410 t gcesareni Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments. SIGNOR-101924 0.571 CTBP1 protein Q13363 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 21681822 t irozzo Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. SIGNOR-259197 0.591 PRKCQ protein Q04759 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates activity phosphorylation Thr227 LEPEALHtPTLMTTP 9606 27816489 t Manara PKCθ-induced phosphorylations, in part at T217 and T227 residues, strongly and specifically increased Fra-1 transcriptional activity through the stimulation of Fra-1 transactivation domain, without affecting JUN factors. SIGNOR-260879 0.2 OTX2 protein P32243 UNIPROT RBP3 protein P10745 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10354480 f miannu OTX2, as well as CRX, a homeodomain protein very similar to OTX2, activates the human IRBP promoter in co-transfection experiments. SIGNOR-254889 0.309 FOXA2 protein Q9Y261 UNIPROT OTX2 protein P32243 UNIPROT down-regulates activity binding 9606 BTO:0000567 10623575 t miannu Here we show that OTX2 directly associates with LIM1 and HNF-3beta. The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3beta represses, OTX2-directed gene expression. SIGNOR-221164 0.559 MAPK1 protein P28482 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Thr394 SGLPPPRtAMLDGNY -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). From these data we conclude that T373 is the predominant site of phosphorylation, with a low level of phosphorylation at S413 and/or S414.An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262749 0.288 JAK2 protein O60674 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity 9606 14668333 t miannu ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells SIGNOR-252107 0.301 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser301 DAVLPEQsPGDFDFN 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198984 0.326 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM5 protein P08912 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257472 0.8 NLRX1 protein Q86UT6 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity binding 9606 21703539 t Giorgia Immunoprecipitation experiments showed that NLRX1 interacted with TRAF6 and TRAF3, but not with TRAF2 or TRAF5. These results further suggest that NLRX1 specifically inhibits TLR-induced TRAF6-dependent NF-kB signaling through targeting TRAF6. SIGNOR-260364 0.48 MAPK8 protein P45983 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Ser198 GKTKTCEsPVSPIKM -1 28943315 t miannu JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. SIGNOR-277324 0.375 WFS1 protein O76024 UNIPROT ATP1B1 protein P05026 UNIPROT up-regulates quantity binding 9534 BTO:0000298 17947299 t SARA Sodium-potassium ATPase 1 Subunit Is a Molecular Partner of Wolframin, an Endoplasmic Reticulum Protein Involved in ER Stress|We conclude that the interaction may be important for Na+/K+ ATPase beta1 subunit maturation SIGNOR-260999 0.404 CRY2 protein Q49AN0 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267976 0.928 SMO protein Q99835 UNIPROT STK36 protein Q9NRP7 UNIPROT up-regulates binding 9606 17089004 t gcesareni Smo then activates stk36 serine/threonine kinase to stabilize gli family members and to phosphorylate sufu for nuclear accumulation of gli.| sufu binds to the kinesin cos2 to transduce the hh signal downstream of smo SIGNOR-150540 0.489 DAB2IP protein Q5VWQ8 UNIPROT 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR down-regulates activity binding 9606 27858941 t miannu DAB2IP then displaces the inhibitory binding between ASK1 and 14-3-3 protein, favoring ASK1 activation SIGNOR-254773 0.301 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20577053 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-252923 0.2 serotonin smallmolecule CHEBI:28790 ChEBI 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA). SIGNOR-264188 0.8 PYGL protein P06737 UNIPROT alpha-D-glucose 1-phosphate(2-) smallmolecule CHEBI:58601 ChEBI up-regulates quantity chemical modification 9606 3346228 t miannu Mammalian glycogen phosphorylases are found in at least three isozymic forms that can be distinguished by functional and structural properties as well as by the tissues in which they are preferentially expressed [√¢‚Ǩ¬¶] Each phosphorylase isozyme fulfills different physiological requirements even though all forms of the enzyme catalyze the same reaction, the phosphorolysis of glycogen to yield glucose 1-phosphate. SIGNOR-267393 0.8 STK40 protein Q8N2I9 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by destabilization binding 10090 BTO:0000078 32795415 t Gianni The COP1-interacting protein STK40 (Durzynska et al., 2017), which was detected in c/EBPβ complexes from BMDMs (Figure 1B), also appeared to contribute to the suppression of c/EBPβ in microglia. Specifically, deletion of the STK40 pseudokinase increased the amount of c/EBPβ protein without increasing the amount of Cebpb mRNA SIGNOR-261925 0.282 SRC protein P12931 UNIPROT BMX protein P51813 UNIPROT up-regulates phosphorylation Tyr566 RYVLDDQyVSSVGTK 9606 10688651 t lperfetto Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk. SIGNOR-75330 0.523 MAPK10 protein P53779 UNIPROT KIF5C protein O60282 UNIPROT down-regulates activity phosphorylation Ser176 CTERFVSsPEEVMDV -1 19525941 t miannu Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176 SIGNOR-262950 0.324 IGF1R protein P08069 UNIPROT CRK protein P46108 UNIPROT down-regulates activity phosphorylation Tyr221 GGPEPGPyAQPSVNT 10090 BTO:0000944 9480911 t On activation of the IGF-I receptor, Crk-II binds to phosphorylated tyrosine residues, especially in the juxtamembrane region. As a result of this binding, the IGF-I receptor kinase phosphorylates Tyr-221 of Crk-II, resulting in a change in intramolecular folding and binding of the SH2 domain to the phosphorylated Tyr-221, which causes rapid disassociation of the Crk-II-IGF-I receptor complex. SIGNOR-251273 0.715 CSNK2A2 protein P19784 UNIPROT STX1A protein Q16623 UNIPROT unknown phosphorylation Ser14 ELRTAKDsDDDDDVA 10116 BTO:0000142 10844023 t llicata We generated an antibody that specifically recognizes a casein kinase II-mediated phosphorylation on serine-14 of syntaxin 1. In this report we show that this phosphorylation occurs in vivo and is developmentally regulated in the rat brain | Phosphorylated syntaxin is preferentially associated with SNAP-25 and localizes to discrete domains of the axonal plasma membrane that do not colocalize with pools of synaptic vesicles. SIGNOR-251043 0.369 PRKCG protein P05129 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Ser473 PPSGTKKsKRGRGRP 9606 12529391 t llicata Pkc-mediated phosphorylation at s486 does not affect s6k activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. SIGNOR-97295 0.2 NDUFAB1 protein O14561 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The ND5-module corresponds to the distal part of the membrane arm and it is composed of MT-ND5, NDUFB2, NDUFB3, NDUFB7, NDUFB8, NDUFB9 and NDUFAB1 SIGNOR-262161 0.818 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000887 21798082 f lperfetto Foxo factors are required for the transcriptional regulation of the ubiquitin ligases atrogin-1, also called muscle atrophy f-box (mafbx) and muscle ring finger 1 (murf1), leading to the ubiquitylation of myosin and other muscle proteins, and their degradation via the proteasome. SIGNOR-252946 0.2 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr494 TGTDKLMtGVISPER 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141030 0.2 PTEN protein P60484 UNIPROT NCL protein P19338 UNIPROT up-regulates activity dephosphorylation Thr84 PAKKAAVtPGKKAAA 9606 28332494 t miannu The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis. SIGNOR-277166 0.272 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr35 LLKHAEAtLGSGNLR 9606 21808241 t MOB1a and MOB1b are near identical to each other with protein sequence homology>90%, and more importantly, both of them are putative tumor suppressors. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction. SIGNOR-175833 0.898 LIFR protein P42702 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 24710148 t milica The binding of lif to the lifr induces its heterodimerization with gp130. The formation of this complex results in the activation of the receptor-associated janus kinases (jaks), in the phosphorylation of receptor docking sites, and finally in the recruitment of src homology-2 (sh2) domain containing proteins such as stat3 (signal transducer and activator of transcription 3). SIGNOR-204850 0.594 GRK2 protein P25098 UNIPROT SLC9A5 protein Q14940 UNIPROT down-regulates activity phosphorylation Ser709 SEEEEEEsDSSETEK 21296876 t lperfetto Simultaneous mutation of five Ser/Thr residues within 702-714 to Ala ((702)ST/AA(714)) abolished phosphorylation and binding of beta-arrestin2. In transfected cells, the CK2 catalytic alpha subunit formed a complex with NHE5 and decreased wild-type but not (702)ST/AA(714) NHE5 activity, further supporting a regulatory role for this kinase. The rate of internalization of (702)ST/AA(714) was also diminished and relatively insensitive to overexpression of beta-arrestin2. SIGNOR-275504 0.2 CAMK2A protein Q9UQM7 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates activity phosphorylation Ser772 LFKKIFPsLELNITD 9606 BTO:0004553 24614225 t gianni NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity. SIGNOR-266441 0.309 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser124 PALKRSHsDSLDHDI 9606 11298456 t Manara We conclude that Chk2-dependent phosphorylation of Cdc25A on Ser 123 represents a critical step in promoting its rapid destruction in response to IR-induced DNA damage. SIGNOR-260778 0.84 RBPJ protein Q06330 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11432830 f gcesareni The rbp-jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated notch1 through rbp-jkappa-dependent transcription. SIGNOR-109042 0.311 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT up-regulates activity cleavage Leu649 NKGAIIGlMVGGVVI -1 10605825 t lperfetto In this work, we used a sensitive in vitro method of detection to investigate the role of cathepasin D in the proteolytic processing of a 100-amino acid C-terminal fragment (C100) inclusive of βA4 and cytoplasmic domain of APP. Digestion of C100 with cathepsin D resulted in cleavage at the amyloidogenic γ-cleavage sites. This occurred preferentially at Thr43–Val44 and at Ala42–Thr43, generating full length βA4 43 and βA4 42 amyloid peptides, respectively. Cathepsin D was also found to cleave the substrate at the following nonamyloidogenic sites; Leu34–Met35, Thr48–Leu49 and Leu49–Val50. A high concentration of cathepsin D resulted in cleavage also occurring at Phe19–Phe20, Phe20–Ala21 and Phe93–Phe94 of the C100, suggesting that these sites are somewhat less sensitive to the action of cathepsin D. SIGNOR-261783 0.497 LYN protein P07948 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268206 0.701 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Ser) smallmolecule CHEBI:29179 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269496 0.8 PRKN protein O60260 UNIPROT GPR37 protein O15354 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 12666095 t lperfetto Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R). SIGNOR-249706 0.2 DAXX protein Q9UER7 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates binding 9606 BTO:0000776;BTO:0000785 11483955 t gcesareni Tgf-beta-induced apoptosis is mediated by the adapter protein daxx that facilitates jnk activation SIGNOR-109542 0.516 MECOM protein Q03112 UNIPROT TEK protein Q02763 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000669 15889140 t Luana We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2  SIGNOR-266063 0.2 GIGYF1 protein O75420 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR form complex binding 9606 30917308 t lperfetto 4EHP forms complexes with the GYF domain-containing proteins GIGYF1 and GIGYF2, which are critical for this translational repression SIGNOR-261011 0.62 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT down-regulates binding 9606 10929711 t amattioni Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. SIGNOR-171770 0.913 DUSP9 protein Q99956 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates binding 9606 21908610 t inferred from 70% of family members gcesareni Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein. SIGNOR-269924 0.718 DSCAM protein O60469 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity binding 9606 BTO:0000938 30745319 t miannu Our findings now further suggest that STAT3 and the adaptor protein SH2D2A interact with tyrosine‐containing motifs within the DSCAM/L1 ICDs. The SH2 domains of both STAT3 and SH2D2A are known to bind to phosphorylated tyrosine residues in the context of such motifs. Thus, the interactions between DSCAMs and SH2‐domain containing proteins seem to play a central and conserved role in Dscam signaling in the context of dynamic changes of tyrosine‐phosphorylation levels. SIGNOR-264279 0.2 LRRK2 protein Q5S007 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Thr164 LGSQSLHtRTSKLFQ 9606 21048939 t gcesareni Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence SIGNOR-169225 0.463 CGAS protein Q8N884 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR down-regulates activity 9606 31544964 f Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death SIGNOR-259951 0.7 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0000007 SIGNOR-C3 12747827 t lperfetto Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor (a recently identified mTOR-interacting protein), for 4E-BP1 to be efficiently phosphorylated in vitro by themTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor regulated phosphorylation is necessary for 4E-BP’s efficient release from the translational initiation factor eIF4E. We find that the TOS motif is absolutely required for efficient phosphorylation of 4E-BP1 at all the identified mTOR-regulated sites, namely, Thr37/46, Ser65, and Thr70 in vivo. SIGNOR-101123 0.925 TWIST1 protein Q15672 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255535 0.2 XIAP protein P98170 UNIPROT CASP7 protein P55210 UNIPROT down-regulates quantity by destabilization binding -1 11257231 t lperfetto Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase. SIGNOR-105732 0.856 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT unknown phosphorylation Ser304 RASRRSDsASSEPVG 9606 19366211 t llicata This study identifies novel in vitro pkcdelta autophosphorylation sites at thr(141) adjacent to the pseudosubstrate domain, thr(218) in the c1a-c1b interdomain, ser(295), ser(302), and ser(304) in the hinge region, and ser(503) adjacent to thr(505) in the activation loop. SIGNOR-185295 0.2 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 17548358 t gcesareni Dually phosphorylated on thr-180 and tyr-182 by the map2ks map2k3/mkk3, map2k4/mkk4 and map2k6/mkk6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. SIGNOR-155381 0.335 LSM-20934 chemical CHEBI:109533 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258850 0.8 TPP1 protein O14773 UNIPROT Telomere_maintenance phenotype SIGNOR-PH148 SIGNOR up-regulates 9606 22101936 f miannu The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres.  SIGNOR-272723 0.7 EPAS1 protein Q99814 UNIPROT KDM2A protein Q9Y2K7 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271581 0.2 PLK1 protein P53350 UNIPROT CCNT1 protein O60563 UNIPROT down-regulates activity phosphorylation Ser564 KTYSLSSsFSSSSST 9606 BTO:0002181 23977272 t miannu  Further analysis indicated that Plk1 could phosphorylate cyclin T1 at Ser564 and inhibit the kinase activity of cyclin T1/Cdk9 complex on phosphorylation of the C-terminal domain (CTD) of RNA polymerase II.  SIGNOR-276501 0.386 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT up-regulates dephosphorylation 9606 BTO:0000776;BTO:0003076 11994288 t gcesareni These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3, SIGNOR-87154 0.461 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR NRARP protein Q7Z6K4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0000782 11783997 t gcesareni These observations demonstrate that the nrarp gene is an evolutionarily conserved transcriptional target of the notch signaling pathway. SIGNOR-113786 0.415 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CEBPA protein P49715 UNIPROT down-regulates phosphorylation 9606 BTO:0000876 14701740 t inferred from 70% family members lperfetto Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21. SIGNOR-270066 0.2 BCR-Mk complex SIGNOR-C433 SIGNOR SYK protein P43405 UNIPROT up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The tyrosine phosphorylation of the ITAM of CD79 promotes the activation of the non-SRC family tyrosine kinase, spleen tyrosine kinase (SYK), which becomes a key part of a signalosome formed by many other kinases and adaptor proteins. The SYK which is recruited to the phosphorylated CD79- ITAM facilitates the complex formation of B-cell linker protein (BLNK), leading to activation of Bruton’s tyrosine kinase (BTK). SIGNOR-268439 0.708 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR CBFB protein Q13951 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f irozzo However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We found that MLL-BP and the 3 MLL fusion proteins all decreased RUNX1 levels, and MLL-eleven nineteen leukemia (ENL) caused a greater decrease in RUNX1 compared with MLL-AF9 and MLL-AF4 fusion proteins. SIGNOR-255856 0.2 AVPR1A protein P37288 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256805 0.44 ZW10 protein O43264 UNIPROT DCTN2 protein Q13561 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 SIGNOR-C357 20462495 t lperfetto ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores SIGNOR-265016 0.699 CEBPB protein P17676 UNIPROT TNFAIP6 protein P98066 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7876106 t In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. SIGNOR-254055 0.305 LCK protein P06239 UNIPROT PIK3R1 protein P27986 UNIPROT down-regulates activity phosphorylation Tyr688 FAEPYNLySSLKELV 9534 BTO:0004055 9461588 t the regulatory p85 subunit of phosphatidylinositol 3-kinase is phosphorylated on tyrosine residues. We report that this phosphorylation event is readily catalyzed by the Abl and Lck protein-tyrosine kinases in vitro, by Bcr-Abl or a catalytically activated Lck-Y505F in co-transfected COS cells. we have mapped a major phosphorylation site to Tyr-688 in the C-terminal SH2 domain of p85. Tyrosine phosphorylation of p85 in vitro or in vivo was not associated with detectable change in the enzymatic activity of the phosphatidylinositol 3-kinase heterodimer, but correlated with a strong reduction in the binding of some, but not all, phosphoproteins to the SH2 domains of p85. SIGNOR-251383 0.613 FST protein P19883 UNIPROT MSTN protein O14793 UNIPROT down-regulates activity binding 10090 11459935 t gcesareni Binding of myostatin to Act RIIB could be inhibited by the activin-binding protein follistatin and, at higher concentrations, by the myostatin propeptide. T SIGNOR-235150 0.742 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1070 ISTHTVTyGNIEGNA -1 11024032 t Tyr-932, Tyr-1039, Tyr-1070, Tyr-1109, Tyr-1252, Tyr-1336, and Tyr-1472 are Fyn-mediated phosphorylation sites in GluRε2 in vitro. SIGNOR-251170 0.763 KMT5B protein Q4FZB7 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity methylation Lys21 GGAKRHRkVLRDNIQ -1 24396869 t miannu SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation. SIGNOR-266651 0.2 MAPK1 protein P28482 UNIPROT AEBP1 protein Q8IUX7 UNIPROT up-regulates activity phosphorylation Thr621 GEPEFRYtAGIHGNE 10090 BTO:0000944 15654748 t miannu We show that DNA binding by AEBP1 requires both the N- and C-terminal domains of AEBP1, and MAPK interaction with AEBP1 (through its N terminus) results in enhanced DNA binding. A threonine at position 623 within the C-terminal domain of AEBP1 plays an important role in DNA binding by AEBP1, because the mutation results in decreased DNA binding by AEBP1, which leads to a decrease in the transcriptional repression ability of AEBP1. We also show that in vitro phosphorylation of AEBP1 by MAPK is greatly reduced upon mutation of T623. These results suggest that MAPK regulates the transcriptional activity of AEBP1 by a novel dual mechanism, in which MAPK interaction enhances and subsequent phosphorylation decreases the DNA-binding ability of AEBP1. SIGNOR-262897 0.2 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Thr282 RGKEGPGtPTRSSVI 9606 BTO:0001271 18246121 t llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. SIGNOR-160630 0.284 SIK2 protein Q9H0K1 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Ser91 ENLKKSLsCANLSTF 9606 24561619 t lperfetto Sik2 phosphorylates p35 at ser 91, to trigger its ubiquitylation by pja2 and promote insulin secretion. _-cell knockout of sik2 leads to accumulation of p35 and impaired secretion SIGNOR-204648 0.334 LETM1 protein O95202 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 9606 BTO:0000567 18628306 f lperfetto We hypothesize a working model of the function of BCS1L and LETM1 in mitochondrial biogenesis (Fig. 8E). Because BCS1L is an AAA-ATPase, the following three functions are downstream targets: (1) respiratory chain assembly, (2) mitochondrial morphology maintenance and, (3) LETM1 complex formation. BCS1L functions directly in the formation of mitochondrial tubular networks, in addition to the assembly of the supercomplexes. LETM1 has a distinct role in maintenance of mitochondrial volume and shapes, which helps – in concert with BCS1L – to achieve the efficient assembly of the respiratory chains. SIGNOR-262545 0.7 NAE complex SIGNOR-C131 SIGNOR CUL7 protein Q14999 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243172 0.465 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 16403219 t miannu Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. SIGNOR-259423 0.2 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole chemical CHEBI:92005 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu A range of serotonergic agonists and partial agonists were tested for their capacity to stimulate 5-HT1A receptor mediated GTPg binding in CHO-h5-HT1A membranes. The methoxynaphtylpiperazine ligand, S 14671,was the most potent agonist tested, with virtually full agonist activity, relative to 5-HT Table 1; Fig. 2C consistent with its exceptionally potent and efficacious actions in in vivo functional paradigms. Its analogue, S 14506 was also a highly potent and efficacious ligand (Emax90%) in agreement with previous in vivo studies ( Schreiber et al., 1994 ). (+)UH 301 exhibited partial agonist activity at 5-HT1A receptors SIGNOR-258857 0.8 TBR1 protein Q16650 UNIPROT FEZF2 protein Q8TBJ5 UNIPROT down-regulates quantity by repression transcriptional regulation BTO:0000938 21228164 t lperfetto We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene. SIGNOR-268967 0.496 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 17311928 t inferred from 70% family members llicata Sphingosine kinase type 2 activation by erk-mediated phosphorylation. site-directed mutagenesis indicated that hsphk2 is phosphorylated on ser-351 and thr-578 by erk1 SIGNOR-270036 0.2 IKBKG protein Q9Y6K9 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 SIGNOR-C14 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-217382 0.787 ARHGEF15 protein O94989 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260540 0.56 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GJA1 protein P17302 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000567 9535909 t inferred from 70% family members lperfetto These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication. SIGNOR-270148 0.2 PPP3CC protein P48454 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates relocalization 9606 BTO:0000222 BTO:0000887;BTO:0001103 18676376 t gcesareni The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c. SIGNOR-179796 0.695 ID1 protein P41134 UNIPROT TCF12 protein Q99081 UNIPROT down-regulates activity binding 10090 BTO:0004058 SIGNOR-C128 9242638 t 2 miannu All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-241104 0.594 PDK4 protein Q16654 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates activity phosphorylation Ser232 NRYGMGTsVERAAAS -1 11485553 t lperfetto Here we report that the four isoenzymes of protein kinase responsible for the phosphorylation and inactivation of pyruvate dehydrogenase (pdk1, pdk2, pdk3 and pdk4) differ in their abilities to phosphorylate the enzyme. Pdk1 can phosphorylate all three sites (s232, s293, s300), whereas pdk2, pdk3 and pdk4 each phosphorylate only s232 and s293. SIGNOR-109621 0.679 FOXF1 protein Q12946 UNIPROT GH2 protein P01242 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16772323 f miannu Overexpression of FOXF1 in BeWo and HepG2 cells induced the GHV promoter, whereas overexpression of FOXF2 was without effect. These studies indicate that FOXF1 induces GHV expression by interaction with a FOXF1/FOXF2 cis-element in the proximal promoter. SIGNOR-254175 0.2 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 BTO:0000007 16964285 t amattioni Casp8 induces apoptosis by directly activating casp3. SIGNOR-149420 0.718 acetyl-CoA smallmolecule CHEBI:15351 ChEBI hexadecanoic acid smallmolecule CHEBI:15756 ChEBI up-regulates quantity precursor of 9606 15507492 t miannu Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-268089 0.8 AKT1 protein P31749 UNIPROT RNF11 protein Q9Y3C5 UNIPROT down-regulates quantity phosphorylation Thr135 DWLMRSFtCPSCMEP 9606 BTO:0003474 16123141 t gcesareni Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity SIGNOR-252558 0.464 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263783 0.7 GADL1 protein Q6ZQY3 UNIPROT beta-alanine zwitterion smallmolecule CHEBI:57966 ChEBI up-regulates quantity chemical modification 9606 22718265 t miannu Animal glutamate decarboxylase (GDC), aspartate decarboxylase (ADC, also called aspartate Œ±-decarboxylase or aspartate 1-decarboxylase) and cysteine sulfinic acid decarboxylase (CSADC) catalyze the decarboxylation of Œ±-carboxyl group of glutamate, aspartate and cysteine sulfinic acid to produce Œ≥-aminobutyric acid (GABA), Œ≤-alanine and hypotaurine, respectively; these amine products play important role in living organisms. SIGNOR-267546 0.8 GPR35 protein Q9HC97 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256717 0.2 FBXO31 protein Q5XUX0 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002181 29343641 t miannu FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2. SIGNOR-277380 0.326 G3BP1 protein Q13283 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 25520508 f miannu Ras-GTPase-activating protein (SH3 domain) binding protein 1 (G3BP1) is a stress granule-resident protein that nucleates stress granule assembly and is also inactivated or coopted by many viruses to promote productive infection SIGNOR-260747 0.7 POU5F1 protein Q01860 UNIPROT PAX6 protein P26367 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003298 22795133 f lperfetto Knockdown of Oct4 or Nanog induced an increase in the expression of Pax6, Gata4, Gata6, Sox17, and FoxA2 in E, H, and p21KD MSCs ( Figure 3F and Figure S2D) SIGNOR-253163 0.464 TP53 protein P04637 UNIPROT SCO2 protein O43819 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway. SIGNOR-267463 0.632 KCNB1 protein Q14721 UNIPROT VAPB protein O95292 UNIPROT up-regulates quantity relocalization 9606 BTO:0000007 29941597 t lperfetto Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions. SIGNOR-262121 0.2 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 18231581 f lperfetto Induction and over-production of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-a and INF-c, were considered to be main mediators in the pathogenesis of SARS SIGNOR-260258 0.7 SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR Degranulation phenotype SIGNOR-PH92 SIGNOR up-regulates 9606 16470226 f Alessandro Palma So, the association of aggregated FcεRI with the preferentially activated LYN in lipid rafts might be sufficient to shift the equilibrium of FcεRI from a nonphosphorylated state to a phosphorylated state, thereby initiating FcεRI-mediated degranulation SIGNOR-254956 0.7 CECR2 protein Q9BXF3 UNIPROT CERF complex SIGNOR-C340 SIGNOR form complex binding 9606 BTO:0000227 15640247 t miannu Biochemical isolation of CECR2 revealed the presence of this protein as a component of a novel heterodimeric complex termed CECR2-containing remodeling factor (CERF). CERF comprises CECR2 and the ATP-dependent chromatin remodeler SNF2L, a mammalian ISWI ortholog expressed predominantly in the central nervous system. CERF is capable of remodeling chromatin in vitro and displays an ATP hydrolyzing activity that is stimulated by nucleosomes. Together, these data identify a novel chromatin remodeling complex with a critical role in neurulation. SIGNOR-263891 0.391 EGR1 protein P18146 UNIPROT PPARG protein P37231 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003336 29212876 t miannu Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC. SIGNOR-263508 0.612 SYVN1 protein Q86TM6 UNIPROT GPR37 protein O15354 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 18241051 t miannu We demonstrated that endogenous HRD1 interacts with Pael-R, and that HRD1 promotes the degradation of Pael-R and protects cell death caused by the accumulation of Pael-R. SIGNOR-272631 0.406 ANAPC11 protein Q9NYG5 UNIPROT APC-c complex SIGNOR-C150 SIGNOR form complex binding 16896351 t lperfetto The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that has essential functions in and outside the eukaryotic cell cycle. It is the most complex molecular machine that is known to catalyse ubiquitylation reactions, and it contains more than a dozen subunits that assemble into a large 1.5-MDa complex. SIGNOR-252010 0.862 KAT2A protein Q92830 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates activity acetylation 24870244 t lperfetto The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1alpha. SIGNOR-275498 0.2 SRC protein P12931 UNIPROT ARHGDIB protein P52566 UNIPROT unknown phosphorylation Tyr24 ELDSKLNyKPPPQKS 9606 19321744 t llicata Studies confirmed that activated src kinase binds and phosphorylates rhogdi2 in vitro and vivo. Mutagenesis revealed that tyr-153 and, to a lesser degree, tyr-24 were the primary src phosphorylation sites. Phosphorylation decreased the amount of rac1 in rhogdi2 complexes and increased rhogdi2 association with cell membranes. SIGNOR-184912 0.401 PRKACA protein P17612 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 15383283 t gcesareni Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites. SIGNOR-129349 0.349 PKLR protein P30613 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266535 0.8 TEC protein P42680 UNIPROT TEC protein P42680 UNIPROT up-regulates phosphorylation Tyr206 RLERGQEyLILEKND 9606 12573241 t lperfetto Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated SIGNOR-98098 0.2 CSNK2A1 protein P68400 UNIPROT UBE2R2 protein Q712K3 UNIPROT up-regulates activity phosphorylation Ser233 DCYDDDDsGNEES 9606 12037680 t lperfetto Ck2-dependent phosphorylation of the e2 ubiquitin conjugating enzyme ubc3b induces its interaction with beta-trcp and enhances beta-catenin degradation SIGNOR-88050 0.341 NMDA receptor_2A complex SIGNOR-C347 SIGNOR CAMK2A protein Q9UQM7 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu The most abundant signaling protein in the PSD fraction is Ca2+/calmodulin–dependent protein kinase II (CaMKII), which makes up 1 to 2% of the total protein in the forebrain (21). CaMKII is a target for Ca2+ flowing through the NMDA receptor and is necessary for normal synaptic plasticity in pyramidal neurons. The cytosolic tails of the NR2 subunits of the NMDA receptor bind to CaMKII and thus can serve as docking sites for it in the PSD SIGNOR-264214 0.655 CENPW protein Q5EE01 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265202 0.628 CENPU protein Q71F23 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265203 0.81 TNF protein P01375 UNIPROT DIO proteinfamily SIGNOR-PF83 SIGNOR down-regulates quantity by repression transcriptional regulation 10116 9397972 f inferred from family member scontino From the results in Figs. 1-3, it is clear that several cytokines reduce the expression of 5‚Äô-DI mRNA and enzymatic activity in FRTL-5 cells. These include TNF-a, IL-lb and INF-y. SIGNOR-270239 0.26 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates activity 9606 BTO:0000007 14976264 f lperfetto Sirt1 inhibited foxo3's ability to induce cell death. SIGNOR-252995 0.91 PPP1CB protein P62140 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates activity dephosphorylation Ser469 AHEENPEsILDEHVQ 9606 17318175 t The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated SIGNOR-248570 0.2 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F8 protein P00451 UNIPROT down-regulates activity cleavage Arg355 CPEEPQLrMKNNEEA -1 10350471 t lperfetto N-Terminal sequencing along with time courses of proteolysis indicated that VIIa-TF/PL cleaved factor VIII first at R740, followed by concomitant cleavage at R336 and R372. |hus, heavy chain cleavage of factor VIII by VIIa-TF/PL produces an inactive factor VIII cofactor no longer capable of activation by thrombin. SIGNOR-263643 0.463 HDAC1 protein Q13547 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes SIGNOR-199958 0.647 MITF protein O75030 UNIPROT TRPM1 protein Q7Z4N2 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 14744763 f miannu Mice homozygously mutated in MITF showed a dramatic decrease in TRPM1 expression. Finally, the slope of TRPM1 induction by MITF was particularly steep compared with other MITF target genes, suggesting it is a sensitive indicator of MITF expression and correspondingly of melanocytic differentiation. SIGNOR-254588 0.432 PPP2R2B protein Q00005 UNIPROT PP2Ca_R1A_Bd complex SIGNOR-C133 SIGNOR form complex binding 9606 23454242 t gcesareni [PP2A] ... is multifarious as it is composed of catalytic, scaffold and regulatory subunits. The catalytic and scaffold subunits have two isoforms and the regulatory subunit has four different families containing different isoforms. The regulatory subunit is the most diverse with temporal and spatial specificity. SIGNOR-243507 0.756 DMPK protein Q09013 UNIPROT PLN protein P26678 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 15598648 t gcesareni Coimmunoprecipitation studies showed that dmpk and pln can physically associate. Furthermore, purified wild-type dmpk, but not a kinase-deficient mutant (k110a dmpk), phosphorylates pln in vitro SIGNOR-131371 0.527 E2F1 protein Q01094 UNIPROT LRBA protein P50851 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15064745 f miannu We also show that LRBA promoter activity and endogenous LRBA mRNA levels are reduced by p53 and increased by E2F1, indicating that mutations in the tumor suppressors p53 and Rb could contribute to the deregulation of LRBA. SIGNOR-253846 0.2 leuprolide acetate chemical CHEBI:63597 ChEBI GNRHR protein P30968 UNIPROT up-regulates activity chemical activation 9606 22416801 t miannu Clinical data have shown that the GnRH antagonist, degarelix, is associated with more rapid PSA suppression and improved PSA PFS compared with the GnRH agonist, leuprolide. SIGNOR-259163 0.8 tolcapone chemical CHEBI:63630 ChEBI COMT protein P21964 UNIPROT down-regulates activity chemical inhibition 10090 26919286 t miannu The present work illustrates the potential therapeutic efficacy of COMT inhibition in alleviating cognitive impairment. A brain-penetrant COMT inhibitor, tolcapone, was tested in normal and phencyclidine-treated rats and COMT-Val transgenic mice. SIGNOR-258475 0.8 CSNK2A2 protein P19784 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250979 0.288 CSNK2A1 protein P68400 UNIPROT CCAR2 protein Q8N163 UNIPROT up-regulates activity phosphorylation Thr454 AAEAAPPtQEAQGET 9606 24962073 t lperfetto CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1 SIGNOR-267666 0.2 CDK2 protein P24941 UNIPROT CEBPB protein P17676 UNIPROT up-regulates phosphorylation Thr235 SSSSPPGtPSPADAK 9606 SIGNOR-C83 22369944 t fspada Mass spectrometric analysis revealed that cdk2/cyclina phosphorylates c/ebpbeta on thr(188) and is required for phosphorylation (on ser(184) or thr(179)) of c/ebpbeta by gsk3beta and maintenance of dna binding activity. SIGNOR-196372 0.402 ARRB2 protein P32121 UNIPROT ADRB2 protein P07550 UNIPROT down-regulates activity binding -1 2163110 t The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors SIGNOR-256501 0.718 Caspase 3 complex complex SIGNOR-C221 SIGNOR CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-256440 0.628 DIO2 protein Q92813 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20978344 f miannu The active thyroid hormone 3,5,3' triiodothyronine (T3) is a major regulator of skeletal muscle function. The deiodinase family of enzymes controls the tissue-specific activation and inactivation of the prohormone thyroxine (T4). Here we show that type 2 deiodinase (D2) is essential for normal mouse myogenesis and muscle regeneration. Indeed, D2-mediated increases in T3 were essential for the enhanced transcription of myogenic differentiation 1 (MyoD) and for execution of the myogenic program. SIGNOR-256203 0.267 ARF1 protein P84077 UNIPROT Vesicle_transport phenotype SIGNOR-PH172 SIGNOR up-regulates 14973189 f lperfetto ADP-ribosylation factors (ARF) are 20-kDa GTPases of the ras superfamily that regulate vesicular transport in eukaryotic cells. There are three classes of ARFs: class I (ARF1–3), which function in endoplasmic reticulum-Golgi trafficking; the much less studied class II (ARF4–5); and class III (ARF6), with significant roles in endocytotic pathways and cytoskeletal dynamics near the cell surface SIGNOR-272149 0.7 mTORC2 complex SIGNOR-C2 SIGNOR AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Thr450 TAQMITItPPDQDDS 10090 BTO:0002572 18566586 t gcesareni MTORC2 phosphorylates newly synthesized Akt at the TM (Thr450) site to facilitate carboxyl-terminal folding and to stabilize Akt SIGNOR-252438 0.638 DIO3 protein P55073 UNIPROT iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity chemical modification 9606 34674502 t scontino Three different deiodinases have been described: iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3. Deiodination is the first step in the activation/inactivation process of THs and involves the removal of removes one iodine atom from the outer tyrosyl ring of T4 to produce T3. SIGNOR-266952 0.8 Hypoxia stimulus SIGNOR-ST25 SIGNOR HIF-1 complex complex SIGNOR-C418 SIGNOR up-regulates 9606 27692180 f miannu Hypoxia-Inducible Factor-1 (HIF-1) is a key transcription factor that regulates gene expression under hypoxic conditions (Semenza, 2012, 2010a). HIF-1 consists of two subunits, HIF-1α and HIF-1β. While HIF-1β protein is constitutively expressed and present in excess, HIF-1α protein has a short half-life SIGNOR-267449 0.7 Immunoglobulin kappa light chain protein P0DOX7 UNIPROT BCR-Dk complex SIGNOR-C435 SIGNOR form complex binding 9606 BTO:0000776 20176268 t scontino Immunoglobulins (Igs) belong to the eponymous immunoglobulin super-family (IgSF). They consist of two heavy (H) and two light (L) chains, where the L chain can consist of either a κ or a λ chain. There are five main classes of heavy chain C domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. SIGNOR-268194 0.2 MADD protein Q8WXG6 UNIPROT RAB3A protein P20336 UNIPROT up-regulates activity guanine nucleotide exchange factor 10116 BTO:0000142 11809763 t miannu Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). SIGNOR-265579 0.403 PRKCB protein P05771 UNIPROT SDC2 protein P34741 UNIPROT unknown phosphorylation Ser188 LGERKPSsAAYQKAP -1 9244383 t lperfetto We investigated phosphorylation of syndecan-2 cytoplasmic domain by PKC | Peptide mapping and substitution studies showed that both serines were phosphoacceptors, but each had slightly different affinity, with that of serine-197 being higher than serine-198. SIGNOR-248977 0.331 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT down-regulates phosphorylation Ser2392 AGLHHSLsHSLLAVA 9606 20708153 t lperfetto Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation SIGNOR-167488 0.324 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT up-regulates activity phosphorylation Ser757 NARVKKEsGSSAAGI 9606 BTO:0000007 21532585 t miannu PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. Replacement of all of four serine residues by alanines (4SA: Ser 757/Ser 899/Ser 954/Ser 1056) fully abrogated PKA phosphorylation of PHF2 (Fig. 2h). SIGNOR-264510 0.2 TFAP4 protein Q01664 UNIPROT SALL2 protein Q9Y467 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000452 21228219 f miannu The transcription factor AP4 increases along with SALL2 in quiescent cells and positively regulates SALL2 expression. SIGNOR-255426 0.2 BACH1 protein O14867 UNIPROT HK2 protein P52789 UNIPROT up-regulates quantity transcriptional regulation 9606 31257027 t BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells. SIGNOR-259338 0.2 FBXO11 protein Q86XK2 UNIPROT DTL protein Q9NZJ0 UNIPROT down-regulates binding 9606 23478441 t miannu We determined that the f-box protein fbxo11 interacts with cdt2,a dcaf protein that controls cell-cycle progression, and recruits cdt2 to the scf(fbxo11)complex to promote its proteasomal degradation. SIGNOR-192325 0.554 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Thr895 KLSFRRRtDKDTEQP 9606 10488078 t lperfetto Deletion of protein kinase a phosphorylation sites in the herg potassium channel inhibits activation shift by protein kinase afour consensus pka phosphorylation sites (s283a, s890a, t895a, s1137a) SIGNOR-70730 0.309 EFNA3 protein P52797 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52387 0.745 CDK1 protein P06493 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser249 EGGKSGKsPRRRAAS 9606 BTO:0001130 18408765 t gcesareni Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1. SIGNOR-252890 0.52 2-[[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine chemical CHEBI:93274 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258880 0.8 PRKCB protein P05771 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser576 CAEMREDsARVYENV 9606 11781100 t lperfetto  In summary, SHP2 is phosphorylated on serine residues 576 and 591 by PKC isoforms alpha, beta 1, beta 2, and eta. SIGNOR-249136 0.334 CLTCL1 protein P53675 UNIPROT AP-1/clathrin vescicle complex SIGNOR-C251 SIGNOR form complex binding 9606 23103167 t lperfetto Clathrin-coated pits and vesicles are diffraction-limited objects with typical diameters ranging between 75 and 130 nm. The smaller ∼75 nm coats contain at least 36 copies of clathrin, a heterohexameric protein of three heavy chains and three light chains, and about half that number of copies of the heterotetrameric AP adaptor complex | Intracellular clathrin-coated vesicles contain AP1 or AP3 adaptors SIGNOR-260679 0.724 GTF3A protein Q92664 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR up-regulates activity binding 9308965 t lperfetto At present, it is known that transcription factors TFIIIB, TFIIIC2, TFIIIC1, and TFIIIA (5S gene only) are involved in transcription of tRNA, VA RNA, and 5S RNA genes by human RNA Pol III. SIGNOR-266180 0.455 CAMK1 protein Q14012 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser498 RPLSRTQsSPLPQSP 9606 BTO:0000887 11114197 t gcesareni Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation. SIGNOR-85022 0.426 PPARGC1A protein Q9UBK2 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 20404331 f lperfetto Capacity of PGC-1alpha and PGC-1beta to inhibit FoxO3 and NFkappaB actions and proteolysis helps explain how exercise prevents muscle atrophy.overexpression of PGC-1_ inhibits muscle wasting induced by denervation, starvation, and even caFoxO3 expression SIGNOR-252969 0.573 GSK3A protein P49840 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 19214430 t gcesareni Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd. SIGNOR-183969 0.323 PIP3 smallmolecule CHEBI:16618 ChEBI WIPI2 protein Q9Y4P8 UNIPROT up-regulates chemical activation 9606 22082875 t gcesareni We identified the human wipi protein family and found that wipi-1 specifically binds ptdins(3)p, accumulates at the phagophore and becomes a membrane protein of generated autophagosomes. SIGNOR-177226 0.8 VCPIP1 protein Q96JH7 UNIPROT VCP protein P55072 UNIPROT up-regulates activity binding 23500464 t lperfetto Golgi biogenesis requires two distinct p97ATPase-mediated membrane fusion, the p97/p47 and p97/p37 pathways. |We clarified that VCIP135, an essential factor in both p97 membrane fusion pathways, is phosphorylated on Threonine-760 and Serine-767 by Cdc2 at mitosis and that this phosphorylated VCIP135 does not bind to p97. SIGNOR-265039 0.561 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr227 PAPPEGAtPTSPVGH 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-252954 0.708 AKT2 protein P31751 UNIPROT FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 10377430 t lperfetto Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus. SIGNOR-68652 0.65 ELK3 protein P41970 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000567 12933792 f miannu From HeLa cells an Ets family of protein, Ets-related protein (ERP), binds to double-stranded PNR element. The ERP.PNR complex inhibited the activity of the basal transcription complex from homologous as well as heterologous promoters in a PNR position-independent manner, suggesting that ERP acts as a silencer of alpha-MHC gene expression in non-muscle cells. SIGNOR-253900 0.2 PRKCA protein P17252 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates phosphorylation Ser4517 LYMGGHGsRHSLAST 9606 15272003 t lperfetto Serine and threonine phosphorylation of the low density lipoprotein receptor-related protein by protein kinase calpha regulates endocytosis and association with adaptor moleculesthese results indicate that elimination of serine and threonine phosphorylation sites in the lrp cytoplasmic domain reduces the extent of tyr63 phosphorylation and leads to impaired association with the adaptor protein shc. SIGNOR-126958 0.2 ACE2 protein Q9BYF1 UNIPROT Angiotensin-1 protein P01019-PRO_0000032457 UNIPROT up-regulates activity cleavage Pro40 GDRVYIHpFHLVIHN -1 11815627 t miannu The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus. SIGNOR-260222 0.2 CHEK1 protein O14757 UNIPROT SNCB protein Q16143 UNIPROT unknown phosphorylation Tyr127 EDPPQEEyQEYEPEA 9606 21699177 t llicata Chk preferentially phosphorylates recombinant _-synuclein at tyrosine-127 SIGNOR-174590 0.2 ILK protein Q13418 UNIPROT PPP1R14B protein Q96C90 UNIPROT up-regulates activity phosphorylation Thr57 VRRQGKVtVKYDRKE -1 12144526 t lperfetto We conclude that ILK may activate smooth-muscle contraction both directly, via phosphorylation of myosin, and indirectly, via phosphorylation and activation of CPI-17 and PHI-1, leading to inhibition of MLCP.|CPI-17 and PHI-1 thiophosphorylated by ILK at Thr(38) or Thr(57) respectively inhibited myosin light-chain phosphatase (MLCP) activity bound to myosin SIGNOR-265741 0.382 PRKAA1 protein Q13131 UNIPROT EP300 protein Q09472 UNIPROT down-regulates phosphorylation Ser89 SELLRSGsSPNLNMG 9606 BTO:0000801;BTO:0001271;BTO:0000876 21940946 t gcesareni The mechanism of ampk-mediated anti- inflammation involves the induction of p300 ser89 phosphor- ylation and subsequent inactivation of p300 hat activity. SIGNOR-176637 0.381 ATXN7 protein O15265 UNIPROT SAGA complex complex SIGNOR-C465 SIGNOR form complex binding 9606 34811519 t lperfetto Here we present the cryogenic-electron microscopy (cryo-EM) structure of human SAGA (hSAGA)|Human SAGA is a 20-subunit, 1.4-MDa complex with five functional modules (Fig. ​(Fig.1a):1a): a scaffolding core that includes TBP-associated factors (TAFs); a TRRAP (Transformation/Transcription domain Associated Protein) containing a phosphoinositide-3-kinase (PI3K)-related pseudoprotein kinase (ΨPIKK); a histone acetyltransferase (HAT); a deubiquitinase (DUB) and a metazoan-specific splicing (SPL) module SIGNOR-269576 0.666 DDC protein P20711 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI up-regulates quantity chemical modification 7955 23940784 t brain lperfetto AADC is responsible for the decarboxylation step in the catecholamine and dopamine biosynthesis. Dopamine and serotonin can be synthesized by AADC from L-3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively [7]. A deficiency in AADC will lead to reduced biogenic monoamines, including dopamine, norepinephrine, epinephrine, and serotonin SIGNOR-263987 0.8 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-252683 0.435 KANSL1 protein Q7Z3B3 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000567 26243146 f miannu Here we uncover a novel function of the NSL complex members in mitosis. As the cell enters mitosis, KANSL1 and KANSL3 undergo a marked relocalisation from the chromatin to the mitotic spindle. By stabilizing microtubule minus ends in a RanGTP-dependent manner, they are essential for spindle assembly and chromosome segregation. SIGNOR-267170 0.7 BUB1 protein O43683 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity phosphorylation Ser153 NRLKVLYsQKATPGS 9606 BTO:0000567 15525512 t llicata Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.  SIGNOR-250604 0.992 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257911 0.8 GPR119 protein Q8TDV5 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257308 0.251 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser206 ATPPTLSsTVLIVRN 9606 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102494 0.549 LCK protein P06239 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation Tyr315 RADNDKEyLVLTLTK 9606 11948419 t gcesareni Thus, y240a and y315a are involved in the ability of mmac/pten to dephosphorylate ptdins and regulate tumor cell growth in vitro and in vivo. SIGNOR-116499 0.379 GFPT1 protein Q06210 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 21310273 t miannu GFPT1 catalyzes the transfer of an amino group from glutamine onto fructose-6-phosphate, yielding glucosamine-6-phosphate (GlcN-6-P) and glutamate. This transamidase reaction has been identified as the first and rate-limiting step of the hexosamine biosynthesis pathway, which is the obligatory source of essential amino sugars for the synthesis of glycoproteins, glycolipids, and proteoglycans SIGNOR-267816 0.8 ARHGEF6 protein Q15052 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 BTO:0000599 23776207 f lperfetto Activation of ARF6 promotes cortical actin assembly (9) and plasma membrane remodeling  SIGNOR-272236 0.7 MAOB protein P27338 UNIPROT 3,4-dihydroxyphenylacetaldehyde smallmolecule CHEBI:27978 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|dopamine is metabolized to 3-methoxytyramine by COMT, which is in turn converted to 3-methoxy-4-hydroxyacetaldehyde by MAO. SIGNOR-264004 0.8 TFEC protein O14948 UNIPROT MYH9 protein P35579 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000567 11467950 f miannu we have focused on element F of the NMHC-A gene. We have identified and characterized the factors which are capable of binding to element F. The basic helix_loop_helix leucine zipper (bHLH-LZ) proteins, TFEC-l and -s, which are alternatively spliced isoforms, TFE3, USF1, and USF2 have all been found to bind to element F with different binding activities and with different transcriptional activation potencies. SIGNOR-222551 0.2 NFATC2 protein Q13469 UNIPROT IL4 protein P05112 UNIPROT up-regulates transcriptional regulation 9606 23612709 f Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255460 0.519 RBPJ protein Q06330 UNIPROT NFKB2 protein Q00653 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 9528780 f gcesareni Rbp-jkappa is a strong transcriptional repressor of nf-kappab2. Moreover, this repression can be overcome by activated notch-1. SIGNOR-56100 0.269 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr936 SESTNHIySNLANCS 9606 10377264 t miannu Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr SIGNOR-68647 0.2 SRC protein P12931 UNIPROT DAG1 protein Q14118 UNIPROT down-regulates phosphorylation Tyr892 PYRSPPPyVPP 9606 BTO:0000887;BTO:0001103 12795607 t lperfetto Tyrosine 892 is now thought to be the principal site for recognition by the c-src tyrosine kinase;. We show that upon tyrosine phosphorylation, beta-dystroglycan undergoes a profound change in its sub-cellular localization (e.g., from the plasma membrane to an internal membrane compartment). One possibility is that the net negative charge at position 892 causes the redistribution of beta-dystroglycan to this intracellular vesicular location SIGNOR-101655 0.538 embelin chemical CHEBI:4778 ChEBI XIAP protein P98170 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0001271 28704451 t lperfetto Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells. SIGNOR-262013 0.8 GCK protein P35557 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266458 0.8 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT down-regulates quantity by destabilization ubiquitination Lys66 QFETSAAkLKRKYWW 9606 BTO:0000007 23353890 t miannu Here, we show that Godzilla/RNF167 regulates endosome recycling by the ubiquitylation of VAMP3 on Lys66, Lys68 and Lys77; namely, two adjacent Lys residues on the both sides of the critical interface of SNARE complex are ubiquitylated. In agreement with VAMP3 being a target for Goliath family ubiquitin ligases, we show that recycling endosome trafficking is abrogated in response to their activity. While we observed ubiquitylation of VAMP3 by Godzilla, we are unable to describe the nature of this ubiquitination, be it mono-ubiquitin or extended ubiquitin chains. SIGNOR-272093 0.332 A4/b7 integrin complex SIGNOR-C187 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257728 0.553 PRKCB protein P05771 UNIPROT TRPV1 protein Q8NER1 UNIPROT up-regulates activity phosphorylation Thr705 WKLQRAItILDTEKS 9606 BTO:0000007 24920628 t miannu PKCβII causes the downregulation of TRPV1 by phosphorylating the channel. The increased threonine phosphorylation was substantially reduced by mutating Thr705, showing that Thr705 is indeed a major PKCβII phosphorylation site. SIGNOR-276638 0.2 SIRT1 protein Q96EB6 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity deacetylation Lys14 VKEGWLHkRGEYIKT 10090 BTO:0000562 21775285 t gcesareni We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation. SIGNOR-252445 0.613 CDK1 protein P06493 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 11553333 t lperfetto Phosphorylation of 4e-bp1 is critical in causing its dissociation from eif-4e, leaving 4e available to form translationally active eif-4f complexes, switching on mrna translation. We show that the cyclin-dependent kinase, cdc2, phosphorylates 4e-bp1 at thr-70 and that phosphorylation of this site is permissive for ser-65 phosphorylation. Crucially, the increased phosphorylation of 4e-bp1 during mitosis results in its complete dissociation from eif-4e. SIGNOR-110416 0.404 EPC2 protein Q52LR7 UNIPROT NuA4 complex complex SIGNOR-C459 SIGNOR form complex binding 9606 14966270 t miannu NuA4 (for nucleosome acetyltransferase of H4) is a 12-subunit HAT complex responsible for acetylation of histone H4 and H2A N-terminal tails. SIGNOR-269306 0.582 PRSS3 protein P35030 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Arg36 TNRSSKGrSLIGKVD -1 10978167 t lperfetto Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3. SIGNOR-263604 0.379 AMPK complex SIGNOR-C15 SIGNOR KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the α subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559.  SIGNOR-273736 0.294 MAPK1 protein P28482 UNIPROT JAK2 protein O60674 UNIPROT down-regulates phosphorylation Ser523 GVSDVPTsPTLQRPT 9534 BTO:0004055 16705159 t 16705160:the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling. lperfetto We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner SIGNOR-236331 0.5 CACNA1G protein O43497 UNIPROT Action_potential phenotype SIGNOR-PH82 SIGNOR up-regulates 10090 33393208 t miannu Adult hippocampal neurogenesis plays an important role in neuronal plasticity and maintenance in mammals. Low-threshold voltage-gated T-type calcium channels produce calcium spikes that increase fast action potentials in newborn cells in the hippocampal dentate gyrus (DG) SIGNOR-264033 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR POLR2A protein P24928 UNIPROT down-regulates phosphorylation 9606 14662762 t inferred from 70% family members lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-270156 0.2 TWIST2 protein Q8WVJ9 UNIPROT SRPX protein P78539 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255497 0.208 CHIR 99021 chemical CHEBI:91091 ChEBI GSK3B protein P49841 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191000 0.8 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation Tyr1248 PTAENPEyLGLDVPV 9606 BTO:0000007 25081058 t lperfetto PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop. SIGNOR-262597 0.663 N-hydroxy-1-[(4-methoxyphenyl)methyl]-6-indolecarboxamide chemical CHEBI:94192 ChEBI HDAC8 protein Q9BY41 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189684 0.8 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone chemical CHEBI:91372 ChEBI ATM protein Q13315 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-193600 0.8 MTCP1 protein P56278 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-244413 0.466 HNRNPA1 protein P09651 UNIPROT TRA2B protein P62995 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31311954 t lperfetto HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells. SIGNOR-262288 0.689 dopamine smallmolecule CHEBI:18243 ChEBI DRD1 protein P21728 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257477 0.8 PRKD1 protein Q15139 UNIPROT PAK4 protein O96013 UNIPROT up-regulates activity phosphorylation Ser474 KEVPRRKsLVGTPYW 24840177 t lperfetto When PKD3 was knocked-down using isoform-specific shRNA (PKD3-shRNA), PAK4 activity (judged by its phosphorylation status at the activation loop using the pS474-PAK4 antibody) was decreased SIGNOR-275930 0.254 PRKD2 protein Q9BZL6 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates activity phosphorylation Ser978 SPLKRSHsLAKLGSL 21832093 t lperfetto Active PKD Isoforms Phosphorylate and Inactivate SSH1L|Here, we show that active PKD3 also mediates SSH1L phosphorylation at Ser-978 and binding to 14-3-3, further confirming the involvement of all three PKD isoforms in negatively regulating this phosphatase SIGNOR-275937 0.295 BLVRB protein P30043 UNIPROT bilirubin(2-) smallmolecule CHEBI:57977 ChEBI down-regulates quantity chemical modification 9606 BTO:0000759 7929092 t lperfetto This report describes for the first time the identification of four forms of biliverdin reductase including two biliverdin-IX beta reductases and two biliverdin-IX alpha reductases, designated isozymes I and II and isozymes III and IV, respectively, in human liver cytosolic fractions. SIGNOR-275523 0.8 MAP2K1 protein Q02750 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates activity phosphorylation 10090 11730323 t Raf proteins have been shown to phosphorylate and activate MAPKKs (MAP kinase kinases) called MEKs (MAPK or ERK kinases) which in turn phosphorylate and activate MAPKs (MAP kinases) called ERKs SIGNOR-258993 0.743 ERBB2 protein P04626 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 12648465 t Most breast, skin, lung, ovary, and gastrointestinal tract tumors express ErbB-3, and heterodimerization of this receptor with ErbB-2, may be involved in some cancers. gcesareni Although ErbB-2 binds no known ligand, when recruited into heterodimers it increases ligand binding affinity SIGNOR-99569 0.577 mTORC1 complex SIGNOR-C3 SIGNOR MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser60 PHVLEALsPPQTSGL 9606 20516213 t lperfetto The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly. SIGNOR-217149 0.472 RRAGA protein Q7L523 UNIPROT RAGAD complex SIGNOR-C114 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228167 0.771 WT1 protein P19544 UNIPROT SLC29A4 protein Q7RTT9 UNIPROT up-regulates quantity by expression transcriptional regulation 18523561 t lperfetto ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses. SIGNOR-268985 0.276 BIRC5 protein O15392 UNIPROT XIAP protein P98170 UNIPROT up-regulates binding 9606 15218035 t gcesareni Formation of a survivin-xiap complex promotes increased xiap stability against ubiquitination/proteasomal destruction and synergistic apoptosis SIGNOR-126367 0.503 DUSP10 protein Q9Y6W6 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates activity dephosphorylation 9606 26305722 t miannu The inactivation of IRF3 by MKP5 is dependent on MKP5 phosphatase activity or its binding to IRF3.|This is confirmed since MKP5 phosphatasedeficient mutant is unable to dephosphorylate IRF3 and MKP5 mutant lacking IRF3 binding motifs fails to suppress IRF3 nuclear translocation upon virus infection. SIGNOR-277146 0.2 MYC protein P01106 UNIPROT CDKN2A protein P42771 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 20551174 f lperfetto In tissue culture, ectopic expression of Myc suppresses the cell cycle arrest that occurs in response to several anti-mitogenic signals such as transforming growth factor β (TGFβ), since Myc represses expression of the cyclin-dependent kinase inhibitors (CKIs) p15ink4b, p21cip1, and p57kip2 via interaction with Miz1 SIGNOR-267575 0.762 RUNX2 protein Q13950 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni In addition to osteocalcin, cbfa1 regulates expression of several other genes that are activated during osteoblast SIGNOR-107175 0.499 CIB1 protein Q99828 UNIPROT ITGA2B protein P08514 UNIPROT up-regulates activity binding 10029 BTO:0000246 11756406 t Gianni The small GTPase Rac3 interacts with the integrin-binding protein CIB and promotes integrin alpha(IIb)beta(3)-mediated adhesion and spreading SIGNOR-269061 0.48 PKN1 protein Q16512 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS 9534 BTO:0000298 8557118 t lperfetto PRK1 phosphorylates MARCKS at the PKC sites: serine 152, serine 156 and serine 163. SIGNOR-248938 0.369 STK11 protein Q15831 UNIPROT CPS1 protein P31327 UNIPROT down-regulates quantity transcriptional regulation 9606 BTO:0002553 28538732 f Luana LKB1 negatively regulates CPS1 transcription SIGNOR-267919 0.299 PRKACA protein P17612 UNIPROT RARA protein P10276 UNIPROT down-regulates activity phosphorylation Ser219 NSSEQRVsLDIDLWD 9606 20215566 t miannu  Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.  SIGNOR-276281 0.389 CDK5 protein Q00535 UNIPROT SYN1 protein P17600 UNIPROT up-regulates phosphorylation Ser551 PAARPPAsPSPQRQA 9606 10880969 t lperfetto Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin. SIGNOR-78883 0.575 UBE3A protein Q05086 UNIPROT UBE3A protein Q05086 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001968 10864652 t miannu We show here that HPV16 E6 promotes the ubiquitination and degradation of E6AP itself.  SIGNOR-271398 0.2 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT up-regulates activity phosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000182;BTO:0000018 SIGNOR-C2 15718470 t lperfetto The rictor-mtor complex directly phosphorylated akt/pkb on ser473 in vitro and facilitated thr308 phosphorylation by pdk1 SIGNOR-252599 0.929 PI-103 chemical CHEBI:90524 ChEBI PIK3CG protein P48736 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206172 0.8 CSNK2A2 protein P19784 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Ser484 RSRAIHSsDEGEDQA 9606 BTO:0001412 12769847 t llicata We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.  SIGNOR-251049 0.351 ETS2 protein P15036 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11175361 t miannu Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin SIGNOR-259875 0.2 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates activity phosphorylation Ser876 QGLAERIsVL 12058027 t lperfetto Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta.|The position of PKD2 phosphorylated at Ser876 and Ser706/Ser710 is indicated by anarrowhead. SIGNOR-275959 0.2 KCTD11 protein Q693B1 UNIPROT GLI1 protein P08151 UNIPROT down-regulates activity 15249678 f In absence of Hh lperfetto REN(KCTD11) seems to inhibit medulloblastoma growth by negatively regulating the Hedgehog pathway because it antagonizes the Gli-mediated transactivation of Hedgehog target genes, by affecting Gli1 nuclear transfer, and its growth inhibitory activity is impaired by Gli1 inactivation. SIGNOR-249592 0.357 AMFR protein Q9UKV5 UNIPROT GPI protein P06744 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 24810856 t miannu Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. SIGNOR-272177 0.54 paclitaxel chemical CHEBI:45863 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 28298489 t miannu Here we integrate a computational model for microtubule assembly with nanometer-scale fluorescence microscopy measurements to identify the kinetic and thermodynamic basis of kinetic stabilization by the MTAs paclitaxel, an assembly promoter, and vinblastine, a disassembly promoter. We identify two distinct modes of kinetic stabilization in live cells, one that truly suppresses on-off kinetics, characteristic of vinblastine, and the other a "pseudo" kinetic stabilization, characteristic of paclitaxel, that nearly eliminates the energy difference between the GTP- and GDP-tubulin thermodynamic states. By either mechanism, the main effect of both MTAs is to effectively stabilize the microtubule against disassembly in the absence of a robust GTP cap. SIGNOR-259449 0.8 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR STAR protein P49675 UNIPROT up-regulates quantity by expression transcriptional regulation 93934 BTO:0000475 17431006 t lperfetto One such gene was identified, encoding steroidogenic acute regulatory protein (StAR), which showed 24-h changes in expression in the F1 follicle coinciding with those of Per2. Evidence that StAR gene expression is clock driven was obtained by showing that its 5' flanking region contains E-box enhancers that bind to CLOCK/BMAL1 heterodimers to activate gene transcription SIGNOR-253700 0.288 PLK1 protein P53350 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by destabilization phosphorylation 23972993 t For phosphorylated residues see Figure 7 lperfetto Priming phosphorylation of Cdh1 by the Cdk2/cyclin A kinase complex allows Plk1 to bind to Cdh1 and phosphorylate Cdh1 at Ser138 and Ser146. Phosphorylation of Cdh1 at Ser138 and Ser146 then triggers its interaction with, and subsequent ubiquitination by, SCFbeta-TRCP SIGNOR-274053 0.3 AKT proteinfamily SIGNOR-PF24 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser1834 MLRRRMAsMQRTGVV 9606 16926151 t lperfetto We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity SIGNOR-244236 0.2 NBN protein O60934 UNIPROT MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR form complex binding 17713585 t lperfetto The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs). To organize the mrn complex, the mre11 exonuclease directly binds nbs1, dna, and rad50. SIGNOR-251505 0.912 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates activity binding 9606 BTO:0000567 15573378 t ggiuliani The Runx2 WT and deletion constructs (1 √¢‚Ǩ‚Äú495, 1√¢‚Ǩ‚Äú464, and 1√¢‚Ǩ‚Äú432) all physically interact with the BMP2 responsive Smad 1 SIGNOR-255834 0.585 CUL1 protein Q13616 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 SIGNOR-C5 10023660 t lperfetto These results indicate that the cul1/skp1/beta-trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin. SIGNOR-64499 0.587 ZAP70 protein P43403 UNIPROT LAT protein O43561 UNIPROT up-regulates activity phosphorylation Tyr200 SMESIDDyVNVPESG 9606 11368773 t lperfetto In the present study we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. SIGNOR-247026 0.765 TGFB1 protein P01137 UNIPROT PPP2R2A protein P63151 UNIPROT up-regulates activity binding 9606 19114990 t lperfetto The Balpha subunit interacts directly with activated T_RI. The Balpha interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity SIGNOR-217894 0.368 CDK1 protein P06493 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser96 SFSVKDPsPLYDMLR 9606 15735705 t lperfetto Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus SIGNOR-134388 0.413 CERK protein Q8TCT0 UNIPROT ceramide smallmolecule CHEBI:17761 ChEBI down-regulates quantity chemical modification 9606 34202192 t miannu Another relevant enzyme is Ceramide kinase (CerK), which phosphorylates Cer to produce Ceramide 1-phosphate (C1P). SIGNOR-268500 0.8 MLL3 complex complex SIGNOR-C446 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 t miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. SIGNOR-268811 0.2 Angiotensin 1-7 protein P01019-PRO_0000420660 UNIPROT MAS1 protein P04201 UNIPROT up-regulates activity binding 9606 23488800 t miannu Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). SIGNOR-260229 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser5 sPPLRDVD 9606 BTO:0000222 14749395 t lperfetto Myod is phosphorylated on ser5 and ser200 by cyclin b-cdc2, resulting in a decrease of its stability and down-regulation of both myod and p21. SIGNOR-216924 0.323 MED26 protein O95402 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266664 0.662 FBXO5 protein Q9UKT4 UNIPROT ANAPC7 protein Q9UJX3 UNIPROT down-regulates binding 9606 11751633 t gcesareni Emi1 can inhibit apc already activated by cdc20 or cdh1. SIGNOR-113382 0.464 CDK1 protein P06493 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation Thr187 NAGSVEQtPKKPGLR 9606 10931950 t gcesareni Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation. SIGNOR-80230 0.668 RPS6K proteinfamily SIGNOR-PF26 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. SIGNOR-252788 0.2 APOA1 protein P02647 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity 9606 14668333 f miannu ApoA-I Stimulates JAK2 Autophosphorylation. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells SIGNOR-252108 0.301 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9606 BTO:0003316 11777913 t miannu 4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. SIGNOR-250099 0.44 MAP2K3 protein P46734 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates activity phosphorylation Thr180 RHADAEMtGYVVTRW 9606 BTO:0000007 10066767 t done miannu p38-δ is activated by environmental stress, extracellular stimulants, and MAPK kinase-3, -4, -6, and -7. we investigated whether this Thr180-Gly-Tyr182 motif was essential for p38-δ activation. Taken together, these results suggest that the dual phosphorylation TGY motif is required for p38-δ activation. SIGNOR-273950 0.596 KAT2A protein Q92830 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity acetylation Lys10 RTKQTARkSTGGKAP 9606 SIGNOR-C465 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269594 0.2 RPS6KA5 protein O75582 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR down-regulates phosphorylation 9606 15010469 t gcesareni We found that msk1 phosphorylated histone h2a on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by msk1. SIGNOR-265314 0.2 MAX protein P61244 UNIPROT MNT protein Q99583 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240354 0.356 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser40 ASAAGGLsPVTNLTV 9606 BTO:0000017 28192398 t miannu We demonstrate that CyclinD-CDK4/CDK6 complexes mediate the phosphorylation of CDC25A on Ser40 during G1 and that these complexes directly phosphorylate this residue in vitro. Importantly, we also find that CyclinD1-CDK4 decreases CDC25A stability in a ßTrCP-dependent manner and that Ser40 and Ser88 phosphorylations contribute to this regulation.  SIGNOR-277340 0.644 MAPK1 protein P28482 UNIPROT TAGLN2 protein P37802 UNIPROT up-regulates quantity by stabilization phosphorylation Ser145 ARDDGLFsGDPNWFP 9606 BTO:0003491 30041673 t lperfetto ERK2 interacted with 29-31 amino acids of transgelin-2 and subsequently phosphorylated the S145 residue of transgelin-2. S145 phosphorylation of transgelin-2 played important roles in cell proliferation and tumorigenesis of PDAC.| We found that the protein stability of transgelin-2 was regulated by KRAS. ERK-mediated phosphorylation resulted in accumulation of transgelin-2 protein. SIGNOR-265221 0.271 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2R2 protein Q712K3 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271358 0.78 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Met666 VIVITLVmLKKKQYT -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261789 0.497 ADSL protein P30566 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 22812634 t miannu ADSL carries out two non-sequential steps of de novo AMP synthesis, the conversion of succinylaminoimidazolecarboxamide ribonucleotide (SAICAR) and succinyladenosine monophosphate (SAMP) into aminoimidazolecarboxamide ribotide (AICAR) and adenosine monophosphate (AMP), respectively, with the concomitant release of fumarate in each case SIGNOR-266607 0.8 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates binding 9606 BTO:0000801;BTO:0000776 10347215 t milica Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling SIGNOR-67964 0.912 SCF-SKP2 complex SIGNOR-C136 SIGNOR CCNE1 protein P24864 UNIPROT down-regulates quantity by destabilization ubiquitination -1 phosphorylation:Ser399;Thr395 GLLTPPQsGKKQSSG;PLPSGLLtPPQSGKK 11533444 t lperfetto The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro SIGNOR-267558 0.638 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Ser311 EYTIKSHsSLPPNNS 9606 15611134 t lperfetto Zipk autophosphorylates in vitrowe have identified six phosphorylation sites in zipk that regulate both its enzyme activity and localization, including thr180, thr225, thr265, thr299, thr306, and ser311. SIGNOR-132455 0.2 TBXA2R protein P21731 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257023 0.456 L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI glutamic acid smallmolecule CHEBI:18237 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The first two reactions catalyzed by TGART are sequential and produce FGAR, which is then acted upon by the third enzyme in the pathway, formylglycinamidine synthase (PFAS/FGAMS).The transferred ammonia is then used to convert FGAR to FGAM. The FGAMS protein exhibits interesting biophys ical properties and will be covered later in this review. The FGAM produced by FGAMS is then converted into AIR by the AIRS domain of TGART, resulting in a five membered ring closure. SIGNOR-267308 0.8 DIO1 protein P49895 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 1400883 t scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. SIGNOR-266945 0.8 TOP2A protein P11388 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 15942022 f lperfetto Down-regulation of DNA topoisomerase IIalpha leads to prolonged cell cycle transit in G2 and early M phases and increased survival to microtubule-interacting agents SIGNOR-242537 0.7 LYN protein P07948 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000776 25673924 t lperfetto CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades. SIGNOR-242891 0.768 NRXN3 protein Q9Y4C0 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265463 0.2 AMT protein P48728 UNIPROT Glycine cleavage system complex SIGNOR-C437 SIGNOR form complex binding 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268242 0.731 MAPK8 protein P45983 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser358 GQISAGYsPVIDCHT 9606 BTO:0002181 23608534 t miannu Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome.  SIGNOR-276492 0.38 messenger RNA smallmolecule CHEBI:33699 ChEBI 48S_initiation_complex complex SIGNOR-C454 SIGNOR form complex binding 9606 35489072 t lperfetto In eukaryotes, mRNA is recruited to the 43S pre-initiation complex (43S PIC), which consists of the 40S ribosomal subunit, translation initiation factors eIF1, eIF1A, eIF3, eIF5, and a ternary complex (TC) composed of eIF2, GTP and Met-tRNAiMet. 43S PIC binds to the 5′ end of the mRNA and scans along the 5′ untranslated region (5′UTR) in the 3′ direction to find the start codon (AUG) within the context of an optimal Kozak sequence. Start codon recognition stabilizes the 48S initiation complex (48S IC), initiates dissociation of eIF1, eIF1A, eIF2 and eIF5, and promotes recruitment of the 60S ribosomal subunit to form 80S IC ready to enter the elongation cycle of protein synthesis. SIGNOR-269164 0.8 BST1 protein Q10588 UNIPROT nicotinic acid-adenine dinucleotide phosphate smallmolecule CHEBI:76072 ChEBI up-regulates quantity chemical modification 9606 18626062 t miannu The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. SIGNOR-264249 0.8 MYLIP protein Q8WY64 UNIPROT LRP8 protein Q14114 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 20427281 t miannu Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. SIGNOR-271486 0.451 SIRT2 protein Q8IXJ6 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by stabilization 9606 23175188 f miannu Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. SIGNOR-255148 0.473 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation -1 22306293 t inferred from family member PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In¬†vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor SIGNOR-270312 0.2 MST1 protein P26927 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser15 APAPKKGsKKAITKA 9606 21212262 t lperfetto The mst1 is a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn activates its downstream targets, jnk/p38, histone h2b and foxo. Mst1 induces apoptosis by phosphorylating histone h2b on a relatively conserved site, ser-14 in mammalian cells SIGNOR-171005 0.2 KDM5B protein Q9UGL1 UNIPROT NANOG protein Q9H9S0 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000815 31776402 t lperfetto Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. SIGNOR-273451 0.312 RB1 protein P06400 UNIPROT UBTF protein P17480 UNIPROT down-regulates activity binding -1 7877691 t lperfetto Activity of RNA polymerase I transcription factor UBF blocked by Rb gene product SIGNOR-262589 0.38 CDK7 protein P50613 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser403 PEEFISLsPPHEALD 9606 10428966 t lperfetto These results suggest that tfiih-mediated phosphorylation of e2f-1 plays a role in triggering e2f-1 degradation during s phase. here we show that the e2f-1 activation domain interacts with a kinase activity which phosphorylates two sites, ser403 and thr433, within the activation domain. SIGNOR-69776 0.501 C5AR2 protein Q9P296 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263470 0.8 CSTF1 protein Q05048 UNIPROT CSTF complex complex SIGNOR-C441 SIGNOR form complex binding 9606 10669729 t lperfetto We therefore first identified regions of the CstF subunits, CstF-77, CstF-64, and CstF-50, required for interaction with each other.  SIGNOR-268365 0.935 SUN2 protein Q9UH99 UNIPROT RAB5A protein P20339 UNIPROT up-regulates activity binding 9606 BTO:0000567 10818110 t Sara Rab5ip represents a novel rab5 interacting protein that may function on endocytic vesicles as a receptor for rab5-GDP and participate in the activation of rab5 SIGNOR-261309 0.426 CSNK1E protein P49674 UNIPROT DVL3 protein Q92997 UNIPROT down-regulates activity phosphorylation Ser280 DGGIYIGsIMKGGAV -1 24993822 t miannu Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3. SIGNOR-276645 0.659 TAK-901 chemical CID:16124208 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207191 0.8 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 17591690 t llicata We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active SIGNOR-156422 0.726 ANKRD11 protein Q6UB99 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 10090 BTO:0000142 29274743 f miannu We found that Ankrd11 knockdown disrupted dendrite and spine formation in developing pyramidal neurons. SIGNOR-266730 0.7 AKT3 protein Q9Y243 UNIPROT CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 19609947 t gcesareni Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-187062 0.399 BAG5 protein Q9UL15 UNIPROT HSPA1B protein P0DMV9 UNIPROT down-regulates activity binding 9606 BTO:0000142 15603737 t Monia Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction. SIGNOR-261197 0.674 BMPR2 protein Q13873 UNIPROT ACVR1/BMPR2 complex SIGNOR-C30 SIGNOR form complex binding 9606 7791754 t lperfetto Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor. SIGNOR-33437 0.706 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates activity phosphorylation Thr186 KREKRRStSRQFVDG 9606 BTO:0000567 14744859 t llicata It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1 SIGNOR-250590 0.775 SMARCA2 protein P51531 UNIPROT SWI/SNF ACTL6A-ARID1A-SMARCA2 variant complex SIGNOR-C470 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269817 0.831 TRIM22 protein Q8IYM9 UNIPROT TRIM22 protein Q8IYM9 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18656448 t miannu  Importantly, TRIM22 was conjugated with poly-ubiquitin chains and stabilized by the proteasome inhibitor in 293T cells, suggesting that TRIM22 targeted itself for proteasomal degradation through the poly-ubiquitylation. We also found that TRIM22 was located in the nucleus, indicating that TRIM22 might function as a nuclear E3 ubiquitin ligase. SIGNOR-271780 0.2 RPS6KB1 protein P23443 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017876 t llicata Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation. SIGNOR-176858 0.659 NAE complex SIGNOR-C131 SIGNOR CUL2 protein Q13617 UNIPROT up-regulates activity neddylation 9606 25504797 t lperfetto The family of cullin proteins is the most established target for NEDD8. In humans, it is composed of seven cullins (Cul1, 2, 3, 4A, 4B, 5 and 7), whereas PARC (CUL9) and APC2 (component of the anaphase promoting complex APC) contain a cullin-homology domain. All cullins are modified with NEDD8The role of cullin NEDDylation is to enhance the activity of the CRLs and subsequent ubiquitination and degradation of the regulated substrates. SIGNOR-243154 0.533 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates activity phosphorylation Ser393 RGELIPIsPSTEVGG BTO:0000007 10593981 t llicata Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity. SIGNOR-250734 0.714 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000050;BTO:0000056 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268658 0.8 SOS1 protein Q07889 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000938 11560935 t lperfetto Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras SIGNOR-110566 0.775 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Ser555 RALSNSVsNMGLSES 9606 BTO:0000007 17711846 t gcesareni Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization. SIGNOR-252882 0.403 CDK1 protein P06493 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates phosphorylation Ser439 AGSPFQSsPLSLGSR 9606 SIGNOR-C17 16880739 t llicata Cdk1/cyclin b-mediated phosphorylation stabilizes srebp1 during mitosis. SIGNOR-148354 0.29 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR CCNA1 protein P78396 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11090075 f Overexpression of cyclin A1 observed in APL cells is caused by the expression of the aberrant fusion proteins, PML-RARα and PLZF-RARα. PML-RARα itself can lead to activation of the cyclin A1 promoter.Since both fusion proteins disrupt the normal RARα function, our results strongly suggested that the RARα pathway negatively regulates the expression of cyclin A1 and that this negative regulation is disrupted by the aberrant fusion proteins. SIGNOR-255725 0.2 STK4 protein Q13043 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates activity phosphorylation Thr90 CHLAWVNtPKKQGGL -1 23386615 t miannu Mst1 inactivates Prdx1 by phosphorylating it at Thr-90 and Thr-183, leading to accumulation of hydrogen peroxide in cells.Prdx1 is phosphorylated by Mst1 predominantly at Thr-18, Thr-90, and Thr-183. SIGNOR-276487 0.2 D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI D-glyceraldehyde 3-phosphate(2-) smallmolecule CHEBI:59776 ChEBI up-regulates quantity precursor of 9606 24929114 t miannu Transketolase (TK, EC 2.2.1.1) is the key rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway of carbohydrate transformation. TKs (with the exception of the enzymes of mammalian origin) are characterized by broad substrate specificity. Xylulose 5-phosphate (X5P), fructose 6-phosphate (F6P), erythrulose 4-phosphate, and sedoheptulose 7-phosphate are typical donor substrates of TK; ribose 5-phosphate (R5P), glyceraldehyde 3-phosphate (G3P), and erythrose 4-phosphate are typical acceptor substrates. SIGNOR-268142 0.8 N-[6,6-dimethyl-5-[(1-methyl-4-piperidinyl)-oxomethyl]-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide chemical CHEBI:91371 ChEBI CDK1 protein P06493 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206124 0.8 RFC4 protein P35249 UNIPROT RF-C complex complex SIGNOR-C375 SIGNOR form complex binding 12930972 t lperfetto RF‐C, a complex of five subunits, is conserved in all eukaryotes (reviewed in 5). In yeast, all subunits of RF‐C are essential for viability. The genes encoding all five subunits of mammalian RF‐C (145, 40, 38, 37 and 36 kDa) have been cloned SIGNOR-265508 0.803 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR YAP1 protein P46937 UNIPROT down-regulates binding 9606 21084559 t gcesareni Phosphorylation of yap ser127 and of the corresponding sites in yki and taz generates a protein-binding motif for the 14-3-3 family proteins, which, upon binding by a 14-3-3 protein, leads to their cytoplasmic retention. One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73. SIGNOR-169719 0.2 NARS1 protein O43776 UNIPROT tRNA(Asn) smallmolecule CHEBI:29172 ChEBI down-regulates quantity chemical modification 9606 32788587 t miannu Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Asparaginyl-tRNA synthetase1 (NARS1) belongs to the class IIa family, based upon a 7 beta-strand protein structure. There are two NARS genes: NARS1 functions in the cytoplasm while NARS2 functions in mitochondria, solely responsible for asparagine tRNA charging in these locations. SIGNOR-270453 0.8 dexamethasone chemical CHEBI:41879 ChEBI CEBPA protein P49715 UNIPROT up-regulates 9606 11279134 f fspada The differentiation of 3t3-l1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the ccaat/enhancer-binding proteins (c/ebps) and peroxisome proliferator-activated receptor gamma (ppargamma) by dexamethasone (dex), 3-isobutyl-1-methylxanthine (mix), and insulin SIGNOR-250568 0.8 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT up-regulates phosphorylation Ser623 KGEKRASsPFRRVRE 9606 12167624 t gcesareni Here we demonstrate that protein kinase a (pka)-dependent phosphorylation of nopp140 at ser 627, together with c/ebpbeta, induces agp gene expression synergistically. SIGNOR-91186 0.309 SMAD2 protein Q15796 UNIPROT MEF2A protein Q02078 UNIPROT up-regulates binding 10090 BTO:0000165 BTO:0001760 SIGNOR-C8 11160896 t lperfetto Our studies indicate that smad2 and 4 (smad2/4) complexes cooperate with mef2 regulatory proteins in a gal4-based one-hybrid reporter gene assay. SIGNOR-235846 0.395 BMP7 protein P18075 UNIPROT BMP7 protein P18075 UNIPROT up-regulates binding 9606 BTO:0000887 11178121 t lperfetto Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is an absolute requirement for the biological action and interac- tion with receptors SIGNOR-236172 0.2 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 16613856 t lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation SIGNOR-227547 0.534 SMAD6 protein O43541 UNIPROT TBX6 protein O95947 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0000007 19561075 t miannu Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. SIGNOR-272785 0.33 OXGR1 protein Q96P68 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257310 0.2 NALCN protein Q8IZF0 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI up-regulates quantity relocalization 9606 BTO:0000938 32698188 t miannu Persistently depolarizing sodium (Na+) leak currents enhance electrical excitability. The ion channel responsible for the major background Na+ conductance in neurons is the Na+ leak channel, non-selective (NALCN) SIGNOR-265181 0.8 ASAP2 protein O43150 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity gtpase-activating protein -1 10022920 t miannu Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain.  In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6.  Pap protein exhibits Arf GAP activity in vitro. SIGNOR-269706 0.66 KPNA3 protein O00505 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20454918 t gcesareni Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. SIGNOR-165280 0.327 DHCR7 protein Q9UBM7 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI up-regulates quantity chemical modification 9606 9634533 t miannu In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol D7 -reductase. This NADPH-dependent enzyme catalyzes the reduction of the D7 -diene bond in 7-DHC, to form cholesterol. SIGNOR-267252 0.8 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259015 0.406 Nitrendipine chemical CID:4507 PUBCHEM NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition -1 18250364 t Luana Here we report a surprising finding, that the dihydropyridine CCBs have MR antagonist activity. A number of dihydropyridine CCBs compete for aldosterone binding to the MR ligand binding domain (LBD), block aldosterone-induced recruitment of coactivators, and inhibit aldosterone-induced gene expression.  SIGNOR-257767 0.8 VAC14 protein Q08AM6 UNIPROT PAS complex complex SIGNOR-C190 SIGNOR form complex binding 9606 BTO:0000007 17556371 t miannu Here we have identified and characterized Sac3, a Sac domain phosphatase, as the Fig4 mammalian counterpart. Endogenous Sac3, a widespread 97-kDa protein, formed a stable ternary complex with ArPIKfyve and PIKfyve. Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. SIGNOR-253530 0.923 GPR119 protein Q8TDV5 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256768 0.4 CSNK2A1 protein P68400 UNIPROT PSMA3 protein P25788 UNIPROT unknown phosphorylation Ser250 SLKEEDEsDDDNM -1 8619999 t llicata Several C8 protein constructs allow the location of the CKII phosphorylation sites to be the COOH terminal portion of the protein, and direct mutational analyses show that Ser-243 and Ser-250 are the residues of the C8 subunit phosphorylated by CKII. The in vitro phosphorylation of the proteasome by CKII does not affect its proteolytic activity (on proteins or fluorogenic synthetic peptides), therefore suggesting its involvement in the interaction of the proteasome with other cellular proteins, i.e. in the formation of the 26S complex and/or in the interaction with the nuclear translocation machinery. SIGNOR-250939 0.386 EP300 protein Q09472 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates quantity by stabilization acetylation Lys378 TIRMSFVkGWGAEYR 9606 16862174 t miannu Smad proteins are crucial for the intracellular signaling of transforming growth factor-beta (TGF-beta). Upon their receptor-induced activation, Smad proteins are phosphorylated and translocated to the nucleus to activate the transcription of a select set of target genes. Here, we show that the co-activator p300/CBP bound and acetylated Smad3 as well as Smad2 in vivo, and that the acetylation was stimulated by TGF-beta.A major acetylation site of Smad3 by p300/CBP is Lys-378 in the MH2 domain (Smad3C) known to be critical for the regulation of transcriptional activity. SIGNOR-260431 0.731 PLK1 protein P53350 UNIPROT VIM protein P08670 UNIPROT up-regulates phosphorylation Ser83 GVRLLQDsVDFSLAD 9606 BTO:0000150 18056432 t gcesareni We observed that plk1 phosphorylates vimentin on ser82, which in turn regulates cell surface levels of 1 integrin. SIGNOR-159386 0.2 IFI30 protein P13284 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 t scontino Within the phagosome, the internalized antigens are partially degraded by Cathepsin S and the GILT complex, a necessary step for further export to cytosol. SIGNOR-267865 0.8 IRF2BPL protein Q9H1B7 UNIPROT PENK protein P01210 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000938 17627301 t miannu EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity.These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function. SIGNOR-267155 0.311 CID 122201421 chemical CID:122201421 PUBCHEM BRD4 protein O60885 UNIPROT down-regulates activity chemical inhibition 9606 26035625 t Monia Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4; These data confirmed that BRD4 is removed from the cell nuclei in a time dependent manner due to the presence of MZ1 SIGNOR-261097 0.8 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263786 0.8 C2 protein P06681 UNIPROT C3 convertase complex complex SIGNOR-C310 SIGNOR form complex binding -1 cleavage:Arg243 KTKESLGrKIQIQRS 17204478 t complement C2a fragment: PRO_0000027612 lperfetto However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex SIGNOR-263399 0.633 HDAC7 protein Q8WUI4 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT down-regulates deacetylation 9606 16207715 t miannu Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7. SIGNOR-140953 0.259 PF-03814735 chemical CID:49830590 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205956 0.8 MAML2 protein Q8IZL2 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 12370315 f gcesareni We recently cloned a mammalian homologue of the mastermind gene of drosophila melanogaster, maml1 (mastermind-like-1 molecule) and determined that it functions as a transcriptional coactivator for notch receptors. SIGNOR-254307 0.859 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT down-regulates activity cleavage Val55 VTGKGVTvETVFSVD -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263599 0.378 TTL protein Q8NG68 UNIPROT TUBA3E protein Q6PEY2 UNIPROT down-regulates tyrosination 9606 22020298 t miannu Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization SIGNOR-176924 0.445 RAB9A protein P51151 UNIPROT GCC2 protein Q8IWJ2 UNIPROT up-regulates activity 18195106 t lperfetto Rab9-dependent transport from late endosomes to the Golgi requires the Rab9 effectors p40 (Diaz et al., 1997) and TIP47 (Diaz and Pfeffer, 1998), a protein that recognizes the cytoplasmic domains of the two types of MPRs and packages them into nascent transport vesicles (Carroll et al., 2001). MPR recycling also utilizes a TGN-localized coiled-coil protein named GCC185 that is also a Rab9 effector SIGNOR-253087 0.529 SS18L1 protein O75177 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates relocalization 9606 BTO:0000938 15488321 t miannu The calcium-responsive transactivator recruits creb binding protein to nuclear bodies. SIGNOR-129926 0.403 AKT1 protein P31749 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates activity phosphorylation Ser83 ATRGRGSsVGGGSRR 9606 BTO:0000007 11154276 t lperfetto Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1. SIGNOR-252465 0.721 HIC1 protein Q14526 UNIPROT MYC protein P01106 UNIPROT down-regulates activity transcriptional regulation 9606 BTO:0000815 24067369 f miannu HIC1 suppressing the VEGF and c-Myc promoter activity and the colony formation of MDA-MB 231 cells were STAT3-dependent. SIGNOR-254245 0.328 LAMC1 protein P11047 UNIPROT Laminin-1 complex SIGNOR-C183 SIGNOR form complex binding 7496033 t lperfetto Laminin-1 is an extracellular matrix protein composed of three polypeptide chains that are designated alpha 1, beta 1, and gamma 1. SIGNOR-253234 0.608 RNF111 protein Q6ZNA4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity ubiquitination 10090 BTO:0000165;BTO:0000222 17341133 t lperfetto Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling. SIGNOR-235394 0.677 valrubicin chemical CHEBI:135876 ChEBI TOP2A protein P11388 UNIPROT down-regulates activity chemical inhibition 9606 16019763 t miannu Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a semi-synthetic derivative of the anthracycline doxorubicin. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causing extensive chromosomal damage and cell-cycle arrest in the G2 phase. Its principal metabolites inhibit topoisomerase II, thus arresting DNA synthesis. SIGNOR-259383 0.8 LAMA4 protein Q16363 UNIPROT Laminin-8 complex SIGNOR-C181 SIGNOR form complex binding 10809728 t lperfetto Laminins are a large family of heterotrimeric extracellular matrix glycoproteins that, in addition to having structural roles, take part in the regulation of processes such as cell migration, differentiation, and proliferation. The laminin alpha(4) chain is widely distributed both in adults and during development in tissues such as cardiac, skeletal and smooth muscle fibers, vascular endothelia, lungs, and in peripheral nerves. It can associate with laminin beta(1)/gamma(1) chains to form laminin-8 and with the beta(2)/gamma(1) chains to form laminin-9. SIGNOR-253226 0.512 LGALS3 protein P17931 UNIPROT BAD protein Q92934 UNIPROT up-regulates quantity by stabilization 9606 BTO:0000664 21821001 f miannu Our study also showed that a number of K562 cells survived despite the apoptotic stimuli. Within these surviving cells, galectin-3 was upregulated through newly synthesized protein. Notably, inducible galectin-3, which stabilized the pro-survival Bcl-2 family proteins Mcl-1, Bcl-xL, and Bcl-2, was essential for anti-apoptosis. Unpredictably, GSK-3β was critical for inducible galectin-3 expression as well as for cell survival. As summarized in Fig. 4C, we not only found inducible galectin-3 has an anti-apoptotic effect, but we also identified a GSK-3β-regulated mechanism for apoptotic resistance in K562 cells. SIGNOR-261907 0.2 LRP6 protein O75581 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity binding 9606 19107203 t PPPSPxS motif in LRP6/5 must be phosphorylated. lperfetto These observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence binding of wnts to the coreceptors frizzled and lrp6/5 leads to phosphorylation of pppspxs motifs in the lrp6/5 intracellular region and the inhibition of gsk3beta bound to the scaffold protein axin.These Observations demonstrate that phosphorylated lrp6/5 both recruits and directly inhibits gsk3beta using two distinct portions of its cytoplasmic sequence. SIGNOR-227942 0.727 PTK2 protein Q05397 UNIPROT TLN1 protein Q9Y490 UNIPROT up-regulates activity binding 9606 15688067 t miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257731 0.681 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Thr451 PIPKALGtPVLTPPT 9606 BTO:0000848 BTO:0001253 20959475 t lperfetto Braf(v600e) signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-jun nh(2) terminal kinase-mediated activation of foxo4 via its phosphorylation on thr(223), ser(226), thr(447), and thr(451). SIGNOR-252955 0.708 FOXO1 protein Q12778 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 18391974 f Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. SIGNOR-253010 0.7 PDX1 protein P52945 UNIPROT GCK protein P35557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8866550 f miannu The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. SIGNOR-254911 0.597 CAMK1 protein Q14012 UNIPROT GCM1 protein Q9NP62 UNIPROT up-regulates activity phosphorylation Ser47 YAKHIYSsEDKNAQR 9606 BTO:0000007 21791615 t miannu We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation. SIGNOR-262680 0.393 DOK7 protein Q18PE1 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 23467009 t gcesareni In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation. SIGNOR-192264 0.737 MAPK14 protein Q16539 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates activity phosphorylation Ser867 SPVSVGSsPPVKNIS 9606 BTO:0000093 15383283 t miannu P38 MAPK and JNK can phosphorylate multiple sites on SRC-3, including S505, S543, S860, and S867. Our results suggest that several kinases are important for phosphorylating SRC-3 and enhancing its interaction with DNA-dependent transcription factors and other coactivators. SIGNOR-250106 0.513 MK-2206 chemical CHEBI:67271 ChEBI AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 BTO:0001286 21841310 t gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. SIGNOR-252461 0.8 DOK1 protein Q99704 UNIPROT ITGB2 protein P05107 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257680 0.299 MAP3K11 protein Q16584 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0001538 9003778 t lperfetto Immunoprecipitated mlk-3 catalyzed the phosphorylation of sek1 in vitro, and co-transfected mlk-3 induced phosphorylation of sek1 and mkk3 at sites required for activation, suggesting direct regulation of these protein kinases. SIGNOR-45788 0.479 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257866 0.8 NLGN4X protein Q8N0W4 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264145 0.766 PIN1 protein Q13526 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 19151708 t gcesareni Prolyl-isomerase pin1 interacts with notch1 and affects notch1 activation. Pin1 potentiates notch1 cleavage by gamma-secretase, leading to an increased release of the active intracellular domain and ultimately enhancing notch1. pin1 potentiates notch1 cleavage by gamma-secretase SIGNOR-183461 0.389 FGF14 protein Q92915 UNIPROT SCN9A protein Q15858 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253425 0.2 HCRTR1 protein O43613 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257404 0.251 DUSP3 protein P51452 UNIPROT NPM1 protein P06748 UNIPROT down-regulates activity dephosphorylation 9606 33777934 t lperfetto In the absence of DUSP3, these three residues remain phosphorylated and favor the dissociation equilibrium of NPM homo-oligomerization and/or its association with ARF, therefore promoting an early nuc|Therefore, here we focused on the molecular mechanisms used by DUSP3-NPM interaction to affect the abovementioned cellular responses and found out that DUSP3 dephosphorylates three tyrosine residues (Y29, Y67, and Y271) of NPM. SIGNOR-277005 0.2 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates activity phosphorylation Ser792 DKMRRASsYSSLNSL 10090 BTO:0002572 SIGNOR-C15 SIGNOR-C3 18439900 t lperfetto The phosphorylation of raptor by ampk is required for the inhibition of mtorc1 and cell-cycle arrest induced by energy stress. SIGNOR-161375 0.679 AKT proteinfamily SIGNOR-PF24 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates -1 14663477 f Luana Multiple studies supporting the role of Akt in apoptosis suppression have connected Akt to cell death regulation either by demonstrating its downregulation following pro-apoptotic insults, or by using gene-transfer experiments that transduce both activated, anti-apoptotic and inactive, pro-apoptotic mutants of Akt. SIGNOR-260215 0.7 MAP3K7 protein O43318 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity phosphorylation Thr184 GTACDIQtHMTNNKG -1 20538596 t lperfetto Analyses of phosphorylation site mutants of the activation segment indicate that autophosphorylation of Ser-192 precedes TAB1 phosphorylation and is followed by sequential phosphorylation of Thr-178, Thr-187, and finally Thr-184. Finally, we present a model for the chronological order of events governing TAB1-induced TAK1 autoactivation. SIGNOR-227544 0.2 SAR1A protein Q9NR31 UNIPROT SEC24C protein P53992 UNIPROT up-regulates quantity binding SIGNOR-C370 30605680 t lperfetto Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer. SIGNOR-265302 0.703 SOS2 protein Q07890 UNIPROT KRAS protein P01116 UNIPROT up-regulates guanine nucleotide exchange factor 9606 21779497 t gcesareni Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. SIGNOR-175265 0.707 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 16403219 t lperfetto All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death. SIGNOR-259421 0.2 CDK8 protein P49336 UNIPROT H3-3A protein P84243 UNIPROT down-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 18418385 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). lperfetto However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. SIGNOR-273173 0.2 INO80 complex complex SIGNOR-C498 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 25016522 f miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270858 0.7 MAP2K6 protein P52564 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates phosphorylation 9606 9430721 t gcesareni The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms. SIGNOR-54947 0.694 CEBPB protein P17676 UNIPROT CREB1 protein P16220-1 UNIPROT up-regulates activity binding 9534 BTO:0000298 12773552 t miannu We conclude that C/EBP-β can directly bind to the N-terminal Q1 domain of CREB in addition to binding to the leucine zipper domain. The transactivation potential of full-length CREB fused to the DNA-binding domain of Gal4 was increased synergistically by calcium and cGMP, and overexpression of C/EBP-β enhanced the effect, while a dominant negative C/EBP inhibited it SIGNOR-263654 0.572 EFR3A protein Q14156 UNIPROT PI4KA protein P42356 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 t miannu PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B SIGNOR-269092 0.478 PABPN1 protein Q86U42 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity by stabilization binding 9606 25480299 t lperfetto As poly(A)+ mRNAs are associated with poly(A) binding protein (PABP) in cells|his result suggests that PABPC1 binds preferentially to long poly(A) tails and protects them from TUT4/7 and thereby enhances the selectivity of uridylation according to poly(A) tail length. SIGNOR-268320 0.8 MAPKAPK2 protein P49137 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2 SIGNOR-166625 0.602 COL1A1 protein P02452 UNIPROT DDR2 protein Q16832 UNIPROT up-regulates activity binding 9606 BTO:0001282 17318226 t lperfetto The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.  SIGNOR-272342 0.43 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 29901072 t miannu AT7519, a pyrazole 3-carboxyamide compound, was developed by Astex and acts as an inhibitor of CDK1, CDK2, CDK4, CDK6 and CDK9. SIGNOR-262218 0.8 HSP90AB1 protein P08238 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 10944114 t gcesareni The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex. SIGNOR-81043 0.395 pipamperone chemical CHEBI:78549 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition -1 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258571 0.8 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000567 BTO:0000887;BTO:0001103 8454633 t gcesareni Autophosphorylated on tyrosine residues in response to insulin. Dephosphorylated by ptpreand ptpn1 at tyr-999, tyr-1185, tyr-1189 and tyr-1190. SIGNOR-39151 0.382 PPP2CA protein P67775 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates dephosphorylation 9606 20704570 t gcesareni Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a. SIGNOR-167480 0.2 VHL protein P40337 UNIPROT KLF10 protein Q13118 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003781 18359287 f lperfetto In this study, we show that both TGFBI and KLF10 are down-regulated by VHL in 786-0 cells, and that KLF10 may serve as a transactivator of the TGFBI promoter. SIGNOR-253213 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR TSC complex SIGNOR-C101 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 15342917 t lperfetto The mitogen-activated protein kinase (mapk)-activated kinase, p90 ribosomal s6 kinase (rsk) 1, was found to interact with and phosphorylate tuberin at a regulatory site, ser-1798, located at the evolutionarily conserved c terminus of tuberin. Rsk1 phosphorylation of ser-1798 inhibits the tumor suppressor function of the tuberin/hamartin complex, resulting in increased mtor signaling to s6k1 SIGNOR-256311 0.718 ECM stimulus SIGNOR-ST20 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259037 0.7 MRPS12 protein O15235 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261457 0.677 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263782 0.7 PKP2 protein Q99959 UNIPROT DSP protein P15924 UNIPROT up-regulates quantity by stabilization binding 10090 BTO:0003264 22781308 t Simone In contrast to the proper membrane localization of PKP2 and DSP after cotransfection of both WT proteins, mutant PKP2 C796R protein was not able to interact with FLAG-DSP to enable assembly at the junctional plaque, indicating the requirement of functional PKP2 for DSP integration into the desmosome. SIGNOR-261254 0.782 baicalein chemical CHEBI:2979 ChEBI CYP2C9 protein P11712 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190236 0.8 TSPOAP1 protein O95153 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264368 0.2 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000551 15329413 t gcesareni Egfr is a tk of the erbb family that is the presumptive target of the tk inhibitor (tki) gefitinib. SIGNOR-126976 0.8 GLUL protein P15104 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI up-regulates quantity chemical modification 9606 30158707 t miannu Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. certain cell types express glutamine synthetase (GS; also called glutamate-ammonia ligase; GLUL), the enzyme capable of de novo glutamine production from glutamate and ammonia in an ATP and Mg2+/Mn2+ requiring reaction. SIGNOR-267826 0.8 Dinaciclib chemical CID:46926350 PUBCHEM CDK5 protein Q00535 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191328 0.8 IL1R1 protein P14778 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000801 9625767 t lperfetto Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab SIGNOR-249514 0.284 CDKL5 protein O76039 UNIPROT LRRC4C protein Q9HCJ2 UNIPROT unknown phosphorylation Ser631 PLLIRMNsKDNVQET 9606 22922712 t llicata Cdkl5 binds and phosphorylates the cell adhesion molecule ngl-1. This phosphorylation event ensures a stable association between ngl-1 and psd95. SIGNOR-192035 0.436 CDK5 protein Q00535 UNIPROT HTR1A protein P08908 UNIPROT down-regulates quantity by destabilization phosphorylation Thr314 LPSEAGPtPCAPASF 9534 BTO:0004055 30712943 t lperfetto Cyclin-dependent kinase 5 promotes proteasomal degradation of the 5-HT 1A receptor via phosphorylation|5-HT1AR was phosphorylated by the Cdk5-p35 complex at Thr314 in the third cytoplasmic loop. SIGNOR-264406 0.272 KSR1 protein Q8IVT5 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Thr269 NVHMVSTtLPVDSRM 9606 11134016 t lperfetto Here we show that phosphorylation of c-raf-1 on thr(269) by ksr is necessary for optimal activation in response to egf stimulation. SIGNOR-85386 0.644 MAP4K1 protein Q92918 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates phosphorylation Thr165 ISAQIGAtLARRLSF 9606 BTO:0000782 15743830 t gcesareni Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase d1. SIGNOR-134490 0.2 CDKL5 protein O76039 UNIPROT MECP2 protein P51608 UNIPROT unknown phosphorylation -1 16935860 t Luana Phosphorylation assays performed with the wild-type protein confirm its capability to mediate the modification of MeCP2 in vitro, whereas Rett missense mutations within the conserved catalytic domain abrogate or significantly impair the enzymatic activity SIGNOR-264702 0.614 MAPK9 protein P45984 UNIPROT JUNB protein P17275 UNIPROT down-regulates binding 9606 9405416 t gcesareni Jnk targets junb ubiquitination SIGNOR-53827 0.672 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT up-regulates activity phosphorylation 9606 SIGNOR-C14 19632174 t lperfetto Tak1 become activated and then phosphorylates and activates ikk2 which in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation. tak1 kinase complex phosphorylates and activates ikk in a manner that depends on traf6 and ubc13-uev1a our studies suggests that tak1_ acts as an upstream activating kinase for ikkbeta. SIGNOR-187242 0.749 ARHGAP31 protein Q2M1Z3 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260489 0.554 APC-c complex SIGNOR-C150 SIGNOR PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. SIGNOR-272750 0.429 KIF2B protein Q8N4N8 UNIPROT Minus-end directed microtubule movement phenotype SIGNOR-PH217 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272534 0.7 CCNA2 protein P20248 UNIPROT CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR form complex binding 9606 19056339 t lperfetto We therefore compared human cyclin a1- and cyclin a2-containing cdk complexes in vitro by determining kinetic constants and by examining the complexes for their ability to phosphorylate prb and p53. Differences in biochemical activity were observed in cdk2 but not cdk1 when complexed with cyclin a1 versus cyclin a2. Further, cdk1/cyclin a1 is a better kinase complex for phosphorylating potentially physiologically relevant substrates prb and p53 than cdk2/cyclin a2. SIGNOR-182566 0.977 MARCHF5 protein Q9NX47 UNIPROT MFN1 protein Q8IWA4 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000567 20103533 t Barakat MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate. SIGNOR-274133 0.2 TFEB protein P19484 UNIPROT NDUFAF2 protein Q8N183 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Genes responsive to high, sustained levels of nuclear TFEB induced by Torin treatment included CTSF, NPC2, BLOC1S3, and BLOC1S2, which function in lysosomal degradation, transport, and biogenesis; NDUFS4, NDUFA13, NDUFA8, NDUFA1, NDUFB10, and NDUFAF2, subunits of mitochondrial NADH dehydrogenase; PPARG and PPARGC1A, a nuclear receptor and co-factor regulating lipid metabolism; and BHLHE40 and BHLHE41, two transcriptional repressors (Figures 4B and 4D; Table S4). SIGNOR-276703 0.2 TLR4 protein O00206 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates activity binding 10090 22664090 t gcesareni To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-252067 0.846 HMGB1 protein P09429 UNIPROT HOXD3 protein P31249 UNIPROT up-regulates activity binding -1 8890171 t miannu We show that HMG1 interacts with proteins encoded by the HOX gene family by establishing protein-protein contacts between the HMG box domains and the HOX homeodomain. The functional role of these interactions was studied using the transcriptional activity of the human HOXD9 protein as a model. HMG1 enhances, in a dose-dependent fashion, the sequence-specific DNA binding activity in vitro, and the transcriptional activation in a co-transfection assay in vivo, of the HOXD9 protein. SIGNOR-219980 0.3 FGR protein P09769 UNIPROT SRC protein P12931 UNIPROT unknown phosphorylation Tyr530 FTSTEPQyQPGENL -1 9208935 t An eicosapeptide encompassing the C-terminal tail of c-Src (Tyr527) which is conserved in most Src-related protein kinases, is phosphorylated by C-terminal Src kinase (CSK) and by the two Src-related protein kinases c-Fgr and Lyn, with similar kinetic constants.  SIGNOR-251145 0.637 SGK1 protein O00141 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 18570873 t gcesareni Activated sgk1 and p27 phosphorylation at t157, and both were inhibited by short-term rapamycin treatment and by sgk1 shrna.|Akt acts downstream of PI3K to phosphorylate p27 at T157 and T198, leading to impaired nuclear p27 import, p27 accumulation in the cytoplasm, and loss of cyclin E-Cdk2 inhibition SIGNOR-179121 0.477 MBD4 protein O95243 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275714 0.7 17beta-hydroxy-5alpha-androstan-3-one smallmolecule CHEBI:16330 ChEBI COMT protein P21964 UNIPROT up-regulates 9606 17612537 f Regulation of expression miannu Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA. SIGNOR-251962 0.8 COL4A4 protein P53420 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR up-regulates activity binding 35267698 t lperfetto Integrins constitute a major group of receptors for extracellular matrix components, including collagens.|Among the four types, the signaling mechanism of α1β1 and α2β1 integrins has especially been reported. These integrins bind to both collagen types I and IV; however, their affinities differ: α1β1 has a higher affinity for collagen type IV, while α2β1 preferentially binds to collagen type I [13,23]. SIGNOR-272350 0.444 IGF1 protein P05019 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR up-regulates 10090 10448861 f lperfetto Treatment with igf-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor nf-atc1. SIGNOR-252306 0.268 CCNO protein P22674 UNIPROT CDK1 protein P06493 UNIPROT up-regulates activity binding 37197505 t lperfetto CDK2 is the predominant activating complex form of CCNO, but CCNO can bind to CDK1 to form an activating complex in the absence of CDK2. SIGNOR-275617 0.338 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000938 10558990 t lperfetto The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival. SIGNOR-252782 0.2 PPP2CA protein P67775 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni In particular, p38 mapk activity stimulates the physical association between ppa2 and mkk1/2- erk1/2 complex, leading to mkk1/2 dephosphorilation by pp2a. SIGNOR-166649 0.548 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo. SIGNOR-156856 0.663 SLC24A1 protein O60721 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI down-regulates quantity relocalization 9606 30173760 t miannu K+-dependent Na+-Ca2+ Exchangers (NCKX) are bi-directional plasma membrane Ca2+ transporters which belong to the Solute Carrier Family 24 A (SLC24 A) of membrane transporters. NCKXs operate via the alternating access model and mediate the extrusion of one Ca2+ ion coupled with one K+ ion in exchange for four Na+ ions (4Na+↔ 1Ca2+ + 1 K+) SIGNOR-264390 0.8 ATM protein Q13315 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates activity phosphorylation Ser272 LSDTDSHsQDLGSPE 9606 BTO:0000763 11278446 t lperfetto Hyperphosphorylation of hrad9 induced by ir is dependent on atm. Ser(272) of hrad9 is phosphorylated directly by atm in vitro. / our results suggest that the atm-mediated phosphorylation of hrad9 is required for ir-induced checkpoint activation. SIGNOR-105243 0.763 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser307 TRRSRTEsITATSPA 10116 BTO:0000452 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106570 0.762 SAGA complex complex SIGNOR-C465 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269637 0.2 MAPK14 protein Q16539 UNIPROT JDP2 protein Q8WYK2 UNIPROT unknown phosphorylation Thr148 VRTDSVKtPESEGNP -1 12225289 t miannu Wild-type JDP2 exhibited efficient phosphorylation by the p38 kinase, the mutant JDP2 T%)A did not incorporate labelled Figure 5 JDP2 C-terminal domain is necessary but not sufficient for p38 phosphorylation (A) p38 phosphorylated JDP2 at Thr-148. Bacterially purified His-JDP2 (Wt) or His-JDP2 T148A (Ala) were incubated with bacterially purified activated p38 F327S [21] in the presence of [γ- 32P]ATP for 30 min. Proteins were resolved by SDS/PAGE (12 % gel), dried and exposed to autoradiography. (B) The JDP2 C-terminal domain is necessary but not sufficient for phosphorylation by p38 kinase. Bacterially purified GST fusion proteins with full-length JDP2 (Wt) C-terminally truncated JDP2 (∆C) and JDP2 C-terminal fragment (Dock) were used in an in vitro kinase assay as described in (A). A representative experiment is presented. (C) In vitro kinase assay using GST-JDP2 (JDP2wt), JDP2 ∆C and JDP2-Dock as substrates with either activated p38 or HA-JNK2 kinases. Protein mixtures were resolved by SDS/PAGE, fixed, dried and analysed by PhosphorImaging. The results represent meansS.E.M. from three independent experiments. phosphate in the presence of activated p38 kinase. This indicates that both p38 and JNK kinases are able to integrate stress signals to JDP2 Thr-148 SIGNOR-250100 0.385 PRKAA1 protein Q13131 UNIPROT NOS3 protein P29474 UNIPROT up-regulates activity phosphorylation Thr495 TGITRKKtFKEVANA 9606 24379783 t lperfetto The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites SIGNOR-251619 0.286 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1889 SPTTPKYsPTSPTYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself. Cellular kinase cdk9 phosphorylates serine-2 in the c-terminal domain (ctd) of rnap ii SIGNOR-203580 0.773 RIPK3 protein Q9Y572 UNIPROT PDH complex SIGNOR-C402 SIGNOR up-regulates activity phosphorylation -1 29358703 t miannu Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. SIGNOR-268065 0.2 ITGB1 protein P05556 UNIPROT A1/b1 integrin complex SIGNOR-C159 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253170 0.752 PP1 proteinfamily SIGNOR-PF54 SIGNOR AURKA protein O14965 UNIPROT down-regulates dephosphorylation 9606 11551964 t lperfetto Pp1 is shown to dephosphorylate active stk15 and abolish its activity in vitro. SIGNOR-264651 0.2 CUL2 protein Q13617 UNIPROT BAF250b E3 ligase complex SIGNOR-C522 SIGNOR form complex binding 9606 BTO:0000567 20086098 t miannu In the present work, we show that BAF250 associates with elongin C (Elo C), cullin 2 (Cul2), and Roc1 to form an E3 ubiquitin ligase. BAF250 forms an E3 ubiquitin ligase with Elo B/C, Cul2, and Roc1 that targets histone H2B. H2B-Ub has been shown to be required for transcriptional activation in vitro SIGNOR-271440 0.609 PRKCA protein P17252 UNIPROT RHO protein P08100 UNIPROT unknown phosphorylation Ser334 PLGDDEAsATVSKTE -1 9099669 t lperfetto Thus, the primary protein kinase C sites are Ser334 and Ser338, with minor phosphorylation of Thr335/336 and Ser343. SIGNOR-248966 0.446 TARDBP protein Q13148 UNIPROT DICER1 protein Q9UPY3 UNIPROT up-regulates quantity post transcriptional regulation 7227 32620127 t lperfetto Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo.|In agreement with this idea, we found that the suppression of TDP-43 induces the downregulation of Dicer in human neuroblastoma cell lines signifying that the TDP-43 function is required to prevent defects in Dicer protein expression or stability SIGNOR-262114 0.38 FNTA protein P49354 UNIPROT MRAS protein O14807 UNIPROT up-regulates activity 9606 24294527 t lperfetto Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. SIGNOR-242553 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser104 FSFDTDRsPAPMSCD 9606 12591950 t lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) SIGNOR-98384 0.2 IQGAP1 protein P46940 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity binding 15695813 t lperfetto Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.  SIGNOR-261889 0.708 SRC protein P12931 UNIPROT KCND3 protein Q9UK17 UNIPROT up-regulates activity phosphorylation Tyr108 GKLHYPRyECISAYD 9606 BTO:0000007 22198508 t miannu These results indicate that Y108 (for Src-family kinases) and Y136 (for EGFR kinase) are involved in the tyrosine phosphorylation of hKv4.3 channels. SIGNOR-276393 0.341 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates quantity by destabilization phosphorylation Thr32 QSRPRSCtWPLQRPE 19951971 t lperfetto AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation. SIGNOR-252846 0.909 EIF3E protein P60228 UNIPROT PLAU protein P00749 UNIPROT up-regulates quantity translation regulation 9606 BTO:0000815; BTO:0001938 20453879 f irozzo Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. SIGNOR-259155 0.2 SOX9 protein P48436 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 f miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SIGNOR-255187 0.337 CACNA1G protein O43497 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 30849329 t miannu Voltage-gated calcium channels mediate the influx of calcium in response to membrane depolarization in excitable cells. In presynaptic nerve terminals, this calcium influx triggers transmitter release for synaptic transmission. Several neurological and cardiac disorders are caused by pathogenic variants in genes encoding α1-subunits of voltage-gated calcium channels, including CACNA1A (MIM: 601011) (familial hemiplegic migraine [MIM: 141500], episodic ataxia [MIM: 108500], and epilepsy [MIM: 617106]),3, 4, 5 CACNA1C (MIM: 114205) (Timothy syndrome [MIM: 601005]),6, 7 CACNA1D (MIM: 114206) (primary aldosteronism, neurodevelopmental disorders [MIM: 615474]),8, 9 and CACNA1G (MIM: 604065) (spinocerebellar ataxia [MIM: 616795]). SIGNOR-264324 0.8 regorafenib chemical CHEBI:68647 ChEBI FLT4 protein P35916 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259206 0.8 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161686 0.597 EGFR protein P00533 UNIPROT VAV2 protein P52735 UNIPROT up-regulates phosphorylation Tyr142 TENDDDVyRSLEELA 9606 12454019 t miannu To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor. SIGNOR-95972 0.603 Oxotremorine chemical CHEBI:7851 ChEBI CHRM3 protein P20309 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258652 0.8 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr93 EAETLAEtEPERHLG 9606 BTO:0001130 16581776 t llicata In vitro kinase assays followed by mass spectrometric analyses demonstrated that ck2 phosphorylated recombinant nkx3.1 on thr89 and thr93. We have also determined that nkx3.1 is degraded primarily through a proteasomal pathway, suggesting that phosphorylation by ck2 protects nkx3.1 from degradation. SIGNOR-145505 0.319 RAPH1 protein Q70E73 UNIPROT ENAH protein Q8N8S7 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268425 0.554 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t gcesareni Mapkerk1/2 is also able to phopshorylate the egf receptor, the ras exchange factor sos, mkkkraf1, and mkkmek1. The phosphorylation of each of these proteins by mapkerk1/2 is believed to reduce their catalytic activity SIGNOR-64169 0.622 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 11777359 t rheumatoid arthritis gcesareni SIGNOR-251699 0.8 PAX2 protein Q02962 UNIPROT PAX2/TLE4 complex SIGNOR-C152 SIGNOR form complex binding 9606 16631587 t miannu Several Pax proteins are able to interact with groucho (TLE) family members. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. SIGNOR-256359 0.464 MCU_MICU2_variant complex SIGNOR-C502 SIGNOR calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 32315830 t miannu MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. SIGNOR-270878 0.8 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser263 NVGSPLSsPLSSMKS 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276108 0.355 FYN protein P06241 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 10090 BTO:0000775 14707117 t done miannu TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. SIGNOR-273960 0.573 SYN2 protein Q92777 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269185 0.7 hydroxyurea chemical CHEBI:44423 ChEBI RRM2 protein P31350 UNIPROT down-regulates activity chemical inhibition 9606 14583450 t miannu In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation. SIGNOR-259355 0.8 Raf265 derivative chemical CID:23654923 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206394 0.8 CXCL8 protein P10145 UNIPROT CXCR2 protein P25025 UNIPROT up-regulates binding 9606 11350788 t gcesareni Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades. SIGNOR-107983 0.858 beta-Funaltrexamine chemical CHEBI:81527 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258772 0.8 NPNT protein Q6UXI9 UNIPROT A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 10090 22613833 t lperfetto The loss of QBRICK significantly diminished the expression of nephronectin, an integrin α8β1 ligand necessary for renal development. In vivo, nephronectin associated with QBRICK and localized at the sublamina densa region, where QBRICK was also located. Collectively, these findings indicate that QBRICK facilitates the integrin α8β1-dependent interactions of cells with basement membranes by regulating the basement membrane assembly of nephronectin and explain why renal defects occur in Fraser syndrome. SIGNOR-253344 0.673 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-252318 0.641 HDAC3 protein O15379 UNIPROT YY1 protein P25490 UNIPROT down-regulates activity deacetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268837 0.589 GSK3B protein P49841 UNIPROT AHR protein P35869 UNIPROT up-regulates activity phosphorylation Thr697 EMDSMPYtQNFISCN 9606 BTO:0000567 34198826 t miannu A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR. SIGNOR-276661 0.252 SMAD4 protein Q13485 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR form complex binding 9606 9843571 t lperfetto TGF-beta treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus. SIGNOR-229560 0.703 CDK5 protein Q00535 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 20630875 t gcesareni Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily. SIGNOR-166682 0.383 PDIA6 protein Q15084 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-regulates activity 10090 BTO:0004086 17420453 f Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. SIGNOR-256533 0.7 GBF1 protein Q92538 UNIPROT ARF1 protein P84077 UNIPROT up-regulates activity guanine nucleotide exchange factor 9534 BTO:0000298 15616190 t miannu GBF1 Stimulates Production of Arf-GTP In Vivo SIGNOR-277400 0.713 CEP350 protein Q5VT06 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR form complex binding 9606 16314388 t miannu Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring. SIGNOR-142355 0.2 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser341 KALASIYsPDHSSNN 9606 19801649 t llicata Mlk2 inhibits e47 transactivation activity on the trkb promote SIGNOR-161523 0.2 PRKCG protein P05129 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus. SIGNOR-97558 0.695 MYC protein P01106 UNIPROT MYCBP2 protein O75592 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267145 0.421 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser178 EENVSDGsPNAGSVE 9606 10831586 t lperfetto Indeed, p27kip1 was phosphorylated by p42 mapk (erk2) in vitrothese results suggest that ser(10) is the major site of phosphorylation of p27(kip1) and that phosphorylation at this site, like that at thr(187), contributes to regulation of p27(kip1) stability. SIGNOR-244517 0.2 JUNB protein P17275 UNIPROT LORICRIN protein P23490 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000667 12200429 f miannu Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. SIGNOR-254535 0.2 5-phospho-beta-D-ribosylaminium(1-) smallmolecule CHEBI:58681 ChEBI N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI up-regulates quantity precursor of 9606 34283828 t miannu In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). SIGNOR-267296 0.8 RAB33B protein Q9H082 UNIPROT ATG16L1 protein Q676U5 UNIPROT up-regulates binding 9606 18448665 t gcesareni Olgi-resident small gtpase rab33b interacts with atg16l and modulates autophagosome formation. SIGNOR-178542 0.748 STK16 protein O75716 UNIPROT DRG1 protein Q9Y295 UNIPROT unknown phosphorylation Thr100 AYEFTTLtTVPGVIR -1 18184589 t Manara It is therefore likely that MPSK1 regulates DRG1 function by either phosphorylation or through competition with other DRG1 binding partners. SIGNOR-260806 0.398 MAPK3 protein P27361 UNIPROT NR3C2 protein P08235 UNIPROT down-regulates quantity by destabilization phosphorylation Ser227 FGSFPVHsPITQGTP 9606 BTO:0005043 22798426 t miannu  Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation. SIGNOR-276111 0.355 CAK complex complex SIGNOR-C456 SIGNOR CDK4 protein P11802 UNIPROT up-regulates phosphorylation Thr172 YSYQMALtPVVVTLW 9606 8139570 t lperfetto Phosphorylation of cdk4 on threonine 172 by a cdk-activating kinase (cak).  therefore, formation of the cyclin d-cdk4 complex and phosphorylation of the bound catalytic subunit are independently regulated, and in addition to the requirement for cak activity, serum stimulation is required to promote assembly of the complexes in mammalian cells. SIGNOR-269329 0.567 CHEK2 protein O96017 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation 9606 22558186 t gcesareni In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk. SIGNOR-197281 0.289 BMP15 protein O95972 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 BTO:0000975 SIGNOR-C29 16446785 t gcesareni Here we have performed a detailed in situ hybridization analysis of the spatial and temporal expression patterns of the bmp ligands (bmp-2, -3, -3b, -4, -6, -7, -15), receptors (bmpr-ia, -ib, -ii), and bmp antagonist, follistatin, in rat ovaries over the normal estrous cycle. SIGNOR-144098 0.547 EFNB3 protein Q15768 UNIPROT EPHA4 protein P54764 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52621 0.834 ANK2 protein Q01484 UNIPROT DMD protein P11532 UNIPROT up-regulates quantity relocalization 10090 BTO:0001103 19109891 t miannu We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4. SIGNOR-266712 0.54 C1QBP protein Q07021 UNIPROT C1QC protein P02747 UNIPROT down-regulates activity binding SIGNOR-C308 28018340 t lperfetto Previous studies have shown that gC1qR inhibits aggregated IgG-mediated complement activation by binding to the gC1q site on C1q, thereby preventing IgG from binding to the gh’s (28), suggesting that the binding sites for gC1qR and IgG on C1q may be identical or at least overlapping. SIGNOR-263404 0.405 ZMYND8 protein Q9ULU4 UNIPROT VEGFA protein P15692 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001033 27477906 t lperfetto Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported SIGNOR-262041 0.2 AKT1 protein P31749 UNIPROT BAD protein Q92934 UNIPROT down-regulates activity phosphorylation Ser75 EIRSRHSsYPAGTED 9606 BTO:0000007 9381178 t Active Akt induced a significant increase in BAD phosphorylation. mutant BAD with alanine substitutions at Ser112 and Ser136 was not phosphorylated by active Akt . phosphorylation of BAD by Akt will preclude its binding to membrane-anchored Bcl-xL, leading to increased cell survival. SIGNOR-252562 0.819 ZNF692 protein Q9BU19 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 17097062 f gcesareni In this study, we demonstrate that a newly identified transcription factor, arebp, is a novel target of ampk. Arebps function is to repress transcription of the pepck gene upon phosphorylation by ampk. SIGNOR-150556 0.2 GABRA2 protein P47869 UNIPROT GABA-A (a2-b1-g2) receptor complex SIGNOR-C331 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263753 0.601 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1896 SPTSPTYsPTSPVYT 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176817 0.778 NR2F2 protein P24468 UNIPROT NR2F1 protein P10589 UNIPROT up-regulates binding 9606 10900149 t gcesareni Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site. SIGNOR-79443 0.258 EFNB1 protein P98172 UNIPROT EPHB1 protein P54762 UNIPROT up-regulates binding 9606 11713248 t tpavlidou We show here that despite its lack of kinase activity, ephb6 undergoes inducible tyrosine phosphorylation upon stimulation with the eph-b receptor subfamily ligand ephrin-b1. Overexpression of a catalytically active member of the eph-b subfamily, ephb1, resulted in increased ephb6 phosphorylation. Ephb1-induced ephb6 phosphorylation was ligand-dependent and required the functional catalytic activity of ephb1. SIGNOR-111851 0.824 HECTD1 protein Q9ULT8 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 22431752 t Monia We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway. SIGNOR-261199 0.2 ADRA1B protein P35368 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256950 0.28 MAPK3 protein P27361 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates activity phosphorylation Tyr204 HTGFLTEyVATRWYR 1712480 t lperfetto Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation.| SIGNOR-249472 0.2 CLOCK protein O15516 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR form complex binding -1 22653727 t lperfetto Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex|The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock. SIGNOR-253709 0.773 PTPRG protein P23470 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity dephosphorylation Tyr1172 ISLDNPDyQQDFFPK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254700 0.489 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT up-regulates activity cleavage Arg756 KGQAGLQrALEILQE -1 17204478 t lperfetto MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). SIGNOR-263425 0.795 EPAS1 protein Q99814 UNIPROT KDM4C protein Q9H3R0 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271585 0.2 CSF1R protein P07333 UNIPROT CSF1R protein P07333 UNIPROT up-regulates phosphorylation Tyr708 NIHLEKKyVRRDSGF 9606 BTO:0001271 15297464 t lperfetto Csf-1r homodimerizes and autophosphorylates on six tyrosines in the cytoplasmic portion of the receptor. Tyr807 is located in the activation loop of the kinase domain (9) and its phosphorylation is important for kinase activity (10). The remaining tyrosines serve as binding sites for proteins containing src homology 2 (sh2) binding domains. Three sites are found in the ki: grb2/mona (tyr697) (11, 12), p85 subunit of phosphatidylinositol 3-kinase (tyr721) (13), and stat1 (tyr706) (14), the c-cbl binding site is in the cooh terminus (tyr974) (15, 16), and the src family kinase (sfk) binding site is in the jmd (y559) (17). These molecules further propagate the csf-1 signal through activation of ras/erk, phosphatidylinositol 3-kinase/akt, and stat proteins. SIGNOR-127540 0.2 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120212 0.319 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Ser20 APPVRMSsTIFSTGG -1 10075701 t miannu Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197. SIGNOR-250227 0.2 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser561 PFLSRHNsKSSIFSF 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275790 0.284 Nutlin-3 smallmolecule CID:216345 PUBCHEM TP73 protein O15350 UNIPROT up-regulates 9606 17700533 t miannu These results provide the first evidence that Nutlin-3 disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73 and thus, provides a rationale for the use of Nutlin-3 in the large number of human tumors in which p53 is inactivated. SIGNOR-255472 0.8 MTOR protein P42345 UNIPROT MKNK2 protein Q9HBH9 UNIPROT down-regulates activity phosphorylation Ser74 KRGRATDsFSGRFED 9606 BTO:0000007 32170339 t miannu MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. SIGNOR-277516 0.277 Gbeta proteinfamily SIGNOR-PF4 SIGNOR LIFR protein P42702 UNIPROT down-regulates phosphorylation 9606 7777512 t inferred from 70% family members gcesareni Thus, our results identify the human lifr as a substrate for mapk and suggest a mechanism of heterologous receptor regulation of lifr signaling occurring at ser-1044. SIGNOR-270001 0.2 A5/b1 integrin complex SIGNOR-C163 SIGNOR DLL1 protein O00548 UNIPROT up-regulates quantity by expression 10090 25786978 f lperfetto First, EPCs incorporated into the neovascular region recognize the TGFBIp secreted by cells in the environment via binding to integrins a4 and a5. Second, binding of TGFBIp to integrins in EPCs induces phosphorylation of intracellular signaling molecules in a pathway necessary for TGFBIp-mediated angiogenic activity of EPCs. In addition, binding of TGFBIp to integrins activates the NF-kappaB signaling pathway that induces expression of DLL1 and JAG1 in EPCs. SIGNOR-253286 0.269 CAMK2D protein Q13557 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Ser641 RRSVKRNsTVDCNGV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275791 0.284 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Ser54 ELQPMPTsPGVDLQS 9606 SIGNOR-C83 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-100885 0.761 PKC proteinfamily SIGNOR-PF53 SIGNOR KCNJ1 protein P48048 UNIPROT up-regulates activity phosphorylation Ser201 FSKNAVIsKRGGKLC -1 12221079 t miannu We conclude that ROMK1 is a substrate of PKC and that serine residues 4 and 201 are the two main PKC phosphorylation sites that are essential for the expression of ROMK1 in the cell surface. SIGNOR-275990 0.2 PRKAA2 protein P54646 UNIPROT PPP1R12C protein Q9BZL4 UNIPROT down-regulates phosphorylation Ser452 AGLQRSAsSSWLEGT 9606 SIGNOR-C15 22137581 t lperfetto Ampk-induced phosphorylation is necessary for ppp1r12c interaction with 14-3-3 and phosphorylation of myosin regulatory light chain. Both ampk activity and ppp1r12c phosphorylation are increased in mitotic cells and are important for mitosis completion. The interaction between ppp1r12c and 14-3-3_ may inactivate the ppp1r12c-containing phosphatase complex in vivo. SIGNOR-195148 0.261 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR GRB2 protein P62993 UNIPROT down-regulates activity phosphorylation Tyr7 yDFKATAD 9606 BTO:0000007 20554525 t lperfetto More recently, however, tyrosine phosphorylation of Grb2 in BCR-ABL-transformed cells on residues Tyr7, Tyr37, Tyr52, and Tyr209 in the SH3 domains has been reported and shown to negatively regulate the Ras/MAPK pathway. SIGNOR-246285 0.2 ATRX protein P46100 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by repression transcriptional regulation 7227 BTO:0001138 22021382 f 1 miannu XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression. SIGNOR-239733 0.411 PML-RARalpha fusion protein SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT up-regulates activity binding -1 18025157 t We show that PML-RARα physically interacts with Sp1 in the absence of DNA. In this report, we show that PML-RARα interacts with Sp1 and may interfere with the expression of genes that are not normally regulated by retinoic acid receptors. SIGNOR-255729 0.2 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Thr278 LARRRKAtQVGEKTP 9606 17082196 t lperfetto Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology. SIGNOR-216515 0.2 WNT3A protein P56704 UNIPROT LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins are a large family of secreted glycoproteins. Wnt proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131829 0.786 FBXW5 protein Q969U6 UNIPROT SASS6 protein Q6UVJ0 UNIPROT down-regulates quantity by destabilization ubiquitination 21725316 t lperfetto We identify the centriolar protein HsSAS-6 (refs 4,5) as a critical substrate of the SCF-FBXW5 complex. FBXW5 binds HsSAS-6 and promotes its ubiquitylation in vivo. |expression of the wild-type form of FBXW5 accelerated the degradation of HsSAS-6 to a half-life of less than two hours SIGNOR-275478 0.547 RHOA protein P61586 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity binding 9606 8824197 t areggio We found that in the human kidney epithelial cell line, 293T, Cdc42 and all Rho proteins, RhoA, RhoB, and RhoC, but not Rac or Ras can induce activation of JNK. SIGNOR-258974 0.823 BMS-599626 chemical CID:10437018 PUBCHEM EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 17062696 t AC480 significantly enhanced the radiosensitivity of HN-5 cells, expressing both EGFR and Her2. gcesareni The studies described here are intended to characterize the ability of bms-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (her) kinase family, to modulate signaling and growth of tumor cells that depend on her1 and/or her2. SIGNOR-150190 0.8 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser320 QRSRKRLsQDAYRRN 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89197 0.555 NEK7 protein Q8TDX7 UNIPROT KIF11 protein P52732 UNIPROT up-regulates activity phosphorylation Ser1033 GINTLERsKVEETTE 10090 BTO:0000938 29899413 t done miannu NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites.  SIGNOR-273890 0.414 SMAD1 protein Q15797 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C85 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus. SIGNOR-168734 0.661 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270391 0.8 TRIM27 protein P14373 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000671 12807881 f miannu Here we show that ectopic expression of rfp in human embryonic kidney 293 cells causes extensive apoptosis, as assessed by multiple criteria. SIGNOR-102019 0.7 PRKACA protein P17612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81129 0.529 POT1 protein Q9NUX5 UNIPROT RPA3 protein P35244 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263326 0.266 AKT2 protein P31751 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity phosphorylation Ser50 RNRYRDVsPFDHSRI 10090 11579209 t lperfetto We conclude that ptp1b is a novel substrate for akt and that phosphorylation of ptp1b by akt at ser(50) may negatively modulate its phosphatase activity creating a positive feedback mechanism forinsulin signaling SIGNOR-235491 0.377 MAD2L2 protein Q9UI95 UNIPROT CDC20 protein Q12834 UNIPROT down-regulates activity binding -1 11459826 t miannu The APC is activated in mitosis and G1 by CDC20 and CDH1, and inhibited by the checkpoint protein MAD2, a specific inhibitor of CDC20. We show here that a MAD2 homolog MAD2B also inhibits APC. MAD2B directly inhibits activation of APC by CDC20 and CDH1 SIGNOR-264903 0.467 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 17183360 t gcesareni Rela is phosphorylated at: ser276 by the catalytic subunit of protein kinase a (pkac), msk1 and msk2; at ser311 by the atypical pkczeta; at ser468 by ikkbeta, ikkepsilon and glycogen-synthase kinase-3beta (gsk3beta); at ser529 by ck2; and at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1)) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k) . SIGNOR-151422 0.362 AMFR protein Q9UKV5 UNIPROT CD3D protein P04234 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11724934 t miannu Gp78 specifically recruits MmUBC7, a ubiquitin-conjugating enzyme (E2) implicated in ER-associated degradation (ERAD), through a region distinct from the RING finger. gp78 can target itself for proteasomal degradation in a RING finger- and MmUBC7-dependent manner. Importantly, gp78 can also mediate degradation of CD3-delta, a well-characterized ERAD substrate.  SIGNOR-272670 0.481 PRKACA protein P17612 UNIPROT VIM protein P08670 UNIPROT down-regulates activity phosphorylation Ser39 TTSTRTYsLGSALRP -1 2500966 t miannu Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. Domain- and sequence-specific phosphorylation of vimentin induces disassembly of the filament structure. SIGNOR-250067 0.311 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-205819 0.8 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser337 IVSPPPSsPPSSLTT 9606 8087847 t lperfetto Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. SIGNOR-36026 0.692 QYDAFJUKVGVEKO-PKOVDKIBSA-N smallmolecule CID:16132339 PUBCHEM MRGPRX1 protein Q96LB2 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257543 0.8 PRKCD protein Q05655 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr678 RHIVRKRtLRRLLQE 10090 1860884 t lperfetto These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling. SIGNOR-248858 0.373 IL9 protein P15248 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex SIGNOR-108867 0.571 AFDN protein P55196 UNIPROT RIT1 protein Q92963 UNIPROT up-regulates activity binding 9606 10545207 t miannu Rit and Rin were found to interact with the known Ras binding proteins RalGDS, Rlf, and AF-6/Canoe. These interactions were GTP and effector domain dependent and suggest that RalGDS, Rlf, and AF-6 are Rit and Rin effectors. SIGNOR-220917 0.2 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TSC2 protein P49815 UNIPROT down-regulates activity phosphorylation Ser540 KVMARSLsPPPELEE 10090 BTO:0000944 15851026 t lperfetto Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation. SIGNOR-249455 0.2 WNT3A protein P56704 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 15454084 t gcesareni Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf. SIGNOR-129580 0.758 FASN protein P49327 UNIPROT NADPH(4-) smallmolecule CHEBI:57783 ChEBI down-regulates quantity chemical modification 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267759 0.8 ATRX protein P46100 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 BTO:0000584 26428317 f Telomere length must be maintained for the immortalization of malignant cells […] alternative lengthening of telomeres status was perfectly correlated with the loss of expression of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein in pancreatic neuroendocrine tumors SIGNOR-256595 0.7 TIMM10 protein P62072 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267703 0.711 FBXO38 protein Q6PIJ6 UNIPROT KLF7 protein O75840 UNIPROT up-regulates activity binding 9534 BTO:0004055 14729953 t miannu Interaction between MoKA and KLF7 was confirmed by the in vitro glutathione S-transferase pull-down assay and by coimmunoprecipitation of the proteins overexpressed in mammalian cells. Functional assays documented that MoKA is a KLF7 coactivator SIGNOR-224621 0.588 RNF8 protein O76064 UNIPROT Histone H2A proteinfamily SIGNOR-PF70 SIGNOR up-regulates ubiquitination 9606 20551964 t gcesareni Rnf8 and ubc13 ubiquitylate h2a and h2ax, but other substrates probably exist. SIGNOR-265313 0.2 TRIM27 protein P14373 UNIPROT ULK1 protein O75385 UNIPROT down-regulates quantity ubiquitination 10090 35670107 t STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination SIGNOR-270349 0.2 HCK protein P08631 UNIPROT BCR-ABL fusion protein SIGNOR-FP6 SIGNOR up-regulates activity phosphorylation Tyr832 LRYEGRVyHYRINTA 9606 16912036 t Manara Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. | Tyrosine phosphorylation of the SH3-SH2 region is essential for full Bcr-Abl biological activity. SIGNOR-260814 0.2 AURKA protein O14965 UNIPROT KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr799 PPKLRRRtFSLTEVR -1 31881080 t miannu We show that Aurora A phosphorylates the condensin I-dependent pool of KIF4A and thus actively promotes chromosome congression from the spindle poles to the metaphase plate. In vitro kinase assays showed that recombinant KIF4A can be phosphorylated by Aurora A and that this activity is inhibited by the specific Aurora A inhibitor MLN8537 (Fig. 7 C). SIGNOR-265993 0.426 long-chain fatty acyl-CoA(4-) smallmolecule CHEBI:83139 ChEBI arachidonoyl-CoA smallmolecule CHEBI:15514 ChEBI up-regulates quantity precursor of 9606 15189125 t miannu Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Three desaturases, Delta9, Delta6, and Delta5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Delta9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. SIGNOR-267903 0.8 FYN protein P06241 UNIPROT DCBLD2 protein Q96PD2 UNIPROT up-regulates activity phosphorylation Tyr750 PAPDELVyQVPQSTQ -1 23770091 t done miannu Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding. SIGNOR-273944 0.354 KIF14 protein Q15058 UNIPROT CIT protein O14578 UNIPROT up-regulates activity binding 9606 16431929 t miannu We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. SIGNOR-266422 0.717 IDH complex SIGNOR-C396 SIGNOR D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI down-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266251 0.8 PTPN1 protein P18031 UNIPROT PTPN1 protein P18031 UNIPROT down-regulates activity dephosphorylation Tyr153 SEDIKSYyTVRQLEL -1 11506178 t Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B|These results suggest that PTP1B can dephosphorylate itself under in vitro conditions. SIGNOR-248425 0.2 ITGAM protein P11215 UNIPROT ICAM1 protein P05362 UNIPROT up-regulates binding 9606 23994464 t apalma Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. SIGNOR-255041 0.768 CHFR protein Q96EP1 UNIPROT SMARCA4 protein P51532 UNIPROT down-regulates quantity by destabilization polyubiquitination 9534 BTO:0000298 22285184 t miannu Here we report that CHFR interacts with BRG1, SNF5, and BAF60a of the SWI/SNF-like BAF complex and ubiquitinates them to target for degradation through a proteasome-mediated pathway, and that SRG3/mBAF155 stabilizes these components by blocking their interaction with CHFR. These results suggest that CHFR enhances the degradation of the components of the SWI/SNF-like BAF complex by inducing their poly-ubiquitination. SIGNOR-271457 0.336 SRC protein P12931 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity phosphorylation Tyr393 RLMTGDTyTAHAGAK 9606 11847100 t lperfetto c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. SIGNOR-246311 0.525 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BW1 protein Q7Z2G1 UNIPROT down-regulates activity monoubiquitination 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271989 0.2 PHKA1 protein P46020 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation Ser972 KEFGVERsVRPTDSN -1 10487978 t miannu Phk is activated in vitro by autophosphorylation. Ser1018 and at least three of the other six serine residues (Ser972, -985, and -1007) can be phosphorylated in vitro by Phk itself (autophosphorylation) SIGNOR-250281 0.2 U69593 chemical CHEBI:73357 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258827 0.8 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu618 SEVKMDAeFRHDSGY -1 8943232 t lperfetto The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261767 0.497 AMPK complex SIGNOR-C15 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 15866171 t lperfetto Ampk activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate ampk-dependent cell-cycle arrest SIGNOR-216475 0.43 calcium(2+) smallmolecule CHEBI:29108 ChEBI KCNMA1 protein Q12791 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 31152168 t miannu The large-conductance Ca2+- and voltage-activated K+ (BK) channel is a tetramer consisting of four α-subunits encoded by the KCNMA1 gene on chromosome 10q22.3. The BK channel can be allosterically activated by both changes in the membrane voltage (voltage-dependent activation pathway) and intracellular [Ca2+] concentration (calcium-dependent activation pathway) SIGNOR-269192 0.8 HSPA1A protein P0DMV8 UNIPROT ENPP1 protein P22413 UNIPROT up-regulates quantity post transcriptional regulation 9606 19083193 t miannu We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation. SIGNOR-252197 0.2 CAMK2A protein Q9UQM7 UNIPROT ETS2 protein P15036 UNIPROT down-regulates phosphorylation Ser313 QRVPSFEsFEDDCSQ 9606 19182667 t lperfetto Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters SIGNOR-183604 0.2 IKBKB protein O14920 UNIPROT RELA protein Q04206 UNIPROT up-regulates activity phosphorylation Ser536 SGDEDFSsIADMDFS 9606 BTO:0000007 SIGNOR-C13 15489227 t lperfetto Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter. SIGNOR-129935 0.883 PIM proteinfamily SIGNOR-PF34 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000574 16146838 f miannu The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-255732 0.7 C5AR1 protein P21730 UNIPROT SELL protein P14151 UNIPROT down-regulates quantity by repression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263468 0.33 Ile(5)-angiotensin II smallmolecule CHEBI:2719 ChEBI AGTR1 protein P30556 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257459 0.8 CDK1 protein P06493 UNIPROT EEF1D protein P29692 UNIPROT unknown phosphorylation Ser133 APQTQHVsPMRQVEP 9606 12551973 t gcesareni The sequence flanking ser-133 of ef-1delta completely matches the consensus phosphorylation site for a cellular protein kinase, cdc2, and in vitro kinase assays revealed that purified cdc2 phosphorylates ser-133 of ef-1delta. SIGNOR-97733 0.366 CD79B protein P40259 UNIPROT BCR-Dl complex SIGNOR-C436 SIGNOR form complex binding 9606 BTO:0000776 32323266 t scontino BCR consists of a pair of identical immunoglob- ulin heavy (IgH) and light (IgL) chains. though membrane BCR per se is not able to transduce downstream signaling, it does so by making BCR complex with CD79. The extracellular portion of the BCR is non-covalently coupled to a disulfide-linked heterodimer of the CD79A and CD79B. This association allows expression of BCR on the plasma membrane and BCR internalization after antigen recognition. SIGNOR-268201 0.647 SP1 protein P08047 UNIPROT TINF2 protein Q9BSI4 UNIPROT up-regulates quantity by expression transcriptional regulation 21731707 t lperfetto Transfection of a plasmid carrying the Sp1 transcription factor into Sp-deficient SL2 cells strongly activated TIN2 promoter-driven luciferase reporter expression. SIGNOR-271698 0.2 NRXN2 protein P58401 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265461 0.264 Osmotic_stress stimulus SIGNOR-ST28 SIGNOR FUS protein P35637 UNIPROT down-regulates activity relocalization 9606 BTO:0000312 33172210 f We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manne SIGNOR-262815 0.7 NSMCE1 protein Q8WV22 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265483 0.875 SMN1 protein Q16637 UNIPROT SMN complex complex SIGNOR-C158 SIGNOR form complex binding 12065586 t lperfetto SMN is part of a large macromolecular complex that also contains Gemin2, Gemin3, Gemin4, Gemin5, and Gemin6. The SMN complex functions in the assembly of spliceosomal small nuclear ribonucleoproteins and probably other ribonucleoprotein particles. We have identified a novel protein component of the SMN complex termed Gemin7 using native purified SMN complexes and peptide sequencing by mass spectrometry. SIGNOR-253115 0.731 NMDA receptor_2A complex SIGNOR-C347 SIGNOR DLG4 protein P78352 UNIPROT up-regulates activity binding 9606 BTO:0000938 11052931 t miannu Another central component of the NMDA receptor signaling complex is the scaffold protein PSD-95 (also referred to as SAP-90). The first and second PDZ domains bind tightly to the tails of the NR2 subunits of the NMDA receptor SIGNOR-264222 0.797 ATF4 protein P18848 UNIPROT PPP1R15A protein O75807 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 31226023 t miannu ATF4 also induces another bZIP protein C/EBP-homologous protein (CHOP), which is responsible for triggering apoptosis in cells under prolonged ER stress. ATF4 and CHOP further induce growth arrest and DNA damage–inducible protein 34 (GADD34),a regulatory subunit of protein phosphatase 1 (PP1) that dephosphorylates eIF2α. This negative feedback mechanism enables protein synthesis to resume after resolution of ER stress. SIGNOR-260172 0.652 PTPN12 protein Q05209 UNIPROT SHC1 protein P29353 UNIPROT down-regulates dephosphorylation Tyr349 EEPPDHQyYNDFPGK 9606 8939605 t gcesareni The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions. SIGNOR-44361 0.666 WWTR1 protein Q9GZV5 UNIPROT PAX8 protein Q06710 UNIPROT up-regulates binding 9606 BTO:0000763 19010321 t miannu Taz is a coactivator for pax8 and ttf-1, two transcription factors involved in thyroid differentiation. / we show that this interaction leads to a significant enhancement of the transcriptional activity of pax8 and ttf-1 on the thyroglobulin promoter thus suggesting a role of taz in the control of genes involved in thyroid development and differentiation. SIGNOR-182253 0.306 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR5 protein Q9H228 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257580 0.8 buspirone chemical CHEBI:3223 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258885 0.8 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser516 GDRSGYSsPGSPGTP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249352 0.733 PRKCZ protein Q05513 UNIPROT ADARB1 protein P78563 UNIPROT up-regulates activity phosphorylation Ser216 SASPVPAsLAQPPLP 9606 BTO:0001615 29694894 t miannu  Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.  SIGNOR-277391 0.2 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser27 ADREAASsPAGEPLR 9606 20027304 t This phosphorylation increased sirt1 nuclear localization gcesareni Human sirt1 was phosphorylated by jnk1 on three sites: ser27, ser47, and thr530 and this phosphorylation of sirt1 increased its nuclear localization and enzymatic activity. Surprisingly, jnk1 phosphorylation of sirt1 showed substrate specificity resulting in deacetylation of histone h3, but not p53. SIGNOR-162314 0.614 EPAS1 protein Q99814 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20534544 f Regulation miannu We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. SIGNOR-251791 0.287 BICRA protein Q9NZM4 UNIPROT GBAF complex SIGNOR-C467 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-269781 0.2 ADCY4 protein Q8NFM4 UNIPROT 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI up-regulates quantity chemical modification 9606 15385642 t miannu Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. SIGNOR-265006 0.8 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM HDAC3 protein O15379 UNIPROT down-regulates activity chemical inhibition 9606 17868033 t Simone Vumbaca Apicidin inhibited rhHDACs 2 and 3 in the nanomolar range. SIGNOR-261128 0.8 CCK protein P06307 UNIPROT CCKAR protein P32238 UNIPROT up-regulates binding 9606 10368033 t gcesareni Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b SIGNOR-68474 0.782 PRLHR protein P49683 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257198 0.251 BMP7 protein P18075 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 18719589 f induction of mitochondrial biogenesis fspada Bmp7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate prdm16 (pr-domain-containing 16;ref. 4) and pgc-1alpha (peroxisome proliferator-activated receptor-gamma (ppargamma) coactivator-1alpha;ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (ucp1) and adipogenic transcription factors ppargamma and ccaat/enhancer-binding proteins (c/ebps), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (map) kinase-(also known as mapk14) and pgc-1-dependent pathways SIGNOR-180308 0.315 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 12110590 t gcesareni Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway. SIGNOR-90525 0.789 TOP2B protein Q02880 UNIPROT RELN protein P78509 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242207 0.2 PPP1CA protein P62136 UNIPROT WWTR1 protein Q9GZV5 UNIPROT up-regulates activity dephosphorylation Ser89 AQHVRSHsSPASLQL 9606 21189257 t miannu PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. SIGNOR-277116 0.532 MAP3K8 protein P41279 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 BTO:0000567 12207013 t miannu Xplkk1 phosphorylates and activates mammalian plk / xplkk1 phosphorylates thr-210 SIGNOR-92274 0.2 LRFN1 protein Q9P244 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264100 0.7 MAPK1 protein P28482 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 19282669 t gcesareni Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3. SIGNOR-161515 0.709 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys113 KNELKHVkYCQYAFD 9606 12621041 t gcesareni The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses SIGNOR-98993 0.615 AKT1 protein P31749 UNIPROT HK1 protein P19367 UNIPROT up-regulates binding 9606 16892082 t gcesareni The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. SIGNOR-252495 0.453 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120036 0.784 YAP1 protein P46937 UNIPROT DVL1 protein O14640 UNIPROT down-regulates binding 9606 23178811 t gcesareni Yap restricts elevated wnt independently of the axinapcgsk-3beta complex partly by limiting the activity of dishevelled (dvl). SIGNOR-199806 0.337 SREBF1 protein P36956 UNIPROT IDH1 protein O75874 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12923220 t lperfetto IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells|evidence that IDH1 may regulate lipogenesis in hepatic cells SIGNOR-253132 0.285 SMARCA4 protein P51532 UNIPROT SMARCC2 protein Q8TAQ2 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65444 0.938 1-(3-chlorophenyl)piperazine chemical CHEBI:10588 ChEBI HTR2B protein P41595 UNIPROT up-regulates activity chemical activation 10036 BTO:0000452 9459568 t miannu The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor. All of the competition curves for these compounds yielded slope values that were near unity, i.e, they did not significantly fit a two-site binding model better than a one-site binding model. sured against [3H]rauwolscine (Fig. 4), as would be expected since antagonists typically do not discriminate between the agonist high- and low-affinity states. Note that the correlation line is about 0.25 log units from the line of identity, while still having a slope near unity. In fact many compounds, including haloperidol, m-CPP, rauwolscine, ritanserin, spiroxatrine, yohimbine and 1-NP displayed significantly higher affinity for the [3H]rauwolscine than for the [3H]5-HT labeled human 5-HT2B receptor. measured against [3H]5-HT versus the pKi when mea- SIGNOR-258684 0.8 TOP2B protein Q02880 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24463367 f lperfetto While Top2a is essential in proliferating cells and has been linked to DNA replication and chromosome condensation/segregation, Top2b has been clearly indicated in regulating gene expression (e.g. Reln, Dab1, Catna2, Cdh13, Sst, Pbx3, and Epha7) during brain development SIGNOR-242311 0.2 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI iodide smallmolecule CHEBI:16382 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino MIT and DIT, which are deiodinated by iodotyrosine dehalogenase (DEHAL1) that seems to be present in the apical plasma membrane. MIT and DIT are liberated, and the deiodination of these molecules by DEHAL1 is important for providing a sustained source of intrathyroidal iodide. SIGNOR-268093 0.8 HDAC1 protein Q13547 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 17183360 t lperfetto Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1. SIGNOR-217409 0.551 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr225 LGETKQEtLTNISAV 9606 15611134 t gcesareni Mutational analysis showed that phosphorylation of thr180 in the kinase activation t-loop, thr225 in the substrate-binding groove, and thr265 in kinase subdomain x is essential for full zipk autophosphorylation and activity toward exogenous substrates. SIGNOR-132463 0.2 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT up-regulates activity phosphorylation Tyr612 TLHTDDGyMPMSPGV 10029 BTO:0000246 7651388 t lperfetto Therefore, during insulin stimulation irs-1 undergoes tyrosine phosphorylation, and a portion of tyrosine phosphorylated irs-1 associated with the insulin receptor. The insulin receptor substrate-1 (irs-1) is rapidly phosphorylated on several tyrosine residues by the activated insulin receptor. Insulin signals are mediated through tyrosine phosphorylation of specific proteins such as insulin receptor substrate 1 (irs-1) and shc by the activated insulin receptor (ir). SIGNOR-236756 0.913 AURKB protein Q96GD4 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276113 0.62 CUL3 protein Q13618 UNIPROT LZTR1 protein Q8N653 UNIPROT up-regulates activity binding 9606 BTO:0000007 31337872 t Gianni Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. SIGNOR-269070 0.276 CAMK2A protein Q9UQM7 UNIPROT DAGLA protein Q9Y4D2 UNIPROT down-regulates activity phosphorylation Ser782 APLATMEsLSDTESL 23502535 t lperfetto Activated CaMKII interacted with the C-terminal domain of DGLalpha, phosphorylated two serine residues and inhibited DGLalpha activity. |CaMKIIalpha phosphorylates DGLalpha at Ser808 and Ser782 SIGNOR-275539 0.2 PPARGC1A protein Q9UBK2 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0001103 SIGNOR-C13 20404331 f lperfetto In mouse muscles, overexpression of PGC-1beta (like PGC-1alpha) inhibited denervation atrophy, ubiquitin ligase induction, and transcription by NFkappaB SIGNOR-217969 0.357 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 9606 BTO:0000007 11024032 t Tyr-1252, Tyr-1336, and Tyr-1472 of GluRε2 are phosphorylated in 293T cells when active Fyn is co-expressed. SIGNOR-251175 0.763 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR KAT2A protein Q92830 UNIPROT up-regulates activity phosphorylation Thr272 LNYWKLEtPAQFRQR 24870244 t lperfetto Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5|GCN5 T272A/S372A (AA) phosphorylation by cyclin D1-CDK4 kinase is diminished compared to GCN5 wild-type (WT) SIGNOR-275497 0.406 PLK1 protein P53350 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation 21640712 t lperfetto These data indicated that PLK1 phosphorylates CDC25B and that pre-phosphorylation of CDC25B by CDK1/CyclinB enhances its substrate properties for PLK1 in vitro SIGNOR-267560 0.658 HECTD2 protein Q5U5R9 UNIPROT PIAS1 protein O75925 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 26157031 t miannu We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. SIGNOR-272421 0.394 ATXN2 protein Q99700 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 17392519 t miannu Ataxin-2 interacts with the dead/h-box rna helicase ddx6 / ddx6 is an essential component for the assembly of p-bodies/ SIGNOR-154158 0.581 gamma-secretase complex SIGNOR-C98 SIGNOR DSCAM protein O60469 UNIPROT down-regulates quantity cleavage 9606 BTO:0000938 30745319 t miannu γ‐secretase‐mediated intra‐membrane cleavage of DSCAM receptors results in the release of the DSCAM ICD, which is likely proceeded by shedding of the DSCAM ectodomain. Interaction of IPO5 with the NLS of DSCAM then leads to importin‐mediated nuclear import of the DSCAM ICD. In the nucleus, the DSCAM ICD may regulate the transcription of genes involved in neuronal development and function, thereby regulating processes such as neurite outgrowth, branching, and repulsion, as well as synapse formation, axon guidance, and neuronal cell death and survival. SIGNOR-264271 0.2 SMO protein Q99835 UNIPROT TIMP3 protein P35625 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 28709001 f We identified that ciliary Hh signaling in FAPs regulates expression of Timp3. Future experiments will determine whether Timp3 is a direct or indirect target of Hh signaling. SIGNOR-255907 0.2 CCND1 protein P24385 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates binding 9606 15713663 t gcesareni Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function. SIGNOR-134056 0.417 DYRK1A protein Q13627 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 16733250 t lperfetto Here we report that amphiphysin i (amph i) is also a mnb/dyrk1a substrate. This kinase phosphorylated native amph i in rodent brains and recombinant human amph i expressed in escherichia coli. Serine 293 (ser-293) was identified as the major site, whereas serine 295 and threonine 310 were found as minor kinase sitesamph i phosphorylated by mnb/dyrk1a decreased endophilin binding in vitro. From these results we conclude that amph i at ser-293 is phosphorylated by mnb/dyrk1a and that the phosphorylation has physiological significance in controlling the interaction of amphiphysin with endocytic accessory proteins. SIGNOR-146906 0.402 HCRTR1 protein O43613 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257012 0.251 RAI1 protein Q7Z5J4 UNIPROT ARNTL protein O00327 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266843 0.32 LIMK1 protein P53667 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity phosphorylation -1 22214762 t miannu Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.  SIGNOR-276400 0.264 phosphatidic acid smallmolecule CHEBI:16337 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates chemical activation 9606 12401205 t gcesareni The pkc isoform pkc-zeta appear to be activated by direct interactions with pa SIGNOR-94867 0.8 M1_polarization phenotype SIGNOR-PH54 SIGNOR IL1B protein P01584 UNIPROT up-regulates 9606 BTO:0000801 32454942 f miannu Macrophages and microglia show a high plasticity and have been arbitrarily classified into “M1” (proinflammatory) and “M2” (prorepair, anti-inflammatory) phenotypes depending on their activation state, although it is now widely accepted that this classification is hugely oversimplified, particularly for microglia, and only partially reflects the real situation. According to the M1/M2 model, M1 polarized cells are characterized by the release of proinflammatory mediators, such as TNF, IL-1β, and IFNγ SIGNOR-263825 0.7 MAPK12 protein P53778 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR -1 9199504 t miannu Phosphorylation of tau by SAPK3 and SAPK4 markedly reduced the ability of tau to promote microtubule assembly. SAPK3 (also called ERK6 and p38) and SAPK4 phosphorylate recombinant tau protein at multiple Ser/Thr-Pro sites that are hyperphosphorylated in PHF-tau, with SAPK4 and SAPK3 being the most effective. SIGNOR-250084 0.512 SRC protein P12931 UNIPROT SHC1 protein P29353 UNIPROT up-regulates activity phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 8939605 t lperfetto Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway. SIGNOR-44870 0.657 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr345 LTAERIKtPPKRPGG 9606 21659531 t lperfetto Cdk1, which phosphorylates ezh2 at threonines 345 and 487.Phosphorylation of thr-345 and thr-487 promotes ezh2 ubiquitination and subsequent degradation by the proteasome SIGNOR-174054 0.586 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 9606 25486875 f lperfetto During fission, DRP1 is recruited from the cytosol to the outer mitochondrial membrane, where it assembles with FIS1 to constrict the mitochondrial tubule (2) SIGNOR-272975 0.7 CLCF1 protein Q9UBD9 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 BTO:0001271 9143707 t gcesareni Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-6 SIGNOR-47959 0.549 SLC2A1 protein P11166 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266038 0.367 CDK1 protein P06493 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C17 12676926 t gcesareni Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-99742 0.544 ATG16L1 protein Q676U5 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 20639872 t gcesareni Clathrin heavy-chain interacts with atg16l1, and is involved in the formation of atg16l1-positive early autophagosome precursors. SIGNOR-166702 0.468 NOTCH1 protein P46531 UNIPROT BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f gcesareni Other notch target genes identi__ed in the thymoma cell line were dtx1 (gene for deltex1), i__-202, i__-204, i__-d3, adam19 (meltrinb).24 a number of other genes have been reported as being notch targets, including notch1 itself,28 nrarp in xenopus embryos,29 bcl2 in thymoma cells,30 ccnd1 (gene for cyclin d1) in a kidney cell line,31 dkn1a (gene for cyclindependent kinase inhibitor 1a (p21, cip1)) in keratinocytes32 and tcf3 (gene for e2a). SIGNOR-149730 0.265 Class II MHC:Antigen complex SIGNOR-C429 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 31810556 f scontino Once they are formed, peptide/MHC class II molecules complexes are very stable and allow for sustained antigen presentation increasing the chances to encounter the matching CD4+ T lymphocytes. Once CD4+ T cells have become acti- vated, they in turn trigger macrophages to eliminate pathogens that have been previously internalized, and B lymphocytes to produce pathogen- specific antibodies. SIGNOR-267873 0.7 STK38 protein Q15208 UNIPROT AAK1 protein Q2M2I8 UNIPROT up-regulates activity phosphorylation Ser637 AGHRRILsDVTHSAV 10090 BTO:0000142 22445341 t miannu We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation. AAK1 phosphorylation regulates dendrite branching and length SIGNOR-263034 0.273 SSTR1 protein P30872 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256822 0.461 DDB2 protein Q92466 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates binding 9606 BTO:0000567 9418871 t miannu We show that ddb, a putative dna repair protein, associates with the activation domain of e2f1 / expression of ddb specifically stimulated e2f1-activated transcription SIGNOR-54102 0.372 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000801 24352507 t lperfetto We finally confirmed that in the absence of HIF-1α there was a significant reduction at the protein level in pro-caspase-1, activated caspase-1, pro-IL-1β, and ultimately active IL-1β (Fig. 4g and h). These data show that adenosine induced up-regulation of IL-1β is dependent on a CREB/HIF-1α pathway which is distinct from the NF-kB pathway used for initial production of IL-1β in response to LPS. SIGNOR-251718 0.341 glutamic acid smallmolecule CHEBI:18237 ChEBI GRM1 protein Q13255 UNIPROT up-regulates activity chemical activation 9606 25042998 t miannu Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate SIGNOR-264069 0.8 CDK2 protein P24941 UNIPROT SP1 protein P08047 UNIPROT up-regulates activity phosphorylation Ser59 GGQESQPsPLALLAA 10090 BTO:0000944 11598016 t gcesareni Mutation of Sp1 Ser59 abrogates the cyclin A€“CDK augmentation of Sp1-dependent transcriptional transactivation SIGNOR-248232 0.43 TOMM22 protein Q9NS69 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267679 0.775 FUBP1 protein Q96AE4 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 26490982 f irozzo The human far upstream element (FUSE) binding protein 1 (FUBP1) belongs to an ancient family which is required for proper regulation of the c-Myc proto-oncogene. Our results indicated that FUBP1 may potentially stimulate c-Myc expression in ESCC and its expression may promote ESCC progression. SIGNOR-259123 0.42 AURKB protein Q96GD4 UNIPROT ZWINT protein O95229 UNIPROT up-regulates activity phosphorylation Ser262 MGRDPGVsFKAVGLQ -1 21775627 t lperfetto Zwint-1 is a novel Aurora B substrate required for the assembly of a dynein-binding platform on kinetochores|During prometaphase, AurB phosphorylation of zwint-1 is required for recruitment of ZW10-, pT89 dynein-, and RZZ-dependent proteins to kinetochores. This is defective after AurB inhibition or after expression of the triple-A zwint-1 mutant. Triple-E mutant zwint-1 mimics phospho–zwint-1 in RZZ recruitment, even after AurB inhibition SIGNOR-265011 0.643 PKA proteinfamily SIGNOR-PF17 SIGNOR SLC2A2 protein P11168 UNIPROT down-regulates activity phosphorylation Ser491 VPETKGKsFEEIAAE 9534 8626492 t miannu GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity. SIGNOR-250049 0.2 SMURF1 protein Q9HCE7 UNIPROT PARD6/SMURF1 complex SIGNOR-C112 SIGNOR form complex binding 9606 BTO:0004183 15761148 t lperfetto The Par6-Smurf1 complex then mediates the localized ubiquitination of RhoA to enable the TGF_-dependent dissolution of tight junctions during EMT. SIGNOR-227562 0.629 CLK2 protein P49760 UNIPROT CLK2 protein P49760 UNIPROT up-regulates phosphorylation Ser142 HSSRRAKsVEDDAEG 9606 BTO:0000567 20682768 t lperfetto Clk2 was reported to regulate its nuclear localization by autophosphorylating serine 141 SIGNOR-167344 0.2 ACACA protein Q13085 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 20952656 t miannu ACC catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting and first committed step in de novo fatty acid biosynthesis. Two isoforms of ACC exist in mammals, ACC1 and ACC2, and both enzymes function to carboxylate acetyl-CoA to form malonyl-CoA SIGNOR-267105 0.8 ABL1 protein P00519 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Tyr367 TYLQSRYyRAPEIIL 9606 25944899 t Manara The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage SIGNOR-260936 0.408 MAPK14 protein Q16539 UNIPROT CCND1 protein P24385 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins SIGNOR-166594 0.434 IL31 protein Q6EBC2 UNIPROT OSMR protein Q99650 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 BTO:0001253 15184896 t gcesareni Here we identify a four-helix bundle cytokine we have called interleukin 31 (il-31), which is preferentially produced by t helper type 2 cells. Il-31 signals through a receptor composed of il-31 receptor a and oncostatin m receptor. SIGNOR-125347 0.606 Dihydromorphine chemical CHEBI:4575 ChEBI OPRD1 protein P41143 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258788 0.8 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10428798 t lperfetto Within er af-1, serines 104, 106, and 118 represent potential cdk phosphorylation sites, and in this current study, we ascertain their importance in mediating cyclin a-cdk2-dependent enhancement of er transcriptional activity. SIGNOR-217292 0.426 AKT proteinfamily SIGNOR-PF24 SIGNOR YWHAZ protein P63104 UNIPROT unknown phosphorylation Ser58 VVGARRSsWRVVSSI 9606 BTO:0000007 11956222 t lperfetto Ese data indicate that pkb/akt phosphorylates ser-58 on 14-3-3zeta both in vitro and in intact cells. The functional relevance of this phosphorylation remains to be determined. SIGNOR-244381 0.2 ADNP protein Q9H2P0 UNIPROT SWI/SNF complex complex SIGNOR-C92 SIGNOR up-regulates quantity binding 9606 BTO:0000007 17878164 t miannu ADNP Co-precipitates with the SWI/SNF Complex through ADNP C-terminal Interaction. Down-regulation of ADNP by shRNA resulted in morphological changes that are in line with the fact that ADNP contains a homeodomain profile (2) and with the SWI/SNF complex function that is associated with cellular differentiation. Our results suggest that ADNP functionality plays a role in these changes. SIGNOR-266757 0.359 NFIX protein Q14938 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268886 0.2 MMP7 protein P09237 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu273 ANTPHLReLHLDNNK -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256352 0.6 CLTCL1 protein P53675 UNIPROT AP-2/clathrin vescicle complex SIGNOR-C249 SIGNOR form complex binding 9606 24789820 t lperfetto AP2 adaptor complexes, associated at the membrane with PtdIns(4,5)P2 (PIP2), recruit clathin triskelions to initiate lattice assembly.  SIGNOR-260662 0.724 PTPN9 protein P43378 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 20335174 t miannu Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. SIGNOR-277130 0.312 SRC protein P12931 UNIPROT PDCD6IP protein Q8WUM4 UNIPROT down-regulates activity phosphorylation Tyr319 KKDNDFIyHDRVPDL 9606 15557335 t miannu Src phosphorylation of Alix/AIP1 modulates its interaction with binding partners and antagonizes its activities. Phosphorylation of Alix by Src caused it to translocate from the membrane and cytoskeleton to the cytoplasm and reduced its interaction with binding partners SETA/CIN85, epidermal growth factor receptor, and Pyk2. SIGNOR-263201 0.398 2-(4-(4,4-Bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxylic acid methyl ester chemical CID:127728 PUBCHEM HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9760039 t miannu Several compounds proposed as ‘atypical’ antipsychoticagents were found to exhibit agonist activity at 5-HT1A EC values were greater than the respective Kvalues50i .21.8"5.8-fold difference,ns10 and a high degree of correlation was observed. All the compounds displayed high or marked bind-ing affinity at CHO-h5-HT1A receptors except for olanzapine, which exhibited a micromolar Kvalue at h5-HTi1A receptors (table3). SIGNOR-258949 0.8 MAPK3 protein P27361 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000007 14551213 t lperfetto The hematopoietic-specific Galpha16 protein has recently been shown to mediate receptor-induced activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727. Galpha16QL-induced STAT3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (ERK1), SIGNOR-249450 0.714 SRC protein P12931 UNIPROT PRKCI protein P41743 UNIPROT up-regulates phosphorylation Tyr280 LKKTDRIyAMKVVKK 9606 11713277 t llicata Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. SIGNOR-111924 0.52 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 25081058 t miannu In the present study, we demonstrated that PTPN18 specifically dephosphorylates HER2 pY 1112, pY 1196 and pY 1248 sites among ten HER2 and EGFR C-terminal tyrosine phosphorylation sites (XREF_FIG).|Taken together, these data suggest that PTPN18 promotes the proteasome dependent degradation of HER2 through K48 linked polyubiquitination. SIGNOR-277031 0.663 Ionizing radiation stimulus SIGNOR-ST16 SIGNOR CCDC6-RET fusion protein SIGNOR-FP9 SIGNOR up-regulates 9606 23128507 f miannu In PTC, genomic rearrangements juxtapose the RET tyrosine kinase domain to unrelated genes, thereby creating dominantly transforming oncogenes, denominated RET/PTC. The RET/PTC rearrangements are the 2nd most common genetic alteration described in PTC and observed in ∼13–43% of cases, mostly in pediatric cancers or in individuals exposed to ionizing radiation from nuclear accidents SIGNOR-251999 0.7 ritonavir chemical CHEBI:45409 ChEBI UGT1A1 protein P22309 UNIPROT down-regulates activity chemical inhibition 9606 21030469 t Luana Fourteen of the compounds studied inhibited both bilirubin and estradiol glucuronidation (Table 1). Among these 14 compounds, ritonavir, anthraflavic acid, levothyroxine, riluzole, baicalein, farnesol, 4′-OH-phenytoin, 4-methylumbelliferone, raltegravir, and 1-naphthol exhibited very similar IC50 values (differences less than 2-fold) on both bilirubin glucuronidation and estradiol-3-glucuronidation (Table 1). Ketoconazole, carvedilol, and niflumic acid exhibited more disparity with respect to inhibition of the two reactions in that these compounds exhibited at least a 2-fold higher IC50 value against bilirubin glucuronidation than against estradiol-3-glucuronidation. SN-38 only weakly inhibited bilirubin glucuronidation (IC50 = 356 μM) and seemed to be a partial inhibitor of estradiol-3-glucuronidation. SIGNOR-258154 0.8 PRKACA protein P17612 UNIPROT GRIK2 protein Q13002 UNIPROT up-regulates activity phosphorylation Ser715 FMSSRRQsVLVKSNE 9606 BTO:0000007 8094892 t miannu GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. SIGNOR-250315 0.2 AKT1 protein P31749 UNIPROT ADAR protein P55265 UNIPROT down-regulates activity phosphorylation Thr1033 RLGERLRtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276193 0.284 CTNNA3 protein Q9UI47 UNIPROT CDH1 protein P12830 UNIPROT up-regulates quantity relocalization 9606 BTO:0000586 21598020 t miannu Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14 SIGNOR-265492 0.558 GRM8 protein O00222 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264081 0.433 NFE2L3 protein Q9Y4A8 UNIPROT NQO1 protein P15559 UNIPROT down-regulates quantity by repression transcriptional regulation 15385560 t lperfetto Deletion mutation analysis revealed that Nrf3 repression of NQO1 gene expression required heterodimerization and DNA binding domains but not transcriptional activation domain of Nrf3. SIGNOR-268976 0.343 POFUT1 protein Q9H488 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 12909620 t Fucosylation gcesareni Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling. SIGNOR-254326 0.74 gamma-aminobutyric acid smallmolecule CHEBI:16865 ChEBI GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR up-regulates activity chemical activation 9606 18790874 t brain lperfetto Gamma-Aminobutyric acid (GABA1), the major inhibitory neurotransmitter in the brain, exerts its action via ionotropic GABAA and metabotropic GABAB receptors. GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). SIGNOR-263792 0.8 CD40 protein P25942 UNIPROT TRAF3 protein Q13114 UNIPROT up-regulates activity binding 9606 18635759 t lperfetto Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3. SIGNOR-250560 0.917 FYCO1 protein Q9BQS8 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates activity binding 9606 BTO:0000007 26468287 t Giulio The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures. SIGNOR-260598 0.57 CSNK1A1 protein P48729 UNIPROT GSK3B protein P49841 UNIPROT up-regulates activity binding 9606 SIGNOR-C110 22083140 t gcesareni In the absence of secreted wnt ligands, cytosolic beta-catenin is phosphorylated at ser45 by the priming kinase casein kinase 1 (ck1). Consequently, glycogen synthase kinase 3 (gsk3), in complex with axin and adenomatous polyposis coli (apc), phosphorylates beta-catenin at thr41, ser37, and ser33 apc cooperates with axin to promote the phosphorylation of b-catenin by gsk3 [which requires priming phosphorylation by casein kinase 1, alpha-isoform (ck1alpha)] SIGNOR-177233 0.569 YY1 protein P25490 UNIPROT SURF1 protein Q15526 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10858544 f miannu We show that although the Surf-1/Surf-2 promoter does not contain Myc binding sites (E-boxes), Myc over-expression, or the activation of a Myc-oestrogen receptor fusion protein, activates transcription in the Surf-1 direction and that this response to Myc requires a functional YY1 binding site. Our data suggest that the MAP kinase cascade is required for the stimulation of Surf-1 promoter activity and that the Myc-YY1 interaction mediates this response. SIGNOR-254614 0.314 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr31 SNYRAYAtEPHAKKK 9606 BTO:0000671 18986304 t llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). SIGNOR-182057 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR ETV1 protein P50549 UNIPROT up-regulates activity phosphorylation Ser216 PMYQRQMsEPNIPFP 9606 12213813 t lperfetto Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation. SIGNOR-252769 0.2 MMP14 protein P50281 UNIPROT F12 protein P00748 UNIPROT down-regulates quantity by destabilization cleavage Gly376 SMTRVVGgLVALRGA -1 10930399 t lperfetto The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage. SIGNOR-263610 0.334 TAL1 protein P17542 UNIPROT ANGPT2 protein O15123 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22792348 f miannu Here, we identified angiopoietin-2 (ang-2), which encodes a major regulator of angiogenesis, as a direct transcriptional target of tal1,lyl1and lmo2. Knockdown of any of the three transcription factors in human blood and lymphatic endothelial cells caused ang-2 mrna and protein down-regulation. SIGNOR-198279 0.2 PPM1L protein Q5SGD2 UNIPROT CERT1 protein Q9Y5P4 UNIPROT up-regulates activity dephosphorylation 9606 18165232 t miannu The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus. SIGNOR-277113 0.2 GRM2 protein Q14416 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264933 0.8 MLL-AF4 fusion protein SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT up-regulates activity binding 9606 BTO:0001133 18977325 t irozzo Recent studies have identified association of multiple MLL-fusion partners including AF4, AF9, and AF10 with DOT1L, a histone H3K79 methyltransferase.This leads to a model where MLL-AF4 recruits DOT1L to MLL target genes, and promotes methylation of H3K79 at loci with existing H3K4 methylation (i.e., by wildtype MLL or other H3K4 methyltransferases) thus stimulating transcriptional elongation of genes that are normally primed but not fully transcribed. SIGNOR-255871 0.2 REEP5 protein Q00765 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates activity binding 9606 27966653 t miannu In this study, we found that CXCR1 interacted with REEP5 and REEP6, but CXCR2 did not. Overexpression of REEP5 and REEP6 enhanced IL-8-stimulated cellular responses through CXCR1, whereas depletion of the proteins led to the downregulation of the responses. SIGNOR-261366 0.328 PRKCZ protein Q05513 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP. SIGNOR-249261 0.279 procaterol chemical CHEBI:135209 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Denopamine is the most selective ligand for β1-receptors, with regard to intrinsic activity and efficacy, and clenbuterol, procaterol, zinterol, AZ 40140d and salbutamol are more selective for the β2-adrenoceptor than the β1-adrenoceptor based on intrinsic activity and efficacy.  SIGNOR-257864 0.8 FAS protein P25445 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates 9606 9743501 f gcesareni Fas activation induced daxx to interact with ask1 SIGNOR-60167 0.695 NFIX protein Q14938 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268910 0.2 ADORA2B protein P29275 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257152 0.281 SAM complex complex SIGNOR-C422 SIGNOR TOM40 complex complex SIGNOR-C421 SIGNOR up-regulates activity binding 18423394 t lperfetto Homology searches led to the identification of human Sam50 that is required for the biogenesis of human Tom40 [69]. A similar involvement was reported for metaxin 1 and metaxin 2 [70], which are homologs of Sam37 and Sam35, respectively SIGNOR-267686 0.467 terbutaline chemical CHEBI:9449 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257870 0.8 KIF5B protein P33176 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272520 0.7 MAPK8 protein P45983 UNIPROT PKM protein P14618 UNIPROT up-regulates activity phosphorylation Thr365 CIMLSGEtAKGDYPL 9606 BTO:0002181 26258887 t miannu Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. SIGNOR-276933 0.377 ARNTL protein O00327 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253628 0.727 EGFR protein P00533 UNIPROT PKIA protein P61925 UNIPROT up-regulates phosphorylation Tyr8 MTDVETTyADFIASG 9606 1956339 t lperfetto The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency. SIGNOR-22455 0.309 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163912 0.343 CDON protein Q4KMG0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates activity binding 9606 BTO:0000222 19470755 t lperfetto Abl binds a proline-rich motif in cdo via its sh3 domain, and these regions of abl and cdo are required for their promyogenic effects. Cdo is important for full abl kinase activity SIGNOR-185762 0.504 PIM1 protein P11309 UNIPROT RP9 protein Q8TA86 UNIPROT unknown phosphorylation Ser212 KKRKHKSsKSNEGSD -1 10931201 t miannu PAP-1 was phosphorylated in vitro by Pim-1, but not a kinase-negative Pim-1 mutant. The two serine residues of PAP-1 at amino acids 204 and 206 near the C-terminus were phosphorylated by Pim-1. PAP-1 is thus thought to be a target protein for Pim-1 kinase. SIGNOR-263029 0.2 CFH protein P08603 UNIPROT CFB protein P00751 UNIPROT down-regulates activity binding 9606 19050261 t miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) SIGNOR-252142 0.505 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser465 LKHVTQSsRKLIRAD 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation SIGNOR-129304 0.315 GYPC protein P04921 UNIPROT 4.1 complex complex SIGNOR-C386 SIGNOR form complex binding 9606 BTO:0000424 33187473 t lperfetto The cytoskeleton plays a key role in maintaining the morphology and function of erythrocyte membranes. Many proteins, such as ankyrin, spectrin alpha- and beta-chains, proteins 4.1, or 4.1R and actin, cover the inner surface of the erythrocyte membrane to form two protein complexes, the ankyrin and protein 4.1 complex| the latter consists of Band 3 dimers binding Adducins alpha and beta, Glycophorin C, GLUT1 and Stomatin [15, 16] SIGNOR-266034 0.368 MSX2 protein P35548 UNIPROT DLX2 protein Q07687 UNIPROT down-regulates activity binding 10090 BTO:0000945 9111364 t 2 miannu We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities. SIGNOR-240932 0.397 AP-2 complex complex SIGNOR-C245 SIGNOR HIP1 protein O00291 UNIPROT up-regulates activity binding 10116 11517213 t Giorgia HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2.|Here we demonstrate that HIP1 colocalizes with markers of clathrin-mediated endocytosis in neuronal cells and is highly enriched on clathrin-coated vesicles (CCVs) purified from brain homogenates. HIP1 binds to the clathrin adaptor protein 2 (AP2) and the terminal domain of the clathrin heavy chain, predominantly through a small fragment encompassing amino acids 276–335 SIGNOR-260392 0.439 Av/b6 integrin complex SIGNOR-C179 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257725 0.585 AKT proteinfamily SIGNOR-PF24 SIGNOR WNK1 protein Q9H4A3 UNIPROT up-regulates phosphorylation Thr60 EYRRRRHtMDKDSRG 9606 16081417 t llicata Phosphorylation of wnk1 on thr-58 contributes to sgk1 activation. these data suggest that activation of sgk1 by wnk1 requires the catalytic activity of akt. SIGNOR-139391 0.2 NCAPH protein Q15003 UNIPROT Condensin I complex SIGNOR-C341 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263906 0.969 MAPK1 protein P28482 UNIPROT CDC42EP1 protein Q00587 UNIPROT unknown phosphorylation Ser195 RRSDSLLsFRLDLDL 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262766 0.2 belinostat chemical CHEBI:61076 ChEBI HDAC4 protein P56524 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257743 0.8 ATR protein Q13535 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 17526493 t gcesareni We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint. SIGNOR-155214 0.78 HES5 protein Q5TA89 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265147 0.538 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 9606 19864428 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1. SIGNOR-188907 0.719 AMPK complex SIGNOR-C15 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR down-regulates activity phosphorylation 9606 23863160 t lperfetto AMPK inhibits mTORC1 through two means: first, through phosphorylation of TSC2 to activate its GAP (GTPase-activating protein) activity that converts Rheb into an inactive GDP-bound state, thus switching off mitogenic stimulation of mTORC1 [31], and, secondly, through phosphorylation of raptor at Ser722 and Ser792, which leads to 14-3-3 protein binding and mTORC1 inhibition SIGNOR-209862 0.456 CREB5 protein Q02930 UNIPROT RDX protein P35241 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002816 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253809 0.2 MAPK3 protein P27361 UNIPROT JUND protein P17535 UNIPROT up-regulates phosphorylation Ser100 LGLLKLAsPELERLI 9606 22327296 t gcesareni Menin binds the jun family transcription factor jund and inhibits its transcriptional activity. The menin-jund interaction blocks jun n-terminal kinase (jnk)-mediated jund phosphorylation and suppresses jund-induced transcription. We found a role for phosphorylation of the ser100 residue of jund;jund phosphorylation were prevented by inhibitors of calcium, calmodulin, or erk1/2 kinase. SIGNOR-196034 0.467 IQSEC2 protein Q5JU85 UNIPROT ARF6 protein P62330 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000142 18164504 t miannu Here, we characterized IQ-ArfGEF/BRAG1, a guanine nucleotide exchange factor (GEF) for Arf6, in the mouse brain. In vivo Arf pull down assay demonstrated that IQ-ArfGEF/BRAG1 activated Arf6 more potently than Arf1.IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Taken together, IQ-ArfGEF/BRAG1 forms a postsynaptic protein complex containing PSD-95 and NMDA receptors at excitatory synapses, where it may function as a GEF for Arf6. SIGNOR-264906 0.466 Linsitinib chemical CID:11640390 PUBCHEM INSR protein P06213 UNIPROT down-regulates activity chemical inhibition 10090 24712877 t lperfetto Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β-cell functions, and β-cell proliferation in male mice SIGNOR-262029 0.8 SMARCA4 protein P51532 UNIPROT SMARCC1 protein Q92922 UNIPROT up-regulates binding 9606 10078207 t miannu The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added. SIGNOR-65441 0.949 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser108 DVEELTAsQREAAER 9606 19647517 t lperfetto Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry SIGNOR-187388 0.961 PPM1A protein P35813 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates dephosphorylation 9606 10644691 t lperfetto Pp2c utilizes axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that pp2c is a positive regulator of wnt signal transduction and mediates its effects through the dephosphorylation of axin. SIGNOR-227955 0.366 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252757 0.723 PPP4R3A protein Q6IN85 UNIPROT PPP4C protein P60510 UNIPROT up-regulates binding 9606 18715871 t gcesareni Our data demonstrate that pp4r4 forms a novel cytosolic complex with pp4c, independent from the complexes containing pp4r1, pp4r2.PP4R3, and alpha4, and that the regulatory subunits of pp4c have evolved different modes of interaction with the catalytic subunit. SIGNOR-180244 0.2 SP1 protein P08047 UNIPROT THBD protein P07204 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22406829 f miannu In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. The expression of TM is negatively regulated by NF-?B- and GSK3-?-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. SIGNOR-255216 0.2 CYP21A2 protein P08686 UNIPROT 11-deoxycortisol smallmolecule CHEBI:28324 ChEBI down-regulates quantity chemical modification 9606 BTO:0000050 25855791 t lperfetto Cytochrome P450 (P450)4 21A2 is the major steroid 21-hydroxylase, which catalyzes the 21-hydroxylation of progesterone and 17alpha-hydroxyprogesterone (17alpha-OH-progesterone) to form 11-deoxycorticosterone and 11-deoxycortisol, respectively SIGNOR-268644 0.8 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-267285 0.7 IL21R protein Q9HBE5 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 12093291 t gcesareni Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5 SIGNOR-90266 0.618 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI TEK protein Q02763 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194349 0.8 Ub:E1 (UBA1 substrate) complex SIGNOR-C495 SIGNOR UBE2I protein P63279 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271312 0.541 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10567431 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response to insulin and nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217056 0.752 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser171 PLCLSPAsSGSSASF 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248679 0.619 CSNK2A2 protein P19784 UNIPROT SET protein Q01105-2 UNIPROT down-regulates phosphorylation Ser9 SAPAAKVsKKELNSN 9606 23374587 t The effect has been demonstrated using Q01105-2 miannu Ckii-mediated phosphorylation at ser9 hinders nuclear import of set SIGNOR-200802 0.261 PHLPP1 protein O60346 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 BTO:0001544 19261608 t The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells. SIGNOR-248330 0.64 SMARCA1 protein P28370 UNIPROT HNuRF complex SIGNOR-C448 SIGNOR form complex binding 9606 BTO:0000007 14609955 t miannu hNURF is a chromatin remodeler. Here, we describe the purification of the first human SNF2L complex. The subunit composition suggests that it represents the human ortholog of the dNURF complex. In this regard, the hNURF complex also contains BPTF and RbAP46/48. Surprisingly, hNURF does not contain the inorganic pyrophosphatase protein NURF38. Nonetheless, the biochemical activity of hNURF is similar as it displayed predominantly nucleosome-stimulated ATPase activity, as well as potent chromatin-remodeling activity on oligonucleosomal arrays. SIGNOR-268818 0.694 GLUD2 protein P49448 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity chemical modification 9913 11254391 t miannu Glutamate dehydrogenase is found in all organisms and catalyses the oxidative deamination of l-glutamate to 2-oxoglutarate. SIGNOR-268557 0.8 CDK7 protein P50613 UNIPROT POU5F1 protein Q01860 UNIPROT up-regulates quantity by stabilization phosphorylation Ser12 LASDFAFsPPPGGGG 9606 BTO:0001086 31306665 t lperfetto Here, we combined molecular and cellular biology with CRISPR/Cas9-mediated genome engineering to pinpoint the function of serine 12 of OCT4 in ESCs. Using chemical inhibitors and an antibody specific to OCT4 phosphorylated on S12, we identified cyclin-dependent kinase (CDK) 7 as upstream kinase. |Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2. SIGNOR-264404 0.2 GABA-A (a4-b2-d) receptor complex SIGNOR-C326 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263774 0.7 PAMPs stimulus SIGNOR-ST11 SIGNOR NLRC4 inflammasome complex SIGNOR-C223 SIGNOR up-regulates activity 16037825 f miannu Among these sensors, members of the evolutionary conserved NLRs, together with AIM2 and pyrin, can assemble into a multimeric protein complex that is called the inflammasome (see poster).| An inflammasome assembles in response to a diverse range of pathogen-associated or danger-associated molecular patterns (PAMPs or DAMPs). The inflammasome platform leads to activation of caspase-1 through proximity-induced self-cleavage SIGNOR-263124 0.7 AURKA protein O14965 UNIPROT MAP9 protein Q49MG5 UNIPROT up-regulates phosphorylation Ser625 RKQKKRHsFLESEAL 9606 17925329 t llicata Asap is a novel substrate of the oncogenic mitotic kinase aurora-a: phosphorylation on ser625 is essential to spindle formation and mitosis. SIGNOR-158210 0.331 GPC6 protein Q9Y625 UNIPROT PTCH1 protein Q13635 UNIPROT up-regulates activity binding 9606 31756413 t miannu Based on results from in vitro experiments, we had previously proposed that GPC6 stimulates Hh signaling by interacting with Hh and Patched1 (Ptc1), and facilitating/stabilizing their interaction. SIGNOR-264031 0.355 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 SIGNOR-C9 15241418 t llicata We found that ser 203 and ser 207 were phosphorylated by map kinase and that thr 178 was phosphorylated mostly by cdk and to a lesser extent by map kinase SIGNOR-126748 0.74 JUN protein P05412 UNIPROT HSD3B2 protein P26439 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001555 19022561 f miannu We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters. SIGNOR-254874 0.273 GNAQ protein P50148 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT up-regulates activity binding 10090 BTO:0000944 12024019 t Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. SIGNOR-256520 0.427 FGFR4 protein P22455 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 10918587 t Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3. SIGNOR-251142 0.408 D-106669 chemical CID:16048654 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-252649 0.8 SYK protein P43405 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates activity phosphorylation Tyr289 SSCGSSGyFSSSPTL 9606 BTO:0002181 34634301 t miannu We found that tyrosine (Tyr) 289 phosphorylation of DEPTOR impairs its interaction with mTOR, leading to increased mTOR activation. Using proximity biotinylation assays, we identified SYK (spleen tyrosine kinase) as a kinase involved in DEPTOR Tyr 289 phosphorylation in an ephrin (erythropoietin-producing hepatocellular carcinoma) receptor-dependent manner. SIGNOR-277572 0.2 UMPS protein P11172 UNIPROT orotic acid smallmolecule CHEBI:16742 ChEBI down-regulates quantity chemical modification 9606 18020427 t miannu Orotate phosphoribosyltransferase (OPRTase, EC 2.4.2.10) catalyzes the Mg2+-dependent condensation of orotic acid (OA) with PRPP (5-alpha-d-phosphorylribose 1-diphosphate) to yield diphosphate (PPi) and the nucleotide OMP (orotidine 5'-monophosphate). SIGNOR-253580 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Met-tRNA(Met) chemical CHEBI:16635 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270398 0.8 GPHN protein Q9NQX3 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR up-regulates quantity by stabilization binding 10116 BTO:0000938 21994384 t miannu we demonstrate that GABA(A)Rs and gephyrin are intimately associated at inhibitory synapses in cultured rat neurons. Our results suggest that the direct binding of gephyrin to residues 360-375 of the α1 subunit and its modulation are likely to be important determinants for the stabilization of GABA(A)Rs at synaptic sites, thereby modulating the strength of synaptic inhibition. SIGNOR-264964 0.2 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2A protein Q02078 UNIPROT down-regulates binding 9606 21902831 t lperfetto In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-216960 0.27 CHD4 protein Q14839 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263856 0.831 KAT2B protein Q92831 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates binding 9606 11058129 t gcesareni P/caf was found to interact directly with smad3 in vitro. Moreover, smad2 and smad3 interacted with p/caf upon tgf-beta type i receptor activation in cultured mammalian cells. these results demonstrate the co-activator function of p/caf for smad2 and smad3. SIGNOR-83607 0.668 AFF4 protein Q9UHB7 UNIPROT AEP complex complex SIGNOR-C117 SIGNOR form complex binding 9606 BTO:0000664 20153263 t 1 miannu These data demonstrate that AF4, AF5q31 and ENL associate in an endogenous higher-order complex (hereafter referred to as AEP for the AF4 family/ENL family/P-TEFb complex) containing P-TEFb in hematopoietic lineage cells. SIGNOR-239224 0.548 ACOT4 protein Q8N9L9 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI down-regulates quantity chemical modification 33148467 t lperfetto The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). SIGNOR-271807 0.8 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK4 protein Q13043 UNIPROT up-regulates phosphorylation 9606 23431053 t milica In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2. SIGNOR-230710 0.2 GSK3B protein P49841 UNIPROT NACA protein E9PAV3 UNIPROT down-regulates phosphorylation Thr2022 NIQENTQtPTVQEES 9606 BTO:0000007 15005626 t gcesareni Gsk3 beta-dependent phosphorylation of the alpha nac coactivator regulates its nuclear translocation and proteasome-mediated degradation. SIGNOR-123262 0.2 DLL4 protein Q9NR61 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates activity binding 9606 BTO:0000776 16140393 t lperfetto Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. SIGNOR-209744 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1941 SPKGSTYsPTSPGYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203604 0.773 CDK2 protein P24941 UNIPROT TP73 protein O15350 UNIPROT down-regulates activity phosphorylation Thr86 AASASPYtPEHAASV 9606 SIGNOR-C16 12676926 t gcesareni Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73.Furthermore, cyclin a/cdk1/2, cyclin b/cdk1/2, and cyclin e/cdk2 complexes can phosphorylate multiple p73 isoforms in vitro at threonine 86. SIGNOR-99746 0.563 FGB protein P02675 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR form complex binding -1 25427968 t lperfetto Fibrinogen is a plasma glycoprotein mainly synthesised by hepatocytes and circulating as a 340-kDa hexamer consisting of two sets of three different polypeptide chains (Aalpha, Bbeta, and gamma, encoded by the FGA, FGB, and FGG gene, respectively). SIGNOR-263391 0.758 WDFY3 protein Q8IZQ1 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 22653340 f miannu ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. SIGNOR-266794 0.7 PRKCA protein P17252 UNIPROT PRKAA1 protein Q13131 UNIPROT down-regulates activity phosphorylation Ser496 ATPQRSGsVSNYRSC -1 27784766 t miannu Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. SIGNOR-276459 0.2 PRKCE protein Q02156 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation SIGNOR-129308 0.315 AKT1 protein P31749 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 SIGNOR-C7 17964260 t gcesareni Akt1 and 2 promote the association of myod with p300 and pcaf acetyltransferases, via direct phosphorylation of p300. SIGNOR-158624 0.69 DUSP2 protein Q05923 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 8626452 t gcesareni We show that the in vivo substrate specificities of individual phosphatases are unique. Pac1, mkp-2, and mkp-1 recognize erk and p38, erk and jnk, and erk, p38, and jnk, respectively SIGNOR-40918 0.613 PDX1 protein P52945 UNIPROT INS protein P01308 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 11309388 t In conclusion, Pdx1 confers the expression of pancreatic β-cell-specific genes, such as genes encoding insulin, islet amyloid polypeptide, Glut2, and Nkx6.1. SIGNOR-255541 0.635 CYLD protein Q9NQC7 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity deubiquitination 10090 29291351 t gianni Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. SIGNOR-266437 0.627 MBD1 protein Q9UIS9 UNIPROT ALOX5 protein P09917 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001412 19781662 f Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation.|Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. SIGNOR-254030 0.2 PTEN protein P60484 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity dephosphorylation Ser380 EPDHYRYsDTTDSDP 9606 22413754 t miannu Overall, our results suggest that PTEN autodephosphorylation may be a critical event in this process; thus a major protein substrate for PTEN may be PTEN itself.|Various studies have demonstrated that PTEN is itself a phosphoprotein, and that the major sites of phosphorylation are found in an acidic stretch (DHYRYSDTTDSDPENE) near the C-terminus [1]. This prompted us to consider whether PTEN may autodephosphorylate these sites SIGNOR-248544 0.2 PRKACA protein P17612 UNIPROT ARPP21 protein Q9UBL0 UNIPROT up-regulates activity phosphorylation Ser58 QERRKSKsGAGKGKL -1 10854908 t miannu The specificity of antibody G534 was examined using recombinant full-length rat ARPP-21 phosphorylated by PKA. Radiolabeled ARPP-21 from a reaction containing [γ32P]ATP correlated with the detection of phospho-Ser55-ARPP-21 by immunoblotting (Fig. 1A, left and middle panels). SIGNOR-263107 0.2 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser117 SFSLEEKsKISKNRV 9606 20573420 t lperfetto Here, we show that polo-like kinase 1 (plk1) is a novel interacting protein of pinx1. Plk1 interacts with and phosphorylates pinx1 in vivo and in vitro. Moreover, plk1-mediated phosphorylation of pinx1 at five phosphorylation sites is essential for its plk1-induced degradation. SIGNOR-166321 0.367 HIF1A protein Q16665 UNIPROT IL1B protein P01584 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 17548584 t svumbaca The loss of macrophage expression of HIF-1 led to significant decreases in the production of TNF-a, IL-1a, IL-1b, and IL-12 SIGNOR-256235 0.341 IGF1R protein P08069 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates 9606 15829723 f apalma Mechanical loading increases IGF-I release, and IGF-I can stimulate Ca2+ influx and thereby activate calcineurin SIGNOR-255100 0.8 IL1A protein P01583 UNIPROT TNF protein P01375 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000667 19005488 f miannu UVB and proinflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. UVB and IL-1alpha treatment synergistically enhanced TNF-alpha secretion and mRNA levels in human keratinocytes, similar to the findings reported previously in human fibroblasts. SIGNOR-252209 0.502 HDAC1 protein Q13547 UNIPROT HES1 protein Q14469 UNIPROT down-regulates quantity transcriptional regulation 10090 18762022 f These data suggest that the GR recruits cellular HDAC activities to the Hes1 promoter, thereby conferring transcriptional repression in response to GC signaling. SIGNOR-253054 0.374 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 30029643 t Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated SIGNOR-256255 0.681 IKBKB protein O14920 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t gcesareni Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway SIGNOR-252948 0.683 CRYBB2 protein P43320 UNIPROT CRYBB2 protein P43320 UNIPROT up-regulates activity binding 9606 16319073 t miannu βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency. SIGNOR-252154 0.2 GSK3B protein P49841 UNIPROT MAP3K11 protein Q16584 UNIPROT up-regulates activity phosphorylation Ser789 VSAGPRPsPLPSPQP 9606 BTO:0000007 17711861 t miannu  The activation of MLK3 by GSK-3beta occurred via phosphorylation of MLK3 on two amino acid residues, Ser(789) and Ser(793), that are located within the C-terminal regulatory domain of MLK3.  SIGNOR-276071 0.339 DNA polymerase epsilon complex SIGNOR-C377 SIGNOR DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9534 BTO:0004055 12930972 f lperfetto Processive DNA synthesis by DNA polymerases delta and epsilon requires the cellular replication factor C (RF‐C) and proliferating cell nuclear antigen (PCNA). SIGNOR-265514 0.7 SGO1 protein Q5FBB7 UNIPROT Cohesin complex complex SIGNOR-C304 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000567 24055156 t lperfetto The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl. SIGNOR-265264 0.2 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12370315 f gcesareni It has been shown that maml1 binds directly to the ankyrin repeat region of notch1 and forms a dna-binding complex with icn and csl SIGNOR-94029 0.922 AP-2 complex complex SIGNOR-C245 SIGNOR ITSN1 protein Q15811 UNIPROT up-regulates activity binding 10116 BTO:0000142 15496985 t Giorgia Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples SIGNOR-260397 0.649 ARHGAP5 protein Q13017 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260461 0.824 HNF1B protein P35680 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity binding 9606 BTO:0000007 9671480 t 2 miannu The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays. SIGNOR-241323 0.377 RPS6KB1 protein P23443 UNIPROT EEF2K protein O00418 UNIPROT down-regulates activity phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 11500364 t lperfetto We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity SIGNOR-109712 0.73 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser374 GLEQAILsPGQNSGN 9606 22966201 t llicata Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress. SIGNOR-198988 0.326 PRKAR1A protein P10644 UNIPROT PRKACA protein P17612 UNIPROT down-regulates activity binding 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258751 0.883 RNF7 protein Q9UBF6 UNIPROT NF1 protein P21359 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271453 0.251 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244854 0.8 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270407 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR YY1 protein P25490 UNIPROT up-regulates activity acetylation -1 11486036 t miannu Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs. SIGNOR-268834 0.644 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257967 0.8 CREBBP protein Q92793 UNIPROT CSK protein P41240 UNIPROT up-regulates binding 9606 10801129 t gcesareni Here we present cbp--a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the sh2 domain of csk. Cbp is involved in the membrane localization of csk and in the csk-mediated inhibition of c-src. SIGNOR-77139 0.522 SOCS1 protein O15524 UNIPROT JAK2 protein O60674 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 14522994 t lperfetto Shp-2 regulates socs-1-mediated janus kinase-2 ubiquitination/degradation downstream of the prolactin receptor SIGNOR-118407 0.79 malonyl-CoA smallmolecule CHEBI:15531 ChEBI long-chain fatty acid anion smallmolecule CHEBI:57560 ChEBI up-regulates quantity precursor of 9606 15507492 t Human fatty acid synthase (FAS) is a complex homodimeric (552-kDa) enzyme that regulates the¬†de novo¬†biosynthesis of long-chain fatty acids. This cytosolic enzyme catalyzes the formation of 16 carbon (C16) palmitate, from acetyl-coenzyme A (acetyl-CoA) and malonyl-coenzyme A (malonyl-CoA) in the presence of NADPH.¬† SIGNOR-267210 0.8 NUP160 protein Q12769 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262094 0.704 ASXL3 protein Q9C0F0 UNIPROT KDM1A protein O60341 UNIPROT down-regulates activity binding 9606 25450400 t miannu Here, we showed that ASXL3 interacts with HP1α and LSD1, leading to transcriptional repression. SIGNOR-266764 0.268 TRAF6 protein Q9Y4K3 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates activity binding 9606 BTO:0001370 29733298 t miannu Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways.  SIGNOR-273656 0.2 SRC protein P12931 UNIPROT CNKSR1 protein Q969H4 UNIPROT up-regulates activity phosphorylation Tyr26 LDDSLQDyPFEDWQL 26319181 t lperfetto We identified Tyr 26 as a PDGF-induced and, additionally, Tyr 519 and Tyr 665 as SRC-induced tyrosine phosphorylation sites. Phosphomimetic mutants indicate that phosphorylation of Tyr 519 recruits CNK1 to the nucleus and additional phosphorylation of Tyr 26 enables CNK1 to promote SRE-dependent gene expression. SIGNOR-275919 0.493 PHGDH protein O43175 UNIPROT 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI up-regulates activity chemical modification 9606 25406093 t lperfetto PHDGH catalyzes the first reaction of de novo serine biosynthesis, producing 3-phosphohydroxypyruvate by NAD+-coupled oxidation of 3-phosphoglycerate (3PG).|The PHGDH reaction is reversible and, under standard conditions, thermodynamically favors the direction from 3-phosphohydroxypyruvate to 3PG. SIGNOR-268567 0.8 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser391 GAATPRTsQFTKYWT 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141002 0.2 AMPK complex SIGNOR-C15 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t lperfetto Mutation of serine 259 increased the basal raf-1 activity and rendered it largely resistant to inhibition by pka. SIGNOR-216523 0.3 ETNK2 protein Q9NVF9 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 36866238 t lperfetto Ethanolamine kinase 2 (ETNK2) is a protein-coding gene. Spondylometaphyseal dysplasia with cone-rod dystrophy is one of the diseases linked to the ETNKT2 gene. Glycerophospholipid biosynthesis and nuclear receptor meta-pathways are two of the ETNK2-related pathways. SIGNOR-275644 0.8 EPHB2 protein P29323 UNIPROT ARHGEF15 protein O94989 UNIPROT down-regulates quantity by destabilization phosphorylation Tyr353 PLQDEPLyQTYRAAV 9606 BTO:0000007 21029865 t miannu We have identified a RhoA guanine nucleotide exchange factor, Ephexin5, which negatively regulates excitatory synapse development until EphrinB binding to the EphB receptor tyrosine kinase triggers Ephexin5 phosphorylation, ubiquitination, and degradation. EphB2 mediates phosphorylation of Ephexin5 at tyrosine-361 SIGNOR-262864 0.494 DRAM2 protein Q6UX65 UNIPROT ROCK1 protein Q13464 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259144 0.2 CDK1 protein P06493 UNIPROT CDCA5 protein Q96FF9 UNIPROT down-regulates activity phosphorylation Ser164 TSTPGRRsCFGFEGL -1 23901111 t miannu Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.  SIGNOR-276120 0.704 STAT6 protein P42226 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 22025054 f lperfetto IL-4R signals through a JAKSTAT6 pathway, and many of the genes associated with mouse M2 macrophages are regulated by STAT6, including arginase 1 (Arg1), macrophage mannose receptor 1 (Mrc1; also known as Cd206), resistin-like-? (Retnla; also known as Fizz1) and chitinase 3-like 3 (Chi3l3; also known as Ym1). SIGNOR-249541 0.7 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity precursor of 9606 29084849 t miannu Asparagine synthetase (ASNS) converts aspartate and glutamine to asparagine and glutamate in an ATP-dependent reaction. ASNS is present in most, if not all, mammalian organs, but varies widely in basal expression. Human ASNS activity is highly responsive to cellular stress, primarily by increased transcription from a single gene located on chromosome 7. SIGNOR-268070 0.8 SYN3 protein O14994 UNIPROT ACTB protein P60709 UNIPROT up-regulates activity binding 9606 BTO:0000938 15265865 t miannu Synapsins, a family of neuron-specific phosphoproteins, have been demonstrated to regulate the availability of synaptic vesicles for exocytosis by binding to both synaptic vesicles and the actin cytoskeleton in a phosphorylation-dependent manner. SIGNOR-269183 0.2 DUSP7 protein Q16829 UNIPROT GHR protein P10912 UNIPROT down-regulates dephosphorylation 9606 12907755 t gcesareni Identification of protein tyrosine phosphatases with specificity for the ligand-activated growth hormone receptor. SIGNOR-104545 0.316 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT up-regulates activity phosphorylation Tyr420 RLIEDNEyTARQGAK -1 9425276 t Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. Tyr28 This site is also a Fyn autophosphorylation site When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn. SIGNOR-251167 0.2 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates activity 10090 BTO:0000452 16892090 f inferred from family member HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host SIGNOR-270309 0.7 BMPR1A protein P36894 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR form complex binding 9606 7791754 t lperfetto Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors (br-ia and br-ib) and the bmp type ii receptor (br-ii). SIGNOR-255257 0.552 F2RL3 protein Q96RI0 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256772 0.312 HSPA5 protein P11021 UNIPROT ERN1 protein O75460 UNIPROT down-regulates activity binding 9606 31226023 t miannu Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain SIGNOR-260176 0.817 ERO1B protein Q86YB8 UNIPROT ERP44 protein Q9BS26 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0000567 11847130 t Simone Here, we report the functional characterization of a novel UPR-induced ER resident protein (ERp44) that forms mixed disulfides with both hEROs, as well as with partially unfolded Ig subunits. SIGNOR-261048 0.2 MYLK2 protein Q9H1R3 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates activity phosphorylation Thr80 NEPHESRtNSDIVET 9606 BTO:0000007 21556048 t llicata Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis. SIGNOR-238118 0.408 LYN protein P07948 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates activity phosphorylation Tyr381 SESSDDDyDDVDIPT 9534 11514608 t BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. Tyr-379 within HPK1 is essential for binding to BASH and thus strongly suggest that the DDDYDDV sequence containing the phosphorylated Tyr-379 is the binding site for the BASH SH2 domain. SIGNOR-251403 0.385 RNF168 protein Q8IYW5 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 31225475 f miannu L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling. SIGNOR-266789 0.7 sphingosine 1-phosphate smallmolecule CHEBI:37550 ChEBI S1PR3 protein Q99500 UNIPROT up-regulates activity chemical activation 10116 10617617 t We observed that S1P treatment significantly increased proliferation of HTC4 hepatoma cells stably transfected with human S1P receptor Edg3 or Edg5, which was attributable to stimulation of cell growth and inhibition of apoptosis caused by serum starvation. SIGNOR-261142 0.8 SNRPD2 protein P62316 UNIPROT U1 snRNP complex complex SIGNOR-C480 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270685 0.934 AKAP8L protein Q9ULX6 UNIPROT mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 11402034 f miannu These results support the proposal that both RHA and HAP95 facilitated the nuclear export of unspliced, CTE-containing mRNA in human cells. we have extended this earlier study by mapping the functional domains of HAP95 and providing strong evidence for a direct role of HAP95 in RHA-mediated nuclear export of CTE-containing mRNA. SIGNOR-260953 0.7 HDAC2 protein Q92769 UNIPROT MECP2/SIN3A/HDAC complex complex SIGNOR-C360 SIGNOR form complex binding 9606 BTO:0000567 9620804 t Luana We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. SIGNOR-267736 0.715 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1871 SPKYSPTsPKYSPTS 9606 24746699 t lperfetto After PIC formation, Pol II initiates mRNA synthesis, but productive transcription requires Pol II to escape from the PIC and transit into transcription elongation. The transition between initiation and elongation is associated with phosphorylation at the serine 5 (Ser5) residues within the hepta-peptide repeats in the C-terminal domain (CTD) of the largest Pol II subunit. Ser5 phosphorylation is mediated primarily by Kin28, the kinase subunit of the general transcription factor TFIIH SIGNOR-269368 0.721 Complement C1 complex complex SIGNOR-C309 SIGNOR C4A protein P0C0L4 UNIPROT up-regulates activity cleavage Arg679 EKTTRKKrNVNFQKA -1 9087411 t lperfetto The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots. SIGNOR-263433 0.636 GABA-A (a6-b2-d) receptor complex SIGNOR-C328 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268608 0.268 TRADD protein Q15628 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates activity binding 9606 8612133 t lperfetto We show that tradd interacts strongly with rip;rip is a serinethreonine kinase that is recruited by tradd to tnfr1 in a tnf-dependent process. SIGNOR-40043 0.936 PI3K complex SIGNOR-C156 SIGNOR PIK3CD protein O00329 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-252720 0.613 Naltrindole chemical CHEBI:81528 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258818 0.8 ARVCF protein O00192 UNIPROT CDH2 protein P19022 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252128 0.474 IFNG protein P01579 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 32283152 f miannu High levels of expression of IL-1B, IFN-γ, IP-10, and monocyte chemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19. These inflammatory cytokines may activate the T-helper type 1 (Th1) cell response. Th1 activation is a key event in the activation of specific immunity. SIGNOR-261024 0.7 RPL35 protein P42766 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262466 0.859 DNM1L protein O00429 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 10090 BTO:0002295 31063459 t lperfetto Importantly, we found that crosstalk between phosphorylated Drp1S600 (p-Drp1S600) and the actin-binding protein com- plex Arp2/3 is a required step in mitochondrial Drp1 recruitment and mitochondrial fission under HG conditions. SIGNOR-262550 0.286 MAPK11 protein Q15759 UNIPROT EGFR protein P00533 UNIPROT down-regulates phosphorylation 9606 16932740 t gcesareni P38 map kinase mediates stress-induced internalization of egfrthe underlying mechanism entails phosphorylation of egfr at a short segment (amino acids 1002-1022) containing multiple serines and threonines, as well as phosphorylation of two rab5 effectors, eea1 and gdi. SIGNOR-149086 0.338 EDNRA protein P25101 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257427 0.456 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity dephosphorylation Thr387 TMKRRDEtMQPAKPS 9606 20513427 t PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. SIGNOR-248329 0.299 LAT protein O43561 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr161;Tyr200 DDYHNPGyLVVLPDS;SMESIDDyVNVPESG 11368773 t lperfetto By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively. SIGNOR-246060 0.804 SSTR3 protein P32745 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256820 0.437 IKZF3 protein Q9UKT9 UNIPROT LNPEP protein Q9UIQ6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003420 15894523 f miannu Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. SIGNOR-255405 0.2 perifosine chemical CHEBI:67272 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 BTO:0001130 14617782 t Perifosine causes decrease in Akt Ser473 and Thr308 phosphorylation gcesareni Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.| Our results demonstrate that Akt is an important cellular target of perifosine action. In addition, these studies show that the membrane translocation of certain PH domain-containing molecules can be greatly perturbed by the alkylphospholipid class of drugs and imply further that the PI3K/Akt pathway contributes to regulation of p21(WAF1/CIP1) expression. SIGNOR-119189 0.8 RAF1 protein P04049 UNIPROT EEF1A2 protein Q05639 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276407 0.2 MAP3K5 protein Q99683 UNIPROT MAP2K6 protein P52564 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 8974401 t lperfetto A MAP kinase kinase kinase (MAPKKK), termed ASK1, was identified that activated two different subgroups of MAP kinase kinases (MAPKK), SEK1 (or MKK4) and MKK3/MAPKK6 (or MKK6), which in turn activated stress-activated protein kinase (SAPK, also known as JNK; c-Jun amino-terminal kinase) and p38 subgroups of MAP kinases, respectively. SIGNOR-45353 0.602 SKIL protein P12757 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates activity binding 9606 12793438 t lperfetto The ski and snon protein family associate with and repress the activity of smad2, smad3, and smad4, three members of the tgf-fl signaling pathway SIGNOR-236099 0.796 F2 protein P00734 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Arg25 PLLSARTrARRPESK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263568 0.885 ROR2 protein Q01974 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates binding 9606 18667433 t gcesareni Wnt5a stimulation induces activation of the c-jun n-terminal kinase jnk at the wound edge in a ror2-dependent manner, and inhibiting jnk activity abrogates wnt5a-induced lamellipodia formation and mtoc reorientation SIGNOR-179671 0.446 PPP2R2C protein Q9Y2T4 UNIPROT SRC protein P12931 UNIPROT down-regulates activity binding 9606 BTO:0001938 18069897 t gcesareni We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC SIGNOR-247966 0.2 WDR83 protein Q9BRX9 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 15118098 t gcesareni Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex. SIGNOR-124476 0.512 NKX2-5 protein P52952 UNIPROT MYL2 protein P10916 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0003265 9043061 f The mammalian homolog of the Drosophila tinman homeobox gene, Nkx2-5, is specifi- cally required for ventricular chamber-specific myosin light chain-2 (MLC-2v) expression and looping morphogenesis during mammalian heart development. SIGNOR-253645 0.612 ETNK1 protein Q9HBU6 UNIPROT ethanolaminium(1+) smallmolecule CHEBI:57603 ChEBI down-regulates quantity chemical modification 36583229 t lperfetto ETNK1 encodes ethanolamine kinase 1, which is involved in the de novo biosynthesis of phosphatidylethanolamine and is responsible for the phosphorylation of ethanolamine to phosphoethanolamine SIGNOR-275642 0.8 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR RAD51 protein Q06609 UNIPROT up-regulates activity phosphorylation Tyr315 ETRICKIyDSPCLPE 9606 BTO:0002882 11684015 t lperfetto RAD51 is one of six mitotic human homologs of the E. coli RecA protein (RAD51-Paralogs) that play a central role in homologous recombination and repair of DNA double-strand breaks (DSBs).|Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance. SIGNOR-271707 0.2 TERT protein O14746 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR up-regulates 11327115 f lperfetto Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers SIGNOR-252292 0.7 HIF1A protein Q16665 UNIPROT ALAS2 protein P22557 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 21207956 f miannu Hypoxia-induced expression of erythroid-specific ALAS2 is mediated by HIF1 in erythroid cells. SIGNOR-254421 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser339 SPISTPTsPGSLRKH 9606 14741103 t llicata In order to determine the sites of phosphorylation by Cdk5, serine or threonine in the nine potential sites were substituted with alanine by site-directed mutagenesis to create mutant Dcx proteins. hese were analyzed by co-transfection of 293T cells with cdk5/p35. All-sites-A mutant Dcx showed no slower migrating species on Western analysis, indicating that removal of all nine possible sites is sufficient to block the phosphorylation by Cdk5/p35. However, each single mutant Dcx retains the slower migrating species similar to the wild-type Dcx, suggesting that any single mutation is not sufficient to block phosphorylation by Cdk5/p35. SIGNOR-250673 0.412 MAPK1 protein P28482 UNIPROT CDC42EP2 protein O14613 UNIPROT unknown phosphorylation Ser101 RELPDGPsPLLKNAI 10090 22028470 t miannu We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5'-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. With this improved methodology, we detected 98 sites directly phosphorylated by ERK2 on 80 proteins from NIH 3T3-L1 fibroblasts. Thirteen of these proteins are known substrates and the rest represent previously unknown kinase/substrate interactions. (table1) SIGNOR-262770 0.25 PHLPP2 protein Q6ZVD8 UNIPROT PRKCB protein P05771 UNIPROT down-regulates quantity dephosphorylation Ser661 QNEFAGFsYTNPEFV 9606 BTO:0000067 18162466 t gcesareni Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle SIGNOR-237039 0.331 CSNK2A1 protein P68400 UNIPROT GTF2A1 protein P52655 UNIPROT up-regulates activity phosphorylation Ser281 DGTGDTSsEEDEDEE -1 11278496 t llicata We now show that human TFIIA is phosphorylated in vivo on serine residues that are partially conserved between yeast and human TFIIA large subunits. Alanine substitution mutation of serine residues 316 and 321 in TFIIA alphabeta reduced TFIIA phosphorylation significantly in vivo. Additional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels. Mutation of all four serine residues reduced the ability of TFIIA to stimulate transcription in transient transfection assays with various activators and promoters, indicating that TFIIA phosphorylation is required globally for optimal function. SIGNOR-250875 0.384 CAPN3 protein P20807 UNIPROT CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR up-regulates activity cleavage 9606 25969760 t lperfetto Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain SIGNOR-251602 0.328 ABL1 protein P00519 UNIPROT RBM39 protein Q14498 UNIPROT up-regulates activity phosphorylation Tyr95 DRRFRGRyRSPYSGP 9606 BTO:0000007 27018250 t miannu In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner. SIGNOR-262609 0.326 PAH protein P00439 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-263989 0.8 GRM7 protein Q14831 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 29953871 t miannu Ca2+ is arguably the most important second messenger in the brain because of its pivotal roles in presynaptic neurotransmitter release, postsynaptic responses, and plasticity induction. iGluRs and mGluRs can generate intracellular Ca2+ signals, albeit by different mechanisms, whose crosstalk has not been thoroughly explored (Figure 2C). iGluRs allow the influx of extracellular Ca2+ upon pore opening. SIGNOR-264938 0.8 SCF-betaTRCP complex SIGNOR-C5 SIGNOR FOXP3 protein Q9BZS1 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys356 AILEAPEkQRTLNEI 9606 BTO:0002181 27432879 t miannu The ubiquitination site of Foxp3 is Lys356 SIGNOR-277246 0.261 PDGFRB protein P09619 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity phosphorylation Tyr320 RKDTKEIyTHFTCAT -1 33139573 t miannu RTKs directly phosphorylate Gαi on Y154, 155, and Y320. SIGNOR-277234 0.2 CDC42BPA protein Q5VT25 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 19851336 t lperfetto More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above. SIGNOR-188781 0.526 PKM protein P14618 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI down-regulates quantity chemical modification 9606 15996096 t miannu Pyruvate kinase (PK)1 is an important regulatory enzyme that is able to generate ATP under hypoxic conditions as well as regulate glucose consumption. Pyruvate kinase catalyzes the last step in glycolysis converting the substrate phosphoenolpyruvate (PEP) into pyruvate, while producing one molecule of ATP per reaction per cycle (Figure 1A). SIGNOR-266534 0.8 SMAD1/4 complex SIGNOR-C85 SIGNOR PPARG protein P37231 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004058 12589053 f lperfetto Overexpression of Smad6, a natural antagonist for Smad1, blocked PPARgamma expression and adipocytic differentiation induced by BMP2 SIGNOR-236233 0.288 entinostat chemical CHEBI:132082 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257963 0.8 RASGRF2 protein O14827 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260575 0.542 MAPK3 protein P27361 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 10347142 t gcesareni Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation SIGNOR-67634 0.709 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Tyr659 VADERVDyVVVDQQK 9606 BTO:0000018 10734310 t miannu Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF. SIGNOR-250290 0.666 CDK1 protein P06493 UNIPROT KRT18 protein P05783 UNIPROT up-regulates phosphorylation Ser34 RPVSSAAsVYAGAGG 9606 9524113 t lperfetto We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins SIGNOR-55994 0.342 NF1 protein P21359 UNIPROT ADCY9 protein O60503 UNIPROT up-regulates 9606 BTO:0000938 24431436 f miannu Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation SIGNOR-204354 0.308 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Ser1064 SCPIKEDsFLQRYSS 9606 BTO:0000007 10347170 t llicata  We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.  SIGNOR-250619 0.375 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT down-regulates quantity phosphorylation Ser623 NRHSLPFsLPSQMEP 9606 BTO:0000782 11024037 t lperfetto However, under normal conditions, PKC activation resulting from CD43 engagement was required to activate the MAPK pathway, suggesting that phosphorylation of Cbl on serine residues by PKC and its association with 14-3-3 molecules may play a role in preventing the Cbl inhibitory effect on the Ras-MAPK pathway.  SIGNOR-249055 0.325 CASP3 protein P42574 UNIPROT STK4 protein Q13043 UNIPROT up-regulates activity cleavage Asp349 RVASTMTdGANTMIE 9534 BTO:0004055 11517310 t lperfetto In response to apoptotic stimuli, caspase cleavage of mst1 occurs at asp-326 and asp-349, resulting in the separation of its n-terminal kinase domain from the nes-containing c-terminal domain. Thus, caspase cleavage of mst1 serves two purposes: one is activation of mst1 kinase activity and the other is translocation of mst1 into the nucleus. SIGNOR-109878 0.606 ERG protein P11308 UNIPROT SPP1 protein P10451 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 21669963 f miannu Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter. SIGNOR-254066 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD86 protein P42081 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19164127 f miannu We found that upon TLR7 and TLR8 activation, JNK and NF-kappaB positively regulated the expression of CCR7, CD86, CD83, and CD40 and the production of IL-6 and IL-12p40. SIGNOR-254782 0.294 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-207830 0.8 ZNF292 protein O60281 UNIPROT GH1 protein P01241 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 10687855 t lperfetto Rat Zn-15 is a transcription factor activating GH gene expression by synergistic interactions with Pit-1, named for 15 DNA-binding zinc fingers, including fingers IX, X, and XI that are responsible for GH promoter binding. SIGNOR-268969 0.2 SMO protein Q99835 UNIPROT GNB2 protein P62879 UNIPROT up-regulates binding 9606 16885213 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-148589 0.2 PMS1 protein P54277 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates activity 10090 9500552 f Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues appear to be responsible for most cases of hereditary non-polyposis colorectal cancer SIGNOR-257597 0.7 RPS6KA3 protein P51812 UNIPROT WWC1 protein Q8IX03 UNIPROT up-regulates phosphorylation Thr929 STIIRSKtFSPGPQS 9606 BTO:0000149 24269383 t llicata Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2. SIGNOR-203306 0.2 PPP2CB protein P62714 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 9606 18160256 t Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A. SIGNOR-248610 0.481 SLC16A4 protein O15374 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 26384349 f lperfetto Treatment with _-cyano-4-hydroxy cinnamate (CHC), a known inhibitor of MCT1, MCT2 and MCT4, dose-dependently induced cell death in MM cell lines and primary MM cells (Figure 1C). Thus, monocarboxylate transportation across membranes appears crucial for MM cell survival. SIGNOR-242519 0.7 HDAC1 protein Q13547 UNIPROT SNAI2 protein O43623 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 18588516 f miannu The down-regulation of slug in the ERalpha-positive MCF-7 cell line was mediated by direct repression of slug transcription by the formation of a co-repressor complex involving ligand-activated ERalpha protein, HDAC1 (histone deacetylase 1) and N-CoR (nuclear receptor co-repressor). SIGNOR-254228 0.602 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MASTL protein Q96GX5 UNIPROT up-regulates activity phosphorylation Thr207 PRQDYSRtPGQVLSL 8355 22354989 t gcesareni We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop SIGNOR-249652 0.519 SRC protein P12931 UNIPROT BAIAP2L1 protein Q9UHR4 UNIPROT up-regulates activity phosphorylation Tyr274 SNVVRKDyDTLSKCS -1 21840312 t miannu Here, we report that overexpression of IRTKS increases the speed of wound closure of HT1080 cells in a Src-dependent manner. Active Src phosphorylates IRTKS in vivo and in vitro. Deletion mapping and mutation analysis revealed that six tyrosine residues (Y37, Y156, Y163, Y274, Y293 and Y439) were Src-stimulated phosphorylation sites on IRTKS. Disruption of Src-stimulated IRTKS phosphorylation abolished the effect of IRTKS on wound closure. Collectively, these data suggest Src-stimulated IRTKS phosphorylation is essential for its function in cell motility. SIGNOR-263039 0.396 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Thr24 LPRPRSCtWPLPRPE -1 BTO:0000318 10377430 t lperfetto Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export. SIGNOR-252857 0.909 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr362 SPPAEDVyDVPPPAP 10090 12972425 t lperfetto Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs SIGNOR-246409 0.799 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI up-regulates quantity precursor of 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266250 0.8 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCQ protein Q04759 UNIPROT up-regulates activity binding 9606 14967450 t PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. lperfetto The molecular requirements for diacylglycerol (dag) and calcium (ca2+) to promote pkc membrane translocation, the hallmark of pkc activation, have been clarified. SIGNOR-242596 0.8 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR HIRA protein P54198 UNIPROT up-regulates phosphorylation Thr555 LSPSVLTtPSKIEPM 9606 11238922 t lperfetto Hira bound to and was phosphorylated by cyclin a- and e-cdk2 in vitrohira became phosphorylated on threonine 555 in s phase when cyclin-cdk2 kinases are active.ectopic expression of hira in cells caused arrest in s phase and this is consistent with the notion that it is a cyclin-cdk2 substrate that has a role in control of the cell cycle. SIGNOR-216670 0.329 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr573 AENGLLMtPCYTANF 9606 9687510 t lperfetto Thus, MAPK1/ERK1 and MAPK2/ERK2 activate three closely related protein kinases known as MAPK_activated protein kinases_1a, _1b and _1c (MAPKAP_K1a/b/c; also known as RSK1/2/3) SIGNOR-252753 0.755 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12217858 t gcesareni Addition of active c-src and [32p]atp to the purified romk1 protein resulted in the phosphorylation of the romk1 protein. However, c-src did not phosphorylate r1y337a in which tyrosine residue 337 was mutated to alanine. Furthermore, phosphopeptide mapping identified two phosphopeptides from the trypsin-digested romk1 protein. SIGNOR-92513 0.316 HECTD3 protein Q5T447 UNIPROT MALT1 protein Q9UDY8 UNIPROT up-regulates quantity by stabilization polyubiquitination 9606 BTO:0000007 23358872 t miannu HECTD3 promotes MALT1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the MALT1 through its N-terminal destruction of cyclin domain. HECTD3 does not target MALT1 for degradation but stabilize it.  SIGNOR-272096 0.371 AP-2 complex complex SIGNOR-C245 SIGNOR GABA-A proteinfamily SIGNOR-PF61 SIGNOR down-regulates quantity relocalization 9606 BTO:0000938 25600368 t miannu The endocytosis of GABAARs is regulated by the interaction of the AP2 complex with β and γ2 subunits. Phosphorylation of β3 (S408/S409) and γ2 (Y365/Y367) by PKA/PKC and Src/Fyn, respectively, prevents binding to AP2 and thus stabilizes these receptors at the cell surface. SIGNOR-264990 0.2 TBK1 protein Q9UHD2 UNIPROT DDAH2 protein O95865 UNIPROT down-regulates activity phosphorylation Ser245 GGGDLPNsQEALQKL 33850055 t lperfetto TANK-binding kinase 1 (TBK1), a kinase downstream of MAVS, inhibited DDAH2 by phosphorylating DDAH2 at multiple sites. |The T203D, T211D, S245D, and S253D mutations significantly reduced the inhibitory effect of DDAH2 on RLR signaling, suggesting that phosphorylation of these residues was critical for DDAH2 to inhibit activation o SIGNOR-275648 0.2 TFEB protein P19484 UNIPROT GBA protein P04062 UNIPROT up-regulates quantity by expression transcriptional regulation 28552616 t lperfetto Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants SIGNOR-276551 0.33 UTS2R protein Q9UKP6 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256922 0.251 COP1 protein Q8NHY2 UNIPROT COP1 protein Q8NHY2 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001938 19805145 t miannu MTA1 destabilizes COP1 by promoting its autoubiquitination. in addition to polyubiquitination of its substrates, COP1 also catalyzes its autoubiquitination for degradation as a part of an autoregulatory mechanism SIGNOR-271893 0.2 RPS6K proteinfamily SIGNOR-PF26 SIGNOR FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-262998 0.2 RPGRIP1L protein Q68CZ1 UNIPROT RELA protein Q04206 UNIPROT down-regulates demethylation Lys221 LLCDKVQkEDIEVYF 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163320 0.2 CNOT4 protein O95628 UNIPROT KDM5C protein P41229 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19346402 t miannu  In our study, we show that the protein level of the yeast histone H3 Lys 4 (H3 K4) demethylase Jhd2/Kdm5 is modulated through polyubiquitination by the E3 ubiquitin ligase Not4 and turnover by the proteasome.  Finally, we show that human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism. We propose that Not4 is an E3 ubiquitin ligase that monitors and controls a precise amount of Jhd2 protein so that the proper balance between histone demethylase and histone methyltransferase activities occur in the cell, ensuring appropriate levels of H3 K4 trimethylation and gene expression. SIGNOR-271468 0.555 LTBP2 protein Q14767 UNIPROT FBN1 protein P35555 UNIPROT up-regulates activity binding 9606 BTO:0000452 19681046 t Regulation miannu LTBP-2 interacts with fibrillin-1. The association of LTBP-2 with the ECM always coincided with that of fibrillin-1, and in fibroblast cultures the appearance of fibrillar fibrillin-1 structures preceded the assembly of LTBP-2 network. SIGNOR-251891 0.304 CREBBP protein Q92793 UNIPROT CREB1 protein P16220 UNIPROT up-regulates binding 9606 9829964 t gcesareni When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp. SIGNOR-62260 0.941 LCK protein P06239 UNIPROT LCP2 protein Q13094 UNIPROT unknown phosphorylation Tyr426 NEEWYVSyITRPEAE -1 8702662 t Ability of p56lck to phosphorylate Tyr-423/426 within SLP-76 in vitro SIGNOR-251382 0.748 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT up-regulates activity binding 9606 BTO:0000776 12324477 t lperfetto Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated T cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner. cd40 binds its ligand cd40l. SIGNOR-93432 0.928 SEPTIN6 protein Q14141 UNIPROT SEPT6/SEPT7 complex SIGNOR-C72 SIGNOR form complex binding 9606 16914550 t miannu We have characterized the conformation of a complex of filamentous human septins, sept2, sept6, and sept7. / we now show that sept6 and sept7 interact through a parallel coiled-coil, and that sept2 interacts with sept6 through their c-terminal domains. SIGNOR-148895 0.2 Sincalide smallmolecule CID:9833444 PUBCHEM CCKAR protein P32238 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257466 0.8 SIK2 protein Q9H0K1 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 20577053 t gcesareni Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2 SIGNOR-166372 0.738 HSP90AA1 protein P07900 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 18591668 t lpetrilli The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs. SIGNOR-179268 0.42 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni Rsk1/2 phosphorylates the transcription factor c-fos on s362 and increases its activity. SIGNOR-37216 0.397 DTX1 protein Q86Y01 UNIPROT EP300 protein Q09472 UNIPROT up-regulates binding 9606 11564735 t gcesareni We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300. SIGNOR-110629 0.386 GABA-A (a6-b3-d) receptor complex SIGNOR-C329 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268598 0.2 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-233438 0.604 SIRT1 protein Q96EB6 UNIPROT RELA protein Q04206 UNIPROT down-regulates activity deacetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310. SIGNOR-238817 0.718 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269489 0.8 GPR84 protein Q9NQS5 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256983 0.251 PRKCD protein Q05655 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR up-regulates activity phosphorylation 9606 19363025 t gcesareni We identify protein kinase c-delta as the kinase responsible for h3t45ph in vitro and in vivo. Given the nucleosomal position of h3t45, we postulate that h3t45ph induces structural change within the nucleosome to facilitate dna nicking and/or fragmentation. SIGNOR-265368 0.2 AKT1 protein P31749 UNIPROT EIF4B protein P23588 UNIPROT up-regulates phosphorylation Ser422 RERSRTGsESSQTGT 9606 18836482 t gcesareni Using an in vitro kinase assay, we found that pkb can directly phosphorylate eif4b on serine 422 (ser422). This was prevented by pretreatment of cells with the phosphatidylinositol 3-kinase (pi3k) inhibitor ly294002 or pharmacological inhibition of pkb. Phosphorylation regultes the activation of eukaryotic translation initiation factor 4b. SIGNOR-252520 0.4 CDON protein Q4KMG0 UNIPROT CDON/BOC/PTCH1 complex SIGNOR-C95 SIGNOR form complex binding 10090 21664576 t lperfetto Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell-surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. SIGNOR-209596 0.56 UBE2I protein P63279 UNIPROT SOX6 protein P35712 UNIPROT down-regulates activity sumoylation Lys417 TSPVTQkVkDEAAAQP 9606 16442531 t We show that SOX6 is modified in vitro and in vivo by small ubiquitin‐related modifier (SUMO) on two distinct sites. Mutation of both sites abolished SOX6 sumoylation and increased SOX6 transcriptional activity. SUMO dependent repression of SOX6 transcription was promoted by UBC9 whereas siRNA to UBC9, cotransfection of inactive UBC9 or a SUMO protease increased SOX6 transcriptional activity. SIGNOR-256130 0.371 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg707 ESTVMATrKMHDRLE -1 10026263 t lperfetto Thrombin is considered the physiological activator of factor V and is the most potent activator, catalyzing the cleavage of three peptide bonds at Arg709, Arg1018, and Arg1545 SIGNOR-263647 0.498 PDK1 protein Q15118 UNIPROT ITGB3 protein P05106 UNIPROT down-regulates activity phosphorylation Thr779 LYKEATStFTNITYR -1 10896934 t miannu PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3. SIGNOR-250264 0.308 GSK3B protein P49841 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser62 EPDSGSHsRQSSTDS 9606 BTO:0002181 22692215 t miannu GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3  phosphorylation, whereas the Ser-66 is not (Fig. 4D). SIGNOR-277647 0.2 HLA1 proteinfamily SIGNOR-PF87 SIGNOR Class I MHC complex SIGNOR-C425 SIGNOR form complex binding -1 28367149 t scontino One Ig domain is present in each chain of MHC class II, while the second Ig-type domain of MHC class I is provided by non-covalent association of the invariant light chain beta-2 microglobulin (beta2m) with the HC.|The MHC class I HC folds and assembles with beta2m in the lumen of the endoplasmic reticulum (ER) SIGNOR-267776 0.966 PTPN11 protein Q06124 UNIPROT GAB2 protein Q9UQC2 UNIPROT down-regulates dephosphorylation Tyr614 KSTGSVDyLALDFQP 9606 15170389 t gcesareni Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2. SIGNOR-124958 0.737 TRMT10B protein Q6PF06 UNIPROT TIM22 complex complex SIGNOR-C424 SIGNOR form complex binding 9606 BTO:0000007 32901109 t lperfetto Cryo-EM structure of the human mitochondrial translocase TIM22 complex|In humans, TIM22 is a 440-kDa complex comprising at least six components: the hypothetical channel-forming protein Tim22, three small Tim proteins (Tim9, Tim10a and Tim10b), Tim29 and acylglycerol kinase (AGK). SIGNOR-267705 0.205 PRKAB1 protein Q9Y478 UNIPROT PROX1 protein Q92786 UNIPROT down-regulates quantity by destabilization phosphorylation Ser79 KLLKRANsYEDAMMP 9606 BTO:0002181 36433955 t miannu Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. SIGNOR-277609 0.2 PRKACA protein P17612 UNIPROT GRIN2B protein Q13224 UNIPROT up-regulates activity phosphorylation Ser1166 SDDFKRDsVSGGGPC 9606 BTO:0000007 24431445 t miannu Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. SIGNOR-276616 0.4 PDZD11 protein Q5EBL8 UNIPROT TSPAN33 protein Q86UF1 UNIPROT up-regulates activity binding 10116 BTO:0003618 30463011 t Simone Using cell biological and biochemical methods, we now show that ADAM10 is docked to junctions by its transmembrane partner Tspan33, whose cytoplasmic C terminus binds to the WW domain of PLEKHA7 in the presence of PDZD11. The PLEKHA7-PDZD11 Complex Clusters ADAM10 at Junctions through Tspan33 SIGNOR-261252 0.331 PER2 protein O15055 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR down-regulates activity binding 9606 20817722 t miannu The mammalian clock is regulated at the cellular level by a transcriptional/translational feedback loop. BMAL1/clock (or NPAS2) heterodimers activate the expression of the period (PER) and cryptochrome (CRY) genes acting as transcription factors directed to the PER and CRY promoters via E-box elements. PER and CRY proteins form heterodimers and suppress the activity of the BMAL1/clock (or NPAS2) completing the feedback loop. SIGNOR-267977 0.756 PIN4 protein Q9Y237 UNIPROT Ribosome biogenesis phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000567 12860119 f lperfetto Par14 is a pre-rRNA processing factor involved in mammalian ribosome biogenesis, Par14 deficiency slowed cell growth (Fig. 3A) and reduced the production of 18 and 28 S rRNAs  SIGNOR-265754 0.7 GNG2 protein P59768 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 23074268 t gcesareni Furthermore, this work suggested that the gbetagamma subunits released upon gi activation activated phospholipase c-gamma (plc-gamma) to produce inositol 3 phosphate (ip3) which would subsequently increase intracellular ca2+ abundance. SIGNOR-199138 0.2 afatinib chemical CHEBI:61390 ChEBI ErbB receptor family proteinfamily SIGNOR-PF36 SIGNOR down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-259441 0.8 RPS6K proteinfamily SIGNOR-PF26 SIGNOR L1CAM protein P32004 UNIPROT up-regulates activity phosphorylation Ser1152 RSKGGKYsVKDKEDT 10116 BTO:0001009 8663493 t lperfetto Western blot analysis demonstrated that the L1 kinase activity from PC12 cells that phosphorylated this site was co-eluted with the S6 kinase, p90(rsk). Moreover, S6 kinase activity and p90(rsk) immunoreactivity co-immunoprecipitate with L1 from brain, and metabolic labeling studies have demonstrated that Ser1152 is phosphorylated in vivo in the developing rat brain. | These data demonstrate that the membrane-proximal 15 amino acids of the cytoplasmic domain of L1 are important for neurite outgrowth on L1, and the interactions it mediates may be regulated by phosphorylation of Ser1152. SIGNOR-252766 0.2 ARNT protein P27540 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599 21544813 f lperfetto Screening by quantitative reverse-transcription PCR and PCR arrays revealed that cyclin E1, CDK2, Fos and Jun were negatively regulated by ARNT, whereas CDKN1C, CNKN2A, CDKN2B, MAPK11 and MAPK14 were positively regulated in HCC SIGNOR-253692 0.284 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT up-regulates quantity by stabilization phosphorylation Ser757 EGMELNSsITSQDVL 9606 BTO:0000007 15987997 t miannu Phosphorylation and stabilization of HURP by Aurora-A. Four phosphorylated residues were identified, namely, HURP-S627, -S725, -S757, and -S830, with 65% amino acid sequence coverage. we propose here that Aurora-A may phosphorylate HURP and this probably attenuates the negative impact of cdk1 phosphorylation and by inhibiting subsequent proteasome activity and this will generate a longer HURP half-life. SIGNOR-262651 0.745 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 12591950 t lperfetto Biml (bim long) was induced and phosphorylated parallel to jnk activitythese data demonstrate that biml is phosphorylated in vivo on thr-56 and that jnk also phosphorylates biml on at least one serine residue (ser-44 and/or ser-58) SIGNOR-98392 0.2 NOX3 protein Q9HBY0 UNIPROT ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 17237347 t lperfetto Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). SIGNOR-264715 0.7 LPAR3 protein Q9UBY5 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t gcesareni Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2 thereby activating yap and taz transcription co-activators, which are oncoproteins repressed by lats1/2. SIGNOR-198544 0.452 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-37973 0.586 PRKDC protein P78527 UNIPROT YBX1 protein P67809 UNIPROT up-regulates activity phosphorylation Thr89 EDVFVHQtAIKKNNP 9606 BTO:0000007 36475703 t miannu The DNA-PK subunits and YB-1 phosphorylated at T89 were found colocalized suggesting their in vivo interaction.DNA-PK directly phosphorylates YB-1 and, this way, modulates YB-1 function. Point mutation of YB-1 at this residue abrogated the translocation of YB-1 into the nucleus. SIGNOR-277611 0.341 NFATC1 protein O95644 UNIPROT IL2 protein P60568 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10022916 t Barakat Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses. SIGNOR-275405 0.577 ZSWIM2 protein Q8NEG5 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 16522193 f miannu MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.  SIGNOR-271556 0.7 PRKCD protein Q05655 UNIPROT CDK5 protein Q00535 UNIPROT down-regulates activity phosphorylation Thr77 LHSDKKLtLVFEFCD 9606 BTO:0001332 29511352 t miannu This generates a binding site for the C2 domain of PKCδ, which in turn phosphorylates CDK5 on T77. The resulting dissociation of the CDK5R1/CDK5 complex abolishes the activity of CDK5.  SIGNOR-277386 0.2 CDK9 protein P50750 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR form complex binding -1 34955012 t lperfetto Cyclin-dependent-kinases (CDKs) are members of the serine/threonine kinase family and are highly regulated by cyclins, a family of regulatory subunits that bind to CDKs. CDK9 represents one of the most studied examples of these transcriptional CDKs. CDK9 forms a heterodimeric complex with its regulatory subunit cyclins T1, T2 and K to form the positive transcription elongation factor b (P-TEFb).  SIGNOR-267740 0.964 TNF protein P01375 UNIPROT SCN4A protein P35499 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253490 0.259 metformin chemical CHEBI:6801 ChEBI NR0B2 protein Q15466 UNIPROT up-regulates quantity by expression 9606 17909097 f gcesareni In this study, we found that metformin increased shp gene expression via ampk activation and inhibited the expression of the hepatic gluconeogenic genes pepck and g6pase via upregulation of shp. SIGNOR-158059 0.8 CDKN2A protein P42771 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR down-regulates activity binding 9606 11154267 t lperfetto Overexpression of p16INK4a in cells with functional pRb results in inhibition of both Cdk4- and Cdk6-associated kinase activity and pRb phosphorylation, with subsequent cell cycle arrest (46, 50). In addition, inhibition of D cyclin-Cdk4 complex formation by p16INK4a prevents sequestration of p21Cip1 and p27Kip1 by these complexes in early G1, leading to suppression of cyclin E-Cdk2 activity SIGNOR-245459 0.824 MAOA protein P21397 UNIPROT dopamine smallmolecule CHEBI:18243 ChEBI down-regulates quantity chemical modification 9606 NBK536726 t brain lperfetto Dopamine is metabolized after reuptake into dopaminergic neurons or glial cells¬†|It undergoes oxidative deamination, catalyzed by the enzyme monoamine oxidase (MAO) in the presence of flavin adenine dinucleotide (FAD), to produce reactive aldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL). SIGNOR-264001 0.8 PRKCB protein P05771 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 17145764 t lperfetto Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization SIGNOR-151011 0.2 LMX1A protein Q8TE12 UNIPROT NLI/Lmx1.1/Isl1 complex SIGNOR-C103 SIGNOR form complex binding 9606 BTO:0000007 9452425 t lperfetto Interactions between LIM transcription factors were also evaluated in vivo. Cotransfected FLAG-Lmx1.1 and HA-Isl1 were capable of interacting. the NLI-dependent interaction observed between Isl1 and Lmx1.1 is likely to represent a physiologically significant complex found in the endocrine cells of the pancreas. SIGNOR-236812 0.343 CDK9 protein P50750 UNIPROT SUPT5H protein O00267 UNIPROT up-regulates phosphorylation Thr814 PLHDGSRtPAQSGAW 9606 16427012 t lperfetto We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif SIGNOR-143943 0.772 MAPK1 protein P28482 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity phosphorylation Thr693 RELVEPLtPSGEAPN -1 1651322 t lperfetto A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase SIGNOR-20545 0.629 PRKCD protein Q05655 UNIPROT ADD2 protein P35612 UNIPROT unknown phosphorylation Ser726 KKKEKVEs -1 8810272 t lperfetto Ser-726 and Ser-713 in the C-terminal MARCKS-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites for PKC. SIGNOR-248953 0.287 peptide smallmolecule CHEBI:16670 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR up-regulates activity binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3–guanosine triphosphate (GTP) complex. eRF1 recognizes the stop codon, and after hydrolysis of GTP by eRF3, mediates release of the nascent peptide.  SIGNOR-270815 0.8 ATP2A2 protein P16615 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 9606 16402920 t lperfetto In the present study, we have analysed the expression and functional characteristics of SERCA2c relative to SERCA2a and SERCA2b isoforms upon their stable heterologous expression in HEK-293 cells (human embryonic kidney 293 cells). All SERCA2 proteins induced an increased Ca2+ content in the ER of intact transfected cells. SIGNOR-262050 0.8 MAPK1 protein P28482 UNIPROT GRB10 protein Q13322 UNIPROT unknown phosphorylation Ser418 QQRKALLsPFSTPVR -1 15952796 t lperfetto We identified Ser150, Ser418, and Ser476 of human Grb10 as MAPK-mediated in vitro phosphorylation sites. SIGNOR-249405 0.378 ZNRF3 protein Q9ULT6 UNIPROT FZD2 protein Q14332 UNIPROT down-regulates ubiquitination 9606 22575959 t gcesareni Znrf3 is associated with the wnt receptor complex, and inhibits wntby promoting the turnover of frizzled and lrp6. SIGNOR-197417 0.295 EGFR protein P00533 UNIPROT SCAMP1 protein O15126 UNIPROT up-regulates activity phosphorylation Tyr37 VPPGLDEyNPFSDSR -1 9658162 t miannu In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation SIGNOR-262857 0.338 CDK1 protein P06493 UNIPROT KIF20B protein Q96Q89 UNIPROT up-regulates activity phosphorylation Thr1644 VKHPGCTtPVTVKIP 9606 11470801 t miannu Here we report the identification of a novel KRP, termed KRMP1, which undergoes in vivo phosphorylation. The carboxyl-terminal globular tail domain is strongly phosphorylated by mitotic kinase activities almost attributed to cdc2 kinase, which is responsible for phosphorylation on residue Thr-1604 of KRMP1. SIGNOR-262695 0.414 PRKACA protein P17612 UNIPROT AKAP13 protein Q12802 UNIPROT up-regulates phosphorylation Ser2733 SVSPKRNsISRTHKD 9606 15383279 t llicata Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to pkd activation in two ways: it recruits an upstream kinase pkceta and coordinates pka phosphorylation events that release activated protein kinase d. Thus, akap-lbc synchronizes pka and pkc activities in a manner that leads to the activation of a third kinase. SIGNOR-129345 0.335 ORC1 protein Q13415 UNIPROT ORC complex SIGNOR-C419 SIGNOR form complex binding 9606 32808929 t lperfetto The dynamic nature of the human origin recognition complex revealed through five cryoEM structures|Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. |The very first step of this initiation process is accomplished by DNA association with the Origin Recognition Complex (ORC), a six-subunit protein that forms a partial ring around origin DNA SIGNOR-267567 0.944 HECTD4 protein Q9Y4D8 UNIPROT MYC protein P01106 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001321 32814769 t miannu We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop. SIGNOR-267146 0.2 GRK2 protein P25098 UNIPROT MC4R protein P32245 UNIPROT down-regulates activity phosphorylation Thr312 RSQELRKtFKEIICC 9606 12639913 t gcesareni Mutagenesis studies revealed that Thr312 and Ser329/330 in the C-terminal tail are potential sites for PKA and GRK phosphorylation and may play an essential role in the recruitment of beta-arrestin to the activated receptor. SIGNOR-247770 0.2 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 21757781 t gcesareni Rapamycin is an immunosuppressive drug that binds simultaneously to the 12-kda fk506- and rapamycin-binding protein (fkbp12, or fkbp) and the fkbp-rapamycin binding (frb) domain of the mammalian ta rget of rapamycin (mtor) kinase. autophagy is negatively regulated by the mammalian target of rapamycin (mtor) and can be induced in all mammalian cell types by the mtor inhibitor rapamycin. SIGNOR-174886 0.8 MMUT protein P22033 UNIPROT succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 1978672 t miannu Methylmalonyl-CoA mutase (MCM) is an adenosylcobalamin-dependent enzyme that catalyses isomerization between methylmalonyl-CoA and succinyl-CoA (3-carboxypropionyl-CoA). SIGNOR-269109 0.8 PTH1R protein Q03431 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 28363951 t lperfetto This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11. SIGNOR-270551 0.493 SMO protein Q99835 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling as pka suppresses the activity of gli, smo might use the stimulation of pi3k by galfai and gbetagamma subu- nits to block pka in cells that have high levels of camp SIGNOR-199180 0.2 CDC20 protein Q12834 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates activity binding 9606 BTO:0000007 23287467 t miannu  Here, we show that human REV1 undergoes proteosomal degradation mediated by the E3 ubiquitin ligase known as anaphase-promoting complex (APC). REV1 associates with APC. Overexpression of APC coactivator CDH1 or CDC20 promotes polyubiquitination and proteosomal degradation of REV1. SIGNOR-272896 0.874 PKNOX1 protein P55347 UNIPROT HOXB1 protein P14653 UNIPROT up-regulates activity binding -1 9482740 t 2 miannu we observe the formation of a ternary Prep1-Pbx1-HOXB1 complex on a HOXB1-responsive target in vitro. Interaction with Prep1 enhances the ability of the HOXB1-Pbx1 complex to activate transcription in a cooperative fashion from the same target. SIGNOR-241215 0.604 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 9677429 t MAPK3/ERK1 is a MAPK which plays an important role in the MAPK/ERK cascade. gcesareni The mek1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases erk1 and erk2 in mammalian cells. SIGNOR-59157 0.745 PRKACA protein P17612 UNIPROT CACNB2 protein Q08289 UNIPROT up-regulates activity phosphorylation Ser533 KKSQHRSsSSAPHHN 10441130 t miannu Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation SIGNOR-250340 0.421 PPARGC1A protein Q9UBK2 UNIPROT APOC3 protein P02656 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255059 0.279 panobinostat chemical CHEBI:85990 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257754 0.8 MCM10 protein Q7L590 UNIPROT POLA1 protein P09884 UNIPROT up-regulates quantity by stabilization relocalization -1 19608746 t Federica Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin. SIGNOR-261271 0.859 SNAI1 protein O95863 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 f lperfetto Taken together these results suggest that SNAI1 functional blockade is leading to partial re-expression of E-cadherin (i.e. at the level of transcription), to a decrease in PAI-1 and to a more collective migration, while the parental cells expressing SNAI1 have less E-cadherin, more PAI 1, and migrate individually. We suggest that the present study establishes a relation between SNAI1 function, PAI-1 distribution and EMT status. SIGNOR-252259 0.7 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AL/b2 integrin complex SIGNOR-C169 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259024 0.442 RNF2 protein Q99496 UNIPROT Polycomb repressive complex 1 complex SIGNOR-C408 SIGNOR form complex binding 9606 31608994 t miannu PRC1 has been categorised into canonical and noncanonical/variant PRC1; canonical PRC1 (Morey, Aloia, Cozzuto, Benitah, & Di Croce, 2013) includes chromobox (Cbx) proteins, Ring1, human polyhomeotic homologue protein (Hph) and polycomb ring finger (Pcgf) (Pcgf2/Mel18 and Pcgf4/Bmi1) proteins whereas noncanonical/variant PRC1 involves RING1 and YY1 binding protein (Rybp), Ring1 and Pcgf (Pcgf 1–6) proteins (Wu, Johansen, & Helin, 2013). Figure 3 illustrates the various proteins that form the canonical and noncanonical PRC1. The Ring1 along with Pcgf2/4 forms a core heterodimer which interacts with other accessory components of PRC1 complex through C‐terminal ring finger and WD40 ubiquitin‐like (RAWUL) domains see Figure 4b SIGNOR-266811 0.824 APOBEC3D protein Q96AK3 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261328 0.7 KREMEN1 protein Q96MU8 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 12050670 f gcesareni Dkk1 has been shown to inhibit wnt signalling by binding to and antagonizing lrp5/6. Here we show that the transmembrane proteins kremen1 and kremen2 are high-affinity dkk1 receptors that functionally cooperate with dkk1 to block wnt/beta-catenin signalling. SIGNOR-88891 0.632 CCP110 protein O43303 UNIPROT CALM1 protein P0DP23 UNIPROT up-regulates activity binding 9606 16760425 t miannu We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis. SIGNOR-265965 0.323 PEX14 protein O75381 UNIPROT PEX13 protein Q92968 UNIPROT up-regulates activity binding -1 15798189 t miannu Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import SIGNOR-253029 0.919 DKK1 protein O94907 UNIPROT WNT3A protein P56704 UNIPROT down-regulates 9606 22298955 f Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. gcesareni It has been shown that both sclerostin and dkk1 act physiologically as downstream molecules of bmp signaling to inhibit canonical wnt signaling and therefore negatively regulate bone mass. SIGNOR-195573 0.729 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Thr345 GADSDVEtPSNFGKY 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262984 0.304 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates chemical inhibition 9606 23405260 t gcesareni The goal of this study was to compare dacomitinib (pf-00299804), a next generation small molecule tyrosine kinase inhibitor that irreversibly blocks multiple her family receptors (her-1 (egfr), her-2 and her-4 tyrosine kinases), to cetuximab, the current fda approved anti-egfr medication for hnscc and erlotinib, an egfr specific small molecule tyrosine kinase inhibitor. SIGNOR-200908 0.8 WNT3A protein P56704 UNIPROT LRP5 protein O75197 UNIPROT up-regulates activity binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131826 0.693 CSNK2A2 protein P19784 UNIPROT SCN2A protein Q99250 UNIPROT up-regulates activity phosphorylation Ser1124 LNTEEFSsESDMEES 9606 BTO:0000938 19064667 t lperfetto We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G. SIGNOR-275758 0.2 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT down-regulates activity phosphorylation Ser444 PLSLSAQsVMEELNT 9606 BTO:0000938 24614225 t lperfetto The phosphorylation of cyld was completely abolished by the combined mutations of the entire serine cluster (m4, lane 5). Similar results were obtained with the ikk holoenzyme (fig. 4c, panel 1), recombinant ikk_ (panel 2), and recombinant ikk_cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity. SIGNOR-204740 0.537 USP9X protein Q93008 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates quantity cleavage 9606 BTO:0000567 26235645 t miannu Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors. SIGNOR-270831 0.638 YES1 protein P07947 UNIPROT YAP1 protein P46937 UNIPROT up-regulates activity phosphorylation Tyr407 SGLSMSSySVPRTPD 9606 BTO:0000578 35041461 t miannu Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C). SIGNOR-277653 0.714 RAPH1 protein Q70E73 UNIPROT VASP protein P50552 UNIPROT up-regulates activity binding 9606 20417104 t miannu Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins. SIGNOR-268426 0.59 CHEK2 protein O96017 UNIPROT BECN1 protein Q14457 UNIPROT up-regulates activity phosphorylation Ser90 IPPARMMsTESANSF 9606 BTO:0002552 32187724 t lperfetto We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion.|CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, promoting autophagy via Beclin 1 release from Bcl‐2 sequestration SIGNOR-264557 0.302 HTR1D protein P28221 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257116 0.251 TPO protein P07202 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI up-regulates quantity chemical modification 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267039 0.8 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Tyr502 TTANVVYyVGENVVN 9606 BTO:0000567 12637538 t gcesareni Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. [..] Mutation of the other two sites, Tyr432 and Tyr502, had no significant influence on PKD activity. SIGNOR-246215 0.343 TBX2 protein Q13207 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002267 25211658 t lperfetto TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS SIGNOR-249593 0.35 SRC protein P12931 UNIPROT RGS16 protein O15492 UNIPROT up-regulates phosphorylation Tyr177 RFLKSPAyRDLAAQA 9606 12588871 t lperfetto Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. hosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). SIGNOR-98275 0.35 GSK3A protein P49840 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates quantity by destabilization phosphorylation Ser159 NNTSTDGsLPSTPPP 9606 BTO:0000567 16543145 t  MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). Glycogen Synthase Kinase-3 Regulates Mitochondrial Outer Membrane Permeabilization and Apoptosis by Destabilization of MCL-1. threonine 163, which represents the GSK-3 priming phosphorylation in this protein SIGNOR-251217 0.464 GSK3B protein P49841 UNIPROT MAF protein O75444 UNIPROT up-regulates phosphorylation 9606 18042454 t miannu We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity. SIGNOR-159435 0.262 tolazoline chemical CHEBI:28502 ChEBI ADRA2C protein P18825 UNIPROT down-regulates activity chemical inhibition 9606 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258914 0.8 YAP1 protein P46937 UNIPROT SGK1 protein O00141 UNIPROT up-regulates quantity by expression transcriptional regulation 35216681 f lperfetto Importantly, YAP-dependent regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1) is required to activate mTORC1/SREBP and stimulate de novo lipogenesis. SIGNOR-276585 0.283 STAP1 protein Q9ULZ2 UNIPROT TEC protein P42680 UNIPROT up-regulates activity binding 9606 BTO:0000007 10518561 t miannu In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction. SIGNOR-261819 0.397 GNAI2 protein P04899 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR down-regulates binding 9606 8327893 t gcesareni Concentration-dependent inhibition of adenylyl cyclases by purified Gi alpha subunits is described. Activated Gi alpha but not G(o) alpha was effective, and myristoylation of Gi alpha was required SIGNOR-267849 0.624 PPAT protein Q06203 UNIPROT L-glutamine zwitterion smallmolecule CHEBI:58359 ChEBI down-regulates quantity chemical modification 9606 8106516 t Two Genes for de Novo Purine Nucleotide Synthesis on Human Chromosome 4 Are Closely Linked and Divergently Transcribed√¢‚Ǩ¬ù SIGNOR-267187 0.8 TESK1 protein Q15569 UNIPROT CFL2 protein Q9Y281 UNIPROT down-regulates activity phosphorylation Ser3 sGVTVNDE 9606 BTO:0001363 11418599 t lperfetto Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin SIGNOR-246719 0.324 MAPK1 protein P28482 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates activity phosphorylation Ser1178 IMSKHLDsPPAIPPR 9534 BTO:0004055 8816480 t lperfetto In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1 SIGNOR-235925 0.707 ITGB1BP1 protein O14713 UNIPROT ITGB6 protein P18564 UNIPROT down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257662 0.289 PTMS protein P20962 UNIPROT NCOA1 protein Q15788 UNIPROT up-regulates activity binding 9606 BTO:0000567 16150697 t miannu Macromolecular translocation inhibitor II (MTI-II), which was first identified as an in vitro inhibitor of binding between the highly purified glucocorticoid receptor (GR) and isolated nuclei, is an 11.5-kDa Zn2+-binding protein that is also known as ZnBP or parathymosin. MTI-II Enhances GR-dependent Transcription through Its Acidic Domain. MTI-II Enhances GR-dependent Transcription in Cooperation with SRC-1 and p300 in Vivo. CBP and p300 Coprecipitate with MTI-II in a Glucocorticoid Hormone-dependent Manner. Immunoprecipitation analysis showed that in the presence of glucocorticoid hormone, p300 and CREB-binding protein are coprecipitated with MTI-II. Furthermore, the knockdown of endogenous MTI-II by RNAi reduces the transcriptional activity of GR in cells. SIGNOR-268462 0.2 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9606 BTO:0000007 10567369 t lperfetto An ERK2-binding site at the N terminus of MEK1 was reported to mediate their stable association. We examined the importance of this binding site in the feedback phosphorylation of mek1 on thr(292) and thr(386) by erk2 SIGNOR-244912 0.748 ALK protein Q9UM73 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000785 14968112 t gcesareni Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1. SIGNOR-122082 0.536 KMT2A protein Q03164 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates quantity by stabilization binding 9606 23817177 t irozzo RUNX1 wild-type protein first binds to the PU.1 URE region and recruits the MLL complex to open up part of the compact chromatin structure. The partially relaxed chromatin allows the binding of another RUNX1 at the PU.1 promoter region to further distort compact DNA structure. The relaxed form of chromatin facilitates the accumulation of transcription factors and cofactors to initiate transcriptional activity. SIGNOR-255708 0.556 CAV1 protein Q03135 UNIPROT SLC1A2 protein P43004 UNIPROT down-regulates activity binding 9606 BTO:0000938 26690923 t miannu EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers. SIGNOR-264809 0.25 BMX protein P51813 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates quantity phosphorylation Tyr12 NVLAKALyDNVAESP 10090 BTO:0002572 21937722 t miannu Recombinant Bmx kinase was found to effectively phosphorylate the wt CAS SH3 domain on Tyr-12 (Figure 2B). A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells.  SIGNOR-276384 0.515 STAP1 protein Q9ULZ2 UNIPROT STAT5A protein P42229 UNIPROT up-regulates activity binding 9606 BTO:0000007 10679268 t miannu STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells. SIGNOR-261821 0.405 CCT5 protein P48643 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272861 0.747 LDB1 protein Q86U70 UNIPROT LHX2 protein P50458 UNIPROT up-regulates activity binding 9606 BTO:0000007 17005264 t miannu Cofactor CLIM2 promotes the repressive action of LIM homeodomain transcription factor Lhx2 in the expression of porcine pituitary glycoprotein hormone alpha subunit gene. SIGNOR-223962 0.549 Ub:RBR_E3 complex SIGNOR-C520 SIGNOR Protein_ubiquitination phenotype SIGNOR-PH214 SIGNOR up-regulates 9606 34199813 f miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5′-triphosphate (ATP)-dependent manner to form a thioester-linked E1‒Ub conjugate. The activated Ub is then delivered to an E2 enzyme via a transthiolation reaction. Finally, an E3 enzyme, which can bind both a substrate and an E2‒Ub conjugate, mediates the covalent linkage of Ub to the target protein as a tag. SIGNOR-271384 0.7 F2 protein P00734 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates binding 9606 BTO:0001253 11356985 t gcesareni Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2. SIGNOR-108183 0.601 MARCHF9 protein Q86YJ5 UNIPROT PTPRJ protein Q12913 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271535 0.2 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1009 DESSDDDsDSEEPSK 9606 10066810 t gcesareni Mutational analysis of ck2 consensus sites showed that the target for ck2 was in an acidic insert of 19 amino acids in the d2 domain, and ser to ala mutations at amino acids 965, 968, 969, and 973 abrogated ck2 phosphorylation of cd45. Ck2 phosphorylation increased cd45 activity 3-fold toward phosphorylated myelin basic protein, SIGNOR-65277 0.449 SMARCA1 protein P28370 UNIPROT ST7 protein Q9NRC1 UNIPROT down-regulates quantity by repression transcriptional regulation 15485929 t lperfetto Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. SIGNOR-268991 0.2 QRICH1 protein Q2TAL8 UNIPROT TARS2 protein Q9BW92 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269407 0.2 CAMK2G protein Q13555 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275779 0.293 MYO5A protein Q9Y4I1 UNIPROT Dense-core_vesicle_exocytosis phenotype SIGNOR-PH184 SIGNOR up-regulates 9606 21077886 f miannu Myosin Va regulates exocytosis of large dense-core vesicles (LDCVs). interestingly, inhibition of myosin Va potentiates LDCV exocytosis to the same extent as F-actin depolymerization does, suggesting that myosin Va cooperates with the actin cytoskeleton to impede or control LDCV exocytosis SIGNOR-269279 0.7 SOHLH2 protein Q9NX45 UNIPROT KIT protein P10721 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002181 22328502 t Luana Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression. SIGNOR-266206 0.33 fenoterol chemical CHEBI:149226 ChEBI ADRB3 protein P13945 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  SIGNOR-257868 0.8 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 BTO:0000782 9710204 t lperfetto Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2. SIGNOR-59627 0.725 GNAQ protein P50148 UNIPROT ARHGEF25 protein Q86VW2 UNIPROT up-regulates activity binding -1 17606614 t P63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated Galpha(q) relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain SIGNOR-256493 0.578 STK3 protein Q13188 UNIPROT PRKCA protein P17252 UNIPROT up-regulates activity phosphorylation Thr228 PQWNESFtFKLKPSD 9606 BTO:0002181 26414765 t miannu Thus, the phosphorylation of PKCα at Ser226 and Thr228 by Mst1 and Mst2 is required for the optimal activation of PKCα.  SIGNOR-277176 0.2 SNAI2 protein O43623 UNIPROT MMP9 protein P14780 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 22074556 f miannu We demonstrated that forced expression of SLUG elevated CXCR4 and CXCL12 expression in human prostate cancer cell lines PC3, DU145, 22RV1, and LNCaP; conversely, reduced expression of SLUG by shRNA downregulated CXCR4 and CXCL12 expression at RNA and protein levels in prostate cancer cells. Furthermore, ectopic expression of SLUG increased MMP9 expression and activity in PC3, 22RV1, and DU-145 cells, and SLUG knockdown by shRNA downregulated MMP9 expression. SIGNOR-255170 0.461 PDHB protein P11177 UNIPROT PDH complex SIGNOR-C402 SIGNOR form complex binding 9606 20160912 t miannu The human (h) pyruvate dehydrogenase complex (hPDC) consists of multiple copies of several components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2), dihydrolipoamide dehydrogenase (E3), E3-binding protein (BP), and specific kinases and phosphatases. Mammalian PDC has a well organized structure with an icosahedral symmetry of the central E2/BP core to which the other component proteins bind non-covalently. SIGNOR-266547 0.935 RETREG3 protein Q86VR2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261490 0.7 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr136 SEEGYQDyEPEA 9606 BTO:0000975;BTO:0000142 11744621 t llicata Here, we show that alpha-synuclein (alpha-syn) is an outstanding substrate for the protein tyrosine kinase p72syk (syk), which phosphorylates three tyrosyl residues in its c-terminal domain (y-125, y-133, and y-136), here, we show that _-syn is an outstanding substrate for syk and that once it is tyrosine phosphorylated, it loses the ability to form oligomers. SIGNOR-113069 0.519 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FOS protein P01100 UNIPROT up-regulates phosphorylation 9606 7816602 t inferred from 70% family members lperfetto Phosphorylation of the c-fos and c-jun hob1 motif stimulates its activation capacity here we show that the hob1-containing activation domain of c-fos is stimulated by ha-ras in vivo and phosphorylated by a map kinase family member in vitro and that mutating t232 to ala abolishes both functions. SIGNOR-270105 0.2 CSNK2A2 protein P19784 UNIPROT GTF2A1L protein Q9UNN4 UNIPROT up-regulates activity phosphorylation Ser418 VEEDPLNsGDDVSEQ -1 12107178 t llicata ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled. SIGNOR-250993 0.42 FGF5 protein P12034 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates binding 9606 8386828 t gcesareni Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2. SIGNOR-38704 0.7 CSNK2A1 protein P68400 UNIPROT SEPTIN2 protein Q15019 UNIPROT down-regulates phosphorylation Ser218 YHLPDAEsDEDEDFK 9606 16857012 t lperfetto Here we show that human septin 2 is phosphorylated in vivo at ser218 by casein kinase ii. Septin 2 binds and hydrolyses gtp. The purified protein has the capacity to polymerize into long filaments when loaded with gtp or gdp. Moreover, we show that the endogenous protein in hela cells, like that produced in insect cells, is phosphorylated by casein kinase ii and that this phosphorylation alters nucleotide binding. SIGNOR-148010 0.2 PRKACA protein P17612 UNIPROT ITPKB protein P27987 UNIPROT down-regulates activity phosphorylation -1 9374536 t miannu Two isoforms of the inositol 1,4,5-trisphosphate 3-kinase have been identified, the A form and the B form. phosphorylation of isoform A by the cyclic AMP-dependent protein kinase increased activity 1.5-fold, whereas phosphorylation of isoform B decreased activity by 45%. major phosphorylation sites in the protein are Ser119 for PKA. Ser119 in the A isoform is conserved in the B isoform as Ser328 SIGNOR-249995 0.355 NLGN2 protein Q8NFZ4 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 25882190 f miannu Gephyrin is believed to act as a scaffold at inhibitory synapses, in a manner analogous to that of the prototypic excitatory synaptic scaffold, PSD-95. The best-known function of gephyrin is to bring the inhibitory synaptic receptors and to stabilize them at the inhibitory synapses. gephyrin interacts with NL-2 and collybistin, suggesting that it may be critical for the maturation or maintenance of inhibitory synapses. SIGNOR-264977 0.7 NRF1 protein Q16656 UNIPROT ENOX1 protein Q8TC92 UNIPROT up-regulates 9606 BTO:0000934 23939472 f lperfetto We found that NRF-1 positively regulates FAM134C and ENOX1, but negatively regulates C3orf10 in human neuroblastoma IMR-32 cells and primary rat cortical neurons. In IMR-32 cells, FAM134C positively regulates and C3orf10 negatively regulates neurite outgrowth, but ENOX1 plays no role in neurite outgrowth regulation.  SIGNOR-261451 0.267 ABL1 protein P00519 UNIPROT CRKL protein P46109 UNIPROT down-regulates 9606 21779437 f lperfetto Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl SIGNOR-175138 0.709 CDK12 protein Q9NYV4 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates activity phosphorylation Thr134 LKFYDSNtVKQKYLS 9606 BTO:0004828 32483448 t lperfetto Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway SIGNOR-273109 0.2 CYP17A1 protein P05093 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI down-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268657 0.8 SCF-FBW7 complex SIGNOR-C135 SIGNOR STAT2 protein P52630 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 31843895 t miannu  These results demonstrate that the interaction between STAT2 and FBXW7 is involved in the SCF complex containing cullin 1 and RBX1. SIGNOR-276766 0.289 ATM protein Q13315 UNIPROT USP10 protein Q14694 UNIPROT up-regulates quantity by stabilization phosphorylation Ser337 ASGTLPVsQPKSWAS 9606 BTO:0001109 20096447 t miannu The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337.  SIGNOR-276276 0.253 MAPK3 protein P27361 UNIPROT SPIB protein Q01892 UNIPROT unknown phosphorylation Thr56 VAPPVPAtPYEAFDP 9606 BTO:0000776 8632909 t lperfetto The threonine 56 was defined as the erk1 phosphorylation site by using phosphoamino-acid analyses and a spi-b mutant version SIGNOR-41800 0.314 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Ser57 KKDRFYRsILPGDKT 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248598 0.2 CDK5RAP2 protein Q96SN8 UNIPROT CEP63 protein Q96MT8 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 26297806 t lperfetto Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. SIGNOR-271722 0.685 JAK1 protein P23458 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT up-regulates activity phosphorylation Tyr619 NKVDDCNyAIKRIRL 10090 BTO:0000099 25113558 t miannu JAK1 interacts with and phosphorylates PERK. PERK-dependent activation of JAK1 and STAT3 contributes to endoplasmic reticulum stress-induced inflammation. Similarly, PERK is associated with and phosphorylated by JAK1 at Y585 and Y619 (and possibly other JAKs) during ER stress, resulting in PERK- and JAK1-dependent activation of STAT3. SIGNOR-276677 0.2 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 20179209 t lperfetto Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated SIGNOR-163908 0.343 YY1 protein P25490 UNIPROT INO80 complex complex SIGNOR-C498 SIGNOR form complex binding 9606 25016522 t miannu Here, we have systematically investigated the involvement of the catalytic subunit of the human INO80 complex during unchallenged replication and under replication stress by following the effects of its depletion on cell survival, S-phase checkpoint activation, the fate of individual replication forks, and the consequences of fork collapse. We report that INO80 was specifically needed for efficient replication elongation, while it was not required for initiation of replication. SIGNOR-270849 0.543 ZDHHC9 protein Q9Y397 UNIPROT NRAS protein P01111 UNIPROT up-regulates activity palmitoylation 9606 BTO:0000007 16000296 t miannu Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein. SIGNOR-261355 0.411 OPHN1 protein O60890 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity gtpase-activating protein 9606 BTO:0000938 12932438 t miannu OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro SIGNOR-268398 0.628 APOBEC3B protein Q9UH17 UNIPROT Clearance_of_foreign intracellular_DNA phenotype SIGNOR-PH132 SIGNOR up-regulates 9606 29367246 f lperfetto The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3, or A3) family of interferon-inducible cytidine deaminases functions as antiviral restriction factors (reviewed in reference 15). Humans express seven A3 family members: A3A, A3B, A3C, A3D, A3F, A3G, and A3H (16, 17). A3A is notable in that it specifically targets and restricts foreign DNA elements. A3A binds to single-stranded DNA with a high affinity (18), mediates the catabolism of foreign DNA (19), and restricts infection of several DNA viruses, including HPV (20,–24). SIGNOR-261331 0.7 BMI1 protein P35226 UNIPROT CDKN2A protein Q8N726 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20551323 f gcesareni One important pathway in which bmi-1 acts to promote the overall growth of mice and cellular proliferation includes cdkn2a;bmi-1 represses the expression of cdkn2a, which encodes two cyclin-dependent kinase inhibitors, p16ink4a (p16) and p19arf SIGNOR-259359 0.465 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser58 ESETNQNsSSDSEAE -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-251044 0.383 ATM protein Q13315 UNIPROT PIDD1 protein Q9HB75 UNIPROT up-regulates activity phosphorylation Thr788 DAETGFLtQSNLLSV 9606 BTO:0000567 22854598 t miannu ATM phosphorylates PIDD on Thr788 within the DD. This phosphorylation is necessary and sufficient for RAIDD binding and caspase-2 activation. Conversely, nonphosphorylatable PIDD fails to bind RAIDD or activate caspase-2, and engages prosurvival RIP1 instead. Thus, ATM phosphorylation of the PIDD DD enables a binary switch through which cells elect to survive or die upon DNA injury. SIGNOR-262640 0.628 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 SSAGWKNsIRHNLSL 9606 22898666 t gcesareni Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity. SIGNOR-191851 0.676 PTPRD protein P23468 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 BTO:0000551;BTO:0000527 BTO:0000142 19478061 t miannu Transfection of wild-type ptprd resulted in the specific dephosphorylation of stat3 at tyrosine 705, a residue that must be phosphorylated for stat3 to be active SIGNOR-185933 0.527 Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR Microtubule-based_movement phenotype SIGNOR-PH170 SIGNOR up-regulates 16440056 f lperfetto Dyneins are large multi-subunit protein complexes that undertake a wide range of roles within the cell. They are adenosine triphosphate (ATP)–driven, microtubule minus-end-directed molecular motors that can be divided, based on function, into two classes: axonemal and cytoplasmic dyneins SIGNOR-265020 0.7 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249005 0.307 PRKACA protein P17612 UNIPROT ETV1 protein P50549 UNIPROT up-regulates phosphorylation Ser334 PTYQRRGsLQLWQFL 9606 12213813 t lperfetto Pka targets er81 on ser(334) in vivo. Surprisingly, phosphorylation of ser(334) severely reduces the dna-binding ability of er81 but also enhances the transactivation potential of er81. These counteractive effects of pka phosphorylation on er81-dependent transcription may cause the selective up-regulation of promoters with high but not low affinity for er81. SIGNOR-92455 0.294 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CCL20 protein P78556 UNIPROT up-regulates quantity by expression transcriptional regulation 22319003 t lperfetto Combined stimulation with IL-6, sIL-6R, and IL-17 increased the recruitment of phosphorylated NF-B to the CCL20 promoter, increased binding of coactivators such as p300 and CBP, and enhanced H3 and H4 histone acetylation, consistent with a transcriptionally active gene. SIGNOR-271680 0.306 β-D-fructose 6-phosphate smallmolecule CHEBI:57634 ChEBI beta-D-fructofuranose 2,6-bisphosphate smallmolecule CHEBI:28602 ChEBI up-regulates quantity precursor of 9606 9404080 t A full-length cDNA, which encodes a human placental fructose-6-phosphate,2-kinase/ fructose-2,6-bisphosphatase, was constructed and expressed in¬†Escherichia coli. [...]The expressed enzyme was bifunctional with¬†Vmax¬†values of 142 and 0.2 milliunits/mg for the kinase and phosphatase activities, respectively. SIGNOR-267261 0.8 ECM stimulus SIGNOR-ST20 SIGNOR Av/b8 integrin complex SIGNOR-C185 SIGNOR up-regulates 9606 30889378 t miannu Upon binding to the extracellular matrix (ECM), the integrins organize the cytoskeleton and activate intracellular signaling, regulating complex cellular behaviors, including survival, proliferation, migration, and various cell fate transitions SIGNOR-259042 0.7 DUSP4 protein Q13115 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR down-regulates activity dephosphorylation 10116 7535768 t inferred from 70% of family members Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK SIGNOR-269933 0.756 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT down-regulates activity phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0000452 11287630 t lperfetto Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten SIGNOR-106574 0.762 AVP protein P01185 UNIPROT AVPR2 protein P30518 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000671;BTO:0001260 1560825 t gcesareni We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin. SIGNOR-20185 0.732 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR CRY1 protein Q16526 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f lperfetto Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253679 0.938 PRKACA protein P17612 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation Ser173 DGEFLRTsCGSPNYA 9606 19942859 t gcesareni Pka associates with and phosphorylates ampk?1 At ser-173 to impede threonine thr-172 phosphorylation and thus activation of ampk1 by lkb1 in response to lipolytic signals SIGNOR-161860 0.407 CIT protein O14578 UNIPROT KIF14 protein Q15058 UNIPROT up-regulates activity binding 9606 BTO:0000565 16431929 t miannu We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase. SIGNOR-266424 0.717 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT down-regulates activity phosphorylation Ser319 TFRPRTSsNASTISG 9606 11237865 t lperfetto The transcription factor, forkhead in rhabdomyosarcoma (fkhr), is phosphorylated at three amino acid residues (thr-24, ser-256 and ser-319) by protein kinase b (pkb)alpha.Fkhr (forkhead in rhabdomyosarcoma), afx (all1 fused gene from chromosome x) and fkhrl1 (fkhr-like 1) are phosphorylated directly by pkb in cells, preventing them from stimulating gene transcription and leading to their exit from the nucleus SIGNOR-252349 0.2 AUTS2 protein Q8WXX7 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 28505103 f miannu Cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1). SIGNOR-266816 0.7 ING1 protein Q9UK53 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001938 15662138 f miannu Ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. SIGNOR-254488 0.2 ATM protein Q13315 UNIPROT ABL1 protein P00519 UNIPROT up-regulates phosphorylation Ser446 PYPGIDLsQVYELLE 9606 BTO:0000938 9168116 t lperfetto Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl. SIGNOR-48818 0.738 SORT1 protein Q99523 UNIPROT APOA1 protein P02647 UNIPROT up-regulates quantity binding 10029 BTO:0000246 23283348 t miannu Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms. SIGNOR-273722 0.335 sphingosine 1-phosphate(1-) smallmolecule CHEBI:60119 ChEBI S1PR1 protein P21453 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257577 0.8 CRKL protein P46109 UNIPROT MAP4K1 protein Q92918 UNIPROT up-regulates binding 9606 BTO:0000782 9891069 t HPK1 phosphorylated CrkL mainly on serine and weakly on threonine gcesareni We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk. SIGNOR-63991 0.577 NBEAL2 protein Q6ZNJ1 UNIPROT VAC14 protein Q08AM6 UNIPROT unknown binding 10090 BTO:0000132 29187380 t lperfetto In summary, from 129 binding partners of Nbeal2 identified by mass spectrometry, we have confirmed the interaction of 3, Dock7, Sec16a, and Vac14, by different biochemical and cellular approaches|Given the significant reduction of Dock7 levels and its altered localization in Nbeal2−/− platelets, we postulated that this canonical signaling pathway may be disrupted and set out to test this using control and Nbeal2−/− platelets. SIGNOR-261892 0.302 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 9990853 t gcesareni We report here the identification of an ikappab-ubiquitin (ub) ligase complex containing the f-box/wd40-repeat protein, beta-trcp, a vertebrate homolog of drosophila slimb. beta-trcp binds to ikappabalpha only when the latter is specifically phosphorylated by an ikappab kinase complex. here we provide evidence that lysine residues 21 and 22 serve as the primary sites for signal-induced ubiquitination of i kappa b alpha. SIGNOR-64321 0.529 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT up-regulates activity dephosphorylation -1 25624455 t miannu a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254722 0.261 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates activity phosphorylation Ser284 RRDYDDMsPRRGPPP 11231586 t miannu Mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) efficiently phosphorylates hnRNP-K both in vitro and in vivo at serines 284 and 353. Our results establish the role of MAPK/ERK in phosphorylation-dependent cellular localization of hnRNP-K, which is required for its ability to silence mRNA translation. SIGNOR-250082 0.342 RYK protein P34925 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 15454084 t gcesareni Ryk also binds to dishevelled, through which it activates the canonical wnt, providing a link between wnt and dishevelled SIGNOR-129574 0.41 GSK3B protein P49841 UNIPROT PTTG1 protein O95997 UNIPROT down-regulates quantity by destabilization phosphorylation Ser184 NLLQSPSsILSTLDV 9606 BTO:0000567 21757741 t miannu Here, we demonstrate that glycogen synthase kinase-3β (GSK3β) phosphorylates securin to promote its proteolysis via SCF(βTrCP) E3 ubiquitin ligase. SIGNOR-276344 0.2 PRKCE protein Q02156 UNIPROT MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates activity phosphorylation -1 15894802 t inferred from family member lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-270280 0.401 NFX1 protein Q12986 UNIPROT PABPC1 protein P11940 UNIPROT up-regulates activity binding 9606 BTO:0004117 17267499 t miannu NFX1-123 augments the activation of hTERT expression through interactions with PABPCs SIGNOR-226011 0.348 TFEB protein P19484 UNIPROT PPARA protein Q07869 UNIPROT up-regulates quantity by expression transcriptional regulation 33176151 f lperfetto Notably, TFEB regulates genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (for example, Cd36 and Fabps), and the β-oxidation of FFA in mitochondria (for example, Cpt1, Crat, Acadl, Acads and Hdad) and in peroxisomes (Cyp4a genes). SIGNOR-276706 0.28 MED29 protein Q9NX70 UNIPROT Core mediator complex complex SIGNOR-C405 SIGNOR form complex binding 9606 28467824 t miannu Mediator is a multiprotein co-activator that binds the transcription pre-initiation complex (PIC) and regulates RNA polymerase (Pol) II. The Mediator head and middle modules form the essential core Mediator (cMed), whereas the tail and kinase modules play regulatory roles. SIGNOR-266658 0.764 STUB1 protein Q9UNE7 UNIPROT TAL1 protein P17542 UNIPROT down-regulates quantity by destabilization ubiquitination 10090 BTO:0000944 17962192 t miannu Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively. SIGNOR-271393 0.36 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates dephosphorylation 9606 18676376 t lperfetto Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT)2 transcription factor family, allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to induce transcription of target genes. SIGNOR-233441 0.395 PCDHA12 protein Q9UN75 UNIPROT ITGB1 protein P05556 UNIPROT up-regulates activity binding 9606 BTO:0000227 16697637 t miannu The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. SIGNOR-265673 0.2 Vincristine sulfate chemical CHEBI:79401 ChEBI Tubulin proteinfamily SIGNOR-PF46 SIGNOR down-regulates activity chemical inhibition 9606 BTO:0000142 30599272 t miannu Vincristine is commonly administered as an effective anti-brain tumor drug. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. SIGNOR-259254 0.8 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1763 TPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273108 0.749 CCR4-NOT complex complex SIGNOR-C439 SIGNOR RC3H1 protein Q5TC82 UNIPROT down-regulates quantity by repression post transcriptional regulation 9606 31320642 t lperfetto In addition to its role in bulk mRNA decay, CCR4-NOT can also catalyze the deadenylation or promote translational repression of specific mRNA targets to which it is recruited by RNA binding proteins, such as Nanos, Roquin and Puf/Pumilio proteins SIGNOR-268348 0.334 MDM2 protein Q00987 UNIPROT POLQ protein O75417 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0001890 22056306 t miannu DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation SIGNOR-272729 0.2 PRKAA1 protein Q13131 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser358 WPLSRTRsEPLPPSA 9606 SIGNOR-C15 21892142 t gcesareni Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs). SIGNOR-176491 0.275 AMPK complex SIGNOR-C15 SIGNOR GLI1 protein P08151 UNIPROT down-regulates quantity by destabilization phosphorylation Ser408 GPLPRAPsISTVEPK 26190112 t Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency. SIGNOR-253541 0.299 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser568 PQATRQTsVSGPAPP 3118371 t llicata Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II. SIGNOR-250707 0.453 AKT1 protein P31749 UNIPROT SOX2 protein P48431 UNIPROT up-regulates quantity by stabilization phosphorylation Thr116 KYRPRRKtKTLMKKD 9606 BTO:0002428 30894683 t miannu Phosphorylation of SOX2 at threonine 116 by AKT inhibits the interaction of UBR5 with SOX2 and thus stabilizes SOX2.  SIGNOR-277445 0.543 NLGN4Y protein Q8NFZ3 UNIPROT NRXN1 protein Q9ULB1 UNIPROT up-regulates activity binding 9606 BTO:0000938 18923512 t brain lperfetto Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c) SIGNOR-264143 0.2 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates activity phosphorylation Thr356 FREFCIPtSSNIEQQ 9606 BTO:0000007 12123746 t gcesareni These results suggest that two C-terminal amino acids, Ser(355) and Thr(357), are required for short-term homologous desensitization and agonist-induced phosphorylation of mu-opioid receptors expressed in HEK 293 cells SIGNOR-247782 0.2 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120064 0.784 PRKG1 protein Q13976 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser443 PQRKSQRsSYVSMRI -1 12175859 t miannu Here, we have identified phosphorylation sites on the human ρ1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP‐dependent protein kinase (PKA); calmodulin‐dependent kinase (CaMKII); casein kinase (CKII); mitogen‐activated protein kinase (MAPK); and cGMP‐dependent protein kinase (PKG). The 1 IC-loop does not have consensus sequences for PKG, but we found that this enzyme phosphorylated the same sites as PKA: S422, S423 (Fig. 5A).An extensive functional analysis comparing wild type 1 receptors and receptors with select or multiple phosphorylation sites removed as well as pharmacological manipulation of five kinase pathways failed to reveal any functional effects of phosphorylation SIGNOR-262756 0.32 AKT proteinfamily SIGNOR-PF24 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 BTO:0000130 10559253 t esanto Akt phosphorylates p47phox and mediates respiratory burst activity in human neutrophils. A direct interaction between p47(phox) and akt was shown. Active recombinant akt phosphorylated recombinant p47(phox) in vitro. Mutation analysis indicated that 2 aa residues, ser(304) and ser(328), were phosphorylated by akt. Inhibition of akt activity also inhibited fmlp-stimulated neutrophil chemotaxis. SIGNOR-72133 0.2 AMOT protein Q4VCS5 UNIPROT YAP1 protein P46937 UNIPROT down-regulates relocalization 9606 BTO:0000567 21205866 t gcesareni Our results indicate a potential tumor-suppressing role of AMOT family proteins as components of the Hippo pathway, and demonstrate a novel mechanism of YAP and TAZ inhibition by AMOT-mediated tight junction localization. These observations provide a potential link between the Hippo pathway and cell contact inhibition. SIGNOR-201135 0.73 TRPM7 protein Q96QT4 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser5 sEFLKQAW 9606 24103589 t lperfetto Trpm7 was responsible for phosphorylation of the serine 5 (ser5) residue [29]. In 2009, the study focused on an association between anxa1 and trpm7 confirmed the presence of a trpm7/annexin a1/mg2_+ complex, suggesting a novel pathway in bradykinin signaling, dependent on pkc and c-src [30]. Even though that pathway is not fully characterized, the same team that discovered the ser5 phosphorylation of anxa1 also reported crucial relevance of this modification for anxa1 membrane binding and especially for the interaction between annexin a1 and its known partner, the calcium binding protein s100a11 SIGNOR-202804 0.555 EPHB2 protein P29323 UNIPROT RASA1 protein P20936 UNIPROT up-regulates binding 9606 9233798 t gcesareni We have localized an in vitro rasgap-binding site to conserved tyrosine residues y604 and y610 in the juxtamembrane region of ephb2, and demonstrated that substitution of these amino acids abolishes ephrin-b1-induced signalling events in ephb2-expressing ng108-15 cells. SIGNOR-50100 0.565 YBX1 protein P67809 UNIPROT NDRG1 protein Q92597 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255612 0.249 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr70 RNSPVTKtPPRDLPT 9606 12747827 t lperfetto Phosphorylated on serine and threonine residues in response to insulin, egf and pdgf. Phosphorylation at thr-37, thr-46, ser-65 and thr-70, corresponding to the hyperphosphorylated form, is regulated by mtorc1 and abolishes binding to eif4e. SIGNOR-235964 0.754 KLF1 protein Q13351 UNIPROT FLI1 protein Q01543 UNIPROT down-regulates activity binding 10090 BTO:0004475 12556498 t irozzo The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction. SIGNOR-256046 0.375 MAPK3 protein P27361 UNIPROT RPS6KA2 protein Q15349 UNIPROT up-regulates phosphorylation 9606 8939914 t gcesareni Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms SIGNOR-44949 0.71 all-trans-retinoic acid smallmolecule CHEBI:15367 ChEBI RXRB protein P28702 UNIPROT up-regulates activity chemical activation 9606 17132853 t miannu The physiological effects of retinoic acids (RAs) are mediated by members of two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which are encoded by three distinct human genes, RXRalpha, RXRbeta, and RXRgamma. SIGNOR-256191 0.8 CBS protein P35520 UNIPROT L-serine zwitterion smallmolecule CHEBI:33384 ChEBI down-regulates quantity chemical modification 9606 23981774 t lperfetto Cystathionine β-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. SIGNOR-275829 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR Mitotic_checkpoint phenotype SIGNOR-PH28 SIGNOR down-regulates 15549093 f lperfetto The critical target of the G2 checkpoint is the mitosis-promoting activity of the cyclin B/CDK1 kinase, whose activation after various stresses is inhibited by ATM/ATR, CHK1/CHK2 and/or p38-kinase-mediated subcellular sequestration, degradation and/or inhibition of the CDC25 family of phosphatases that normally activate CDK1 at the G2/M boundary SIGNOR-251496 0.7 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT down-regulates activity dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 BTO:0000007 16582879 t Binding of insulin to the IR results in autophosphorylation of each beta‐subunit on at least six different tyrosines. This autophosphorylation occurs first on three tyrosines located in the activation loop of the kinase domain (Y1158, 1162 and 1163), resulting in the stabilization of the kinase in an active conformation.|Termination of the signal involves inactivation of the IR by dephosphorylation of the three tyrosines of the kinase domain (Tonks, 2003). PTP1B is a protein tyrosine phosphatase located in the endoplasmic reticulum that has an important role in the dephosphorylation of these tyrosines after internalization of the IR SIGNOR-248409 0.782 RNMT protein O43148 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity chemical modification 9606 27422871 t lperfetto Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. SIGNOR-268316 0.8 CSNK2B protein P67870 UNIPROT RNF7 protein Q9UBF6 UNIPROT up-regulates activity phosphorylation Thr10 DVEDGEEtCALASHS 9606 BTO:0000567 12748192 t llicata In the present study, we show the evidence that CKBBP1 is phosphorylated on threonine residue at position 10 by CKII in vitro and in vivo. Most importantly, disruption of this phosphorylation in CKBBP1 results in accumulation of IκBα and p27Kip1 in HeLa cells and inhibits cell proliferation that appears to be linked to defects in G1/S transition. SIGNOR-251081 0.332 NRG4 protein Q8WWG1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 BTO:0000887 7477375 t Does not bind to the ERBB1, ERBB2 and ERBB3 receptors gcesareni The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4. SIGNOR-26280 0.689 JQ1 chemical CHEBI:137113 ChEBI BRDT protein Q58F21 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261990 0.8 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 9606 23612709 f Activated NFATc2 stimulates myoblast fusion through the increased production of IL-4 and myoferlin SIGNOR-255466 0.7 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT up-regulates activity phosphorylation Ser363 TSRTPKDsPGIPPSA 9534 BTO:0004055 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-250554 0.2 N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester chemical CHEBI:94187 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257970 0.8 HOXB8 protein P17481 UNIPROT TAGLN protein Q01995 UNIPROT down-regulates quantity by repression transcriptional regulation 10116 BTO:0002196 15886193 t Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively SIGNOR-261642 0.2 NFE2L2 protein Q16236 UNIPROT TFB2M protein Q9H5Q4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15684387 f lperfetto Here, we establish that the expression of human TFB1M and TFB2M promoters is governed by nuclear respiratory factors (NRF-1 and NRF-2), key transcription factors implicated in mitochondrial biogenesis. In addition, we show that NRF recognition sites within both TFB promoters are required for maximal trans activation by the PGC-1 family coactivators, PGC-1alpha and PRC SIGNOR-268996 0.252 SLBP protein Q14493 UNIPROT H2AC21 protein Q8IUE6 UNIPROT up-regulates quantity by expression translation regulation 9606 BTO:0001938 19155325 t lperfetto Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control. SIGNOR-265406 0.2 PRPF6 protein O94906 UNIPROT U4/U6.U5 snRNP complex complex SIGNOR-C478 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270625 0.765 TBK1 protein Q9UHD2 UNIPROT IRF5 protein Q13568 UNIPROT up-regulates phosphorylation Ser158 QRMLPSLsLTEDVKW 9606 22412986 t lperfetto Activation of interferon regulatory factor 5 by site specific phosphorylation. Although the gene induction by irf5 in the presence of tbk-1 was modest, phosphorylation by tbk-1 produced a significant shift in the mobility of irf5 in sds-page. For this reason we identified the residues that are phosphorylated on irf5 by tbk-1 with mass spectrometry. Ser-158 and ser-309 were found to be phosphorylated SIGNOR-196528 0.551 YBX1 protein P67809 UNIPROT TYMS protein P04818 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001023 17072343 f miannu YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. SIGNOR-255613 0.249 IL4 protein P05112 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 12757709 f miannu These data demonstrate that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4, leading to muscle growth SIGNOR-255896 0.7 CHRNB3 protein Q05901 UNIPROT APC protein P25054 UNIPROT up-regulates activity binding 9606 BTO:0002916 14502292 t miannu Treatment of muscle cells with neural agrin causes tyrosine phosphorylation of the AChR β subunit and induces AChR clustering by promoting anchoring of the receptor protein to postsynaptic cytoskeleton. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. By showing a direct requirement for APC in AChR clustering, our present study suggests that the Wnt/β-catenin pathway may crosstalk with the agrin signaling cascade during the formation of mammalian neuromuscular junction. SIGNOR-264261 0.2 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Thr62 VVGIDLGtTNSCVAV 9606 17573779 t lperfetto Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin SIGNOR-156185 0.2 ADRA1A protein P35348 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257084 0.575 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Glu637 QKLVFFAeDVGSNKG -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261768 0.497 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249460 0.624 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1735 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273068 0.635 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 17289999 t gcesareni Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax bax/bak are kept in check by the pro-survival bcl-2 family members and also proposes that for apoptotic death to occur, all pro-survival bcl-2-like proteins present within a given cell need to be neutralised by bh3-only proteins, thereby derepressing bax/bak SIGNOR-152980 0.667 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 t miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation SIGNOR-250093 0.421 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr605 KDLVSCAyQVARGME 9606 12601080 t lperfetto Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways. SIGNOR-98634 0.2 RNF4 protein P78317 UNIPROT SP1 protein P08047 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 21983342 t miannu Here, we identified RNF4 as the ubiquitin E3 ligase of Sp1. From in vitro and in vivo experiments, we found that sumoylated Sp1 can recruit RNF4 as a ubiquitin E3 ligase that subjects sumoylated Sp1 to proteasomal degradation.  SIGNOR-272720 0.395 UVB radiation stimulus SIGNOR-ST17 SIGNOR PAH protein P00439 UNIPROT up-regulates 9606 9204951 f miannu UVB light induces GTP-CH.-1 to increase the de novo synthesis of 6-BH4 in association with a concomitant increase in PAH activities, thus providing more L-tyrosine. SIGNOR-252207 0.7 PRKCB protein P05771 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -1 9677319 t lperfetto Here we show that Rad serves as a substrate for phosphorylation by CaMKII, cAMP-dependent protein kinase (PKA), protein kinase C (PKC) and casein kinase II (CKII) with stoichiometries in vitro of 0.2-1.3 mol of phosphate/mol of Rad. | PKC and CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. These findings suggest that the binding of Rad to calmodulin, as well as its ability to bind GTP, might be regulated by the activation of several serine kinases. SIGNOR-249003 0.307 PAK4 protein O96013 UNIPROT PACSIN1 protein Q9BY11 UNIPROT up-regulates activity phosphorylation Ser346 SQAGDRGsVSSYDRG -1 22371566 t miannu We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. SIGNOR-263023 0.299 MPO protein P05164 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates activity binding 9606 BTO:0000133 15972951 t lperfetto Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are associated with myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (ANCAs). SIGNOR-270585 0.2 GIGYF2 protein Q6Y7W6 UNIPROT EIF4E2/GIGYF2 complex complex SIGNOR-C257 SIGNOR form complex binding 9606 BTO:0000568 22751931 t SARA A Novel 4EHP-GIGYF2 Translational Repressor Complex Is Essential for Mammalian Development|GIGYF2 interacts specifically with m4EHP. The stabilities of m4EHP and GIGYF2 proteins are coregulated. SIGNOR-261009 0.705 SPRY4 protein Q9C004 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002058 20501643 f miannu When Spry4 was stably transfected into H157 and H2122 NSCLC cell lines, decreased migration and invasion were observed. Matrix metalloproteinase-9 activity was decreased, and the expression of matrix metalloproteinase inhibitors TIMP1 and CD82 were increased. Stable expression of Spry4 led to reduced cell growth and reduced anchorage-independent growth in NSCLC cell lines, along with upregulation of tumor suppressors p53 and p21. SIGNOR-253041 0.253 GRM4 protein Q14833 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 BTO:0000227 20055706 t miannu MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits. SIGNOR-264082 0.334 POT1 protein Q9NUX5 UNIPROT RPA1 protein P27694 UNIPROT down-regulates activity binding SIGNOR-C306 18680434 t lperfetto The current model for how telomeres repress ATR signaling proposes that POT1/TPP1 prevents the binding of RPA to the single-stranded telomeric DNA SIGNOR-263325 0.297 lisinopril chemical CHEBI:43755 ChEBI ACE protein P12821 UNIPROT down-regulates activity chemical inhibition -1 12540854 t Monia The structure of tACE bound to the potent inhibitor lisinopril shows that the inhibitor binds in a highly ordered (overall B-factor of 15.26 A˚ 2) SIGNOR-261070 0.8 PRKCE protein Q02156 UNIPROT GRM5 protein P41594 UNIPROT up-regulates activity phosphorylation Thr841 RSAFTTStVVRMHVG -1 15894802 t lperfetto Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839. SIGNOR-249288 0.401 MAPK1 protein P28482 UNIPROT PTPN7 protein P35236 UNIPROT up-regulates activity phosphorylation Thr66 EPICSVNtPREVTLH -1 16226275 t lperfetto First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.| SIGNOR-249437 0.808 TRIM28 protein Q13263 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity binding 9606 BTO:0000007 16107876 t 2 miannu we present evidence that MDM2 interacts with the nuclear corepressor KAP1. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. SIGNOR-240405 0.588 DLGAP4 protein Q9Y2H0 UNIPROT SHANK3 protein Q9BYB0 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264597 0.2 NEDD4 protein P46934 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0002181 26363003 t SARA We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels. SIGNOR-260998 0.27 IRX1 protein P78414 UNIPROT H2BC21 protein Q16778 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20440264 f Luana We identified a number of target genes by global microarray analysis after IRX1 transfection combined with real-time PCR and chromatin immunoprecipitation assay.| Downregulation of BDKRB2, PHYHIPL, HIST2H2BE, FGF7, PTGER1, NPTX1, EGR1, COL9A3, CUGBP2, DKK3 and BPI was confirmed. SIGNOR-261660 0.2 PRKACA protein P17612 UNIPROT GFAP protein P14136 UNIPROT down-regulates activity phosphorylation Ser13 ITSAARRsYVSSGEM -1 2155236 t miannu GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments. SIGNOR-249711 0.285 PER1 protein O15534 UNIPROT SLC5A1 protein P13866 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000195 22526585 f miannu Our findings suggest that PER1 exerts an indirect suppressive effect on SGLT1, possibly acting via other clock-controlled genes binding to non-E-box sites on the SGLT1 promoter. SIGNOR-254912 0.341 PPP1CA protein P62136 UNIPROT IFIH1 protein Q9BYX4 UNIPROT up-regulates activity dephosphorylation Ser88 EALRRTGsPLAARYM 9606 BTO:0000007 23499489 t lperfetto Exogenous PP1alpha or PP1gamma substantially decreased the S88 phosphorylation of Flag-MDA5|we identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation. SIGNOR-264577 0.2 PAK1 protein Q13153 UNIPROT SNAI1 protein O95863 UNIPROT up-regulates phosphorylation Ser246 QACARTFsRMSLLHK 9606 BTO:0000150 15833848 t lperfetto Pak1 regulates the repressor activity of snail by phosphorylating on ser(246). Pak1 phosphorylation of snail supports snail's accumulation in the nucleus as well as its repressor functions. SIGNOR-135605 0.407 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates activity phosphorylation 10090 BTO:0002572 28646232 t Gianni We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3β at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3β activity and restores protein synthesis in Tsc2 −/− MEFs to normal levels SIGNOR-262519 0.356 Hexokinase proteinfamily SIGNOR-PF76 SIGNOR α-D-glucose smallmolecule CHEBI:17925 ChEBI down-regulates quantity chemical modification 9606 16051738 t miannu Hexokinase catalyzes the phosphorylation of glucose to G6P, using ATP as a phosphoryl donor. SIGNOR-266459 0.8 CHN1 protein P15882 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260499 0.657 FOXO1 protein Q12778 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16308421 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-142147 0.2 UBE3A protein Q05086 UNIPROT PSMC2 protein P35998 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 28559284 t lperfetto Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits. SIGNOR-265132 0.392 MC4R protein P32245 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256940 0.271 PKA proteinfamily SIGNOR-PF17 SIGNOR PDE4B protein Q07343 UNIPROT up-regulates activity phosphorylation Ser133 GHSQRREsFLYRSDS 9534 BTO:0001538 12023945 t miannu Phosphorylation of long PDE4 isoforms by PKA. COS1 cells were transfected to express various long PDE4 isoforms. SIGNOR-275986 0.2 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT down-regulates activity phosphorylation Thr19 GSRRGRAtPAQTPRS 9606 BTO:0000567 12714602 t lperfetto We report here that human mcm4, a subunit of the putative dna replicative helicase, is extensively phosphorylated in hela cells when they are incubated in the presence of inhibitors of dna synthesis or are exposed to uv irradiation. The data presented here indicate that the consecutive actions of atr-chk1 and cdk2 kinases are involved in this phosphorylation in the presence of hydroxyurea. Phosphorylation of t19 correlates with lowered level of dna helicase activity of the purified mcm4,6,7 complex. SIGNOR-100893 0.761 MEN1 protein O00255 UNIPROT MLL Fusion fusion protein SIGNOR-FP14 SIGNOR up-regulates activity binding 10090 BTO:0004730 16239140 t miannu We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis.These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity. SIGNOR-260130 0.2 sapropterin smallmolecule CHEBI:59560 ChEBI GCHFR protein P30047 UNIPROT up-regulates activity chemical activation 9606 11361142 t miannu The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine SIGNOR-252204 0.8 APIP protein Q96GX9 UNIPROT APAF1 protein O14727 UNIPROT down-regulates binding 9606 15262985 t acerquone Taken together, these results suggest that apip functions to inhibit muscle ischemic damage by binding to apaf-1 in the apaf-1/caspase-9 apoptosis pathway. SIGNOR-126797 0.536 GNAO1 protein P09471 UNIPROT TAOK2 protein Q9UL54 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto These results suggest that go alpha q205l activates p38 through taos and mek3/6. SIGNOR-235542 0.2 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t lperfetto In the present study, we demonstrate that bcr tyr-246 and at least one of the closely spaced tyrosine residues, tyr-279, tyr-283, and tyr- 289 (3y cluster), are phosphorylated by fes both in vitro and in 32p(i)- labeled cells. tyrosine phosphorylation of bcr by fes suppressed bcr serine/threonine kinase activity toward the 14-3-3 protein and bcr substrate, bap-1. SIGNOR-45330 0.372 PTCD3 protein Q96EY7 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding Q9Y2Q9 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261437 0.723 CAMKK2 protein Q96RR4 UNIPROT PRKAA1 protein Q13131 UNIPROT up-regulates phosphorylation Thr183 SDGEFLRtSCGSPNY 9606 21918180 t gcesareni Ampka1 activators increased phosphorylation level and cytoplasmic localization (reduced nuclear/cytoplasmic ratio). Ampka1 activators reduced rna synthesis in the nucleoli. SIGNOR-176602 0.595 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT unknown phosphorylation Ser410 GLPQRSGsNIEQYIH 9606 10455013 t lperfetto 3-phosphoinositide-dependent protein kinase-1 (pdk1) expressed in unstimulated 293 cells was phosphorylated at ser-25, ser-241, ser-393, ser-396 and ser-410 and the level of phosphorylation of each site was unaffected by stimulation with insulin-like growth factor-1. Mutation of ser-241 to ala abolished pdk1 activity, whereas mutation of the other phosphorylation sites individually to ala did not affect pdk1 activity SIGNOR-236772 0.2 lapatinib chemical CHEBI:49603 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 BTO:0000150 17892419 t gcesareni Recently, lapatinib, a small molecule dual inhibitor of both her2 and egf receptors, has been developed to expand the options for treating her-positive breast cancer. SIGNOR-157867 0.8 ATIC protein P31939 UNIPROT 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267327 0.8 NFIB protein O00712 UNIPROT ETV5 protein P41161 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268880 0.2 DAPK1 protein P53355 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 17339337 t gcesareni A cell-free ser(20) phosphorylation site assay was used to identify a broad range of calcium calmodulin kinase superfamily members, including chk2, chk1, dapk-1, dapk-3, drak-1, and ampk, as ser(20) kinases.Evaluation of these calcium calmodulin kinase superfamily members as candidate ser(20) kinases in vivo has shown that only chk1 or dapk-1 can stimulate p53 transactivation and induce ser(20) phosphorylation of p53. SIGNOR-153487 0.569 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT down-regulates activity phosphorylation Ser518 KTVTPASsAKTSPAK 10116 BTO:0000938 15652488 t lperfetto Ser-518 is also a potential phosphorylation site of CRMP-2 by GSK-3_. SIGNOR-133251 0.717 PRKCE protein Q02156 UNIPROT GJA1 protein P17302 UNIPROT up-regulates phosphorylation Ser369 RPSSRASsRASSRPR 9606 16474210 t lperfetto We previously showed that follicle-stimulating hormone (fsh) promoted phosphorylation of cx43 in rat primary granulosa cells. We further identified ser365, ser368, ser369, and ser373 in the carboxy-terminal tail as the major sites of phosphorylation by fsh, and found that the phosphorylation of these residues was essential for channel activity. SIGNOR-144469 0.446 CTCF protein P49711 UNIPROT MGAT5B protein Q3V5L5 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0001976 21771782 f miannu By EMSA and ChIP analyses we identified two regulatory proteins, NeuroD1 and CTCF that bind to and activate the GnT-IX promoter. We also revealed that GnT-IX expression was suppressed in CTCF- and NeuroD1-depleted cells, indicating that a NeuroD1- and CTCF-dependent epigenetic mechanism governs brain-specific GnT-IX expression. SIGNOR-253826 0.2 ZFP36 protein P26651 UNIPROT EIF4E2/GIGYF1 complex complex SIGNOR-C256 SIGNOR up-regulates activity relocalization 9606 30917308 t lperfetto A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs SIGNOR-261014 0.2 SMO protein Q99835 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 23074268 t gcesareni Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling. SIGNOR-199159 0.504 GABRA5 protein P31644 UNIPROT GABA-A (a5-b1-g2) receptor complex SIGNOR-C335 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263765 0.637 JUN protein P05412 UNIPROT MTHFR protein P42898 UNIPROT up-regulates 9606 18065414 f lperfetto The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression SIGNOR-253147 0.274 RNF7 protein Q9UBF6 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates activity ubiquitination 9606 23136067 t miannu SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase.  by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes. SIGNOR-271451 0.2 DYRK1B protein Q9Y463 UNIPROT DYRK1B protein Q9Y463 UNIPROT up-regulates phosphorylation Tyr273 LGQRIYQyIQSRFYR 9606 10910078 t lperfetto Mirk kinase is activated by autophosphorylation on tyrosine at the y271/y273 site SIGNOR-79810 0.2 CDK2 protein P24941 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 15964852 t lperfetto Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130. SIGNOR-149416 0.953 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCA protein P17252 UNIPROT up-regulates chemical activation 9606 BTO:0000887;BTO:0001103 22944199 t gcesareni The wnt/ca2+ signaling pathway is defined by the activation of plc (phospholipase c) through wnt/fzd resulting in an increase in intracellular ca2+ levels, which activate pkcs (protein kinase c) and camkii (calcium-calmodulin-dependent kinase ii) or cn (calcineurin), a phosphatase that activates the transcription factor nfat (nuclear factor of activated t cell). SIGNOR-198822 0.8 PRKCG protein P05129 UNIPROT GSTP1 protein P09211 UNIPROT up-regulates activity phosphorylation Ser43 VETWQEGsLKASCLY -1 15604283 t miannu Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently SIGNOR-276018 0.2 MAPK3 protein P27361 UNIPROT LIPE protein Q05469 UNIPROT up-regulates activity phosphorylation Thr891 NSETSSDtPEMSLSA 10090 BTO:0000944 11581251 t lperfetto Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL. SIGNOR-249470 0.421 CDC25A protein P30304 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates activity dephosphorylation 9606 BTO:0000093 11154267 t lperfetto Cyclin E-Cdk2 complexes from p16INK4a-expressing MCF-7 cells are activated in vitro and in vivo by Cdc25A SIGNOR-245452 0.741 SMURF proteinfamily SIGNOR-PF29 SIGNOR BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t inferred from 70% family members gcesareni Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps SIGNOR-270212 0.2 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 14967450 t lperfetto The egf-r coimmunoprecipitated with p85 alpha SIGNOR-121959 0.805 GRIP1 protein Q9Y3R0 UNIPROT KIF5C protein O60282 UNIPROT up-regulates activity binding 9606 BTO:0000142 31757889 t miannu HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro SIGNOR-264061 0.328 EIF2B4 protein Q9UI10 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269132 0.748 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MAP3K8 protein P41279 UNIPROT down-regulates binding 9606 22435554 t lperfetto Tpl-2 is stoichiometrically complexed with the nf-kb inhibitory protein, nf-kb1 p105, and the ubiquitin-binding protein abin-2, both of which are required to maintain tpl-2 protein stability. Binding to p105 also prevents tpl-2 from phosphorylating mek SIGNOR-216289 0.553 CTDSPL protein O15194 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates activity dephosphorylation Ser214 PTSSDPGsPFQMPAD 9606 BTO:0000552 17085434 t Smad proteins transduce bone morphogenetic protein (BMP) and transforming growth factor-beta (TGFbeta) signals upon phosphorylation of their C-terminal SXS motif by receptor kinases.|Phosphatases that dephosphorylate the linker region are therefore likely to play an integral part in the regulation of Smad activity. We reported previously that small C-terminal domain phosphatases 1, 2, and 3 (SCP1-3) dephosphorylate Smad1 C-terminal tail, thereby attenuating BMP signaling. |The linker region of Smad1 consists of four MAPK phosphorylation sites (Ser-187, Ser-195, Ser-206, and Ser-214) SIGNOR-248316 0.484 Avagacestat chemical CID:46883536 PUBCHEM APP protein P05067 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190479 0.8 CSTF complex complex SIGNOR-C441 SIGNOR mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 10669729 f lperfetto Polyadenylation of mRNA precursors is a two-step reaction requiring multiple protein factors. Cleavage stimulation factor (CstF) is a heterotrimer necessary for the first step, endonucleolytic cleavage, and it plays an important role in determining the efficiency of polyadenylation. SIGNOR-268369 0.7 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1647 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120000 0.784 CSNK2A1 protein P68400 UNIPROT EIF5 protein P55010 UNIPROT up-regulates activity phosphorylation Ser174 DKENGSVsSSETPPP 9606 11861906 t llicata Mass spectrometric analysis of maximally in vitro phosphorylated eIF5 localized the major phosphorylation sites at Ser-387 and Ser-388 near the C-terminus of eIF5. These serine residues are embedded within a cluster of acidic amino acid residues and account for nearly 90% of the total in vitro eIF5 phosphorylation. A minor phosphorylation site at Ser-174 was also observed. | The results suggest that phosphorylation of eIF5 may have a role in stimulating the rate of eIF5-promoted GTP hydrolysis. SIGNOR-250861 0.399 KIF1C protein O43896 UNIPROT RAB6C protein Q9H0N0 UNIPROT up-regulates quantity relocalization -1 20360680 t miannu Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation. SIGNOR-266879 0.247 AURKA protein O14965 UNIPROT PLK1 protein P53350 UNIPROT up-regulates phosphorylation Thr210 YDGERKKtLCGTPNY 9606 18615013 t gcesareni We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210). SIGNOR-179422 0.655 EIF4A3 protein P38919 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265240 0.947 ruxolitinib phosphate chemical CHEBI:66917 ChEBI JAK2 protein O60674 UNIPROT down-regulates activity chemical inhibition 9606 23061804 t miannu Ruxolitinib is a selective inhibitor of Janus kinases (JAK) 1 and 2, which are involved in the signalling pathway of various cytokines and growth factors essential to haematopoiesis. SIGNOR-259171 0.8 GRM2 protein Q14416 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264349 0.7 AMPK complex SIGNOR-C15 SIGNOR ULK1/Atg13/Fip200 complex SIGNOR-C100 SIGNOR up-regulates activity phosphorylation 9606 23863160 t lperfetto Under energy deprivation, AMPK positively regulates ULK1 to induce autophagy, with various studies revealing that AMPK binds to and phosphorylates ULK1 SIGNOR-209913 0.418 AKT2 protein P31751 UNIPROT ADARB1 protein P78563 UNIPROT down-regulates activity phosphorylation Thr553 LQGERLLtMSCSDKI -1 31095429 t miannu AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively SIGNOR-276196 0.2 nintedanib chemical CHEBI:85164 ChEBI FLT1 protein P17948 UNIPROT down-regulates activity chemical inhibition -1 18559524 t Luana In this report, we describe the preclinical profile of BIBF 1120, a combined VEGFR, FGFR, and PDGFR inhibitor currently entering phase III clinical studies in non–small cell lung carcinoma and other cancers. SIGNOR-257800 0.8 AP-3 complex complex SIGNOR-C247 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 f lperfetto Lysosome-related organelles (LROs) 6 are present in a range of cells in multicellular eukaryotes and include lytic granules, lung lamellar bodies, platelet-dense granules, and melanosomes (1.). The melanosome of the pigment cells in the skin and eye is the best studied of the LROs (1., 2.). The biogenesis of the melanosome and other LROs requires the AP-3 adaptor complex, the class C Vps complex, and three BLOC (biogenesis of lysosome-related organelles complex) complexes SIGNOR-265941 0.7 CSNK1D protein P48730 UNIPROT GJA1 protein P17302 UNIPROT up-regulates activity phosphorylation Ser330 AGSTISNsHAQPFDF 10116 BTO:0000067 12270943 t lperfetto We have examined the role of casein kinase 1 (CK1) in connexin-43 (Cx43) gap junction assembly. Cellular co-immunoprecipitation experiments and in vitro CK1 phosphorylation reactions indicate that CK1 interacted with and phosphorylated Cx43, initially on serine(s) 325, 328, or 330.| To examine CK1 function, normal rat kidney cells were treated with CKI-7, and Cx43 content was analyzed by Triton X-100 extraction, cell-surface biotinylation, and immunofluorescence. Western blot analysis indicated a slight increase in total Cx43, whereas gap junctional (Triton-insoluble) Cx43 decreased, and non-junctional plasma membrane Cx43 increased (as detected by cell surface biotinylation). SIGNOR-249331 0.593 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT up-regulates activity cleavage Ala36 PESKATNaTLDPRSF -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus SIGNOR-263575 0.426 NEUROG1 protein Q92886 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 18400164 f lperfetto While the mechanisms by which Ngn2 promotes neurogenesis have been characterized, little is known about how Ngn2 confers neuronal cell-type identity during spinal cord development. Ngn1 and Ngn2, two mammalian orthologs of the Drosophila proneural bHLH gene atonal, are expressed in overlapping patterns throughout the developing nervous system and act as important regulators of developmental neurogenesis SIGNOR-265172 0.7 PRKCB protein P05771 UNIPROT LASP1 protein Q14847 UNIPROT down-regulates activity phosphorylation Ser146 MEPERRDsQDGSSYR 9606 12571245 t lperfetto Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration SIGNOR-97942 0.2 TWIST2 protein Q8WVJ9 UNIPROT RAP1A protein P62834 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255508 0.2 PRKG2 protein Q13237 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser78 PAYSRALsRQLSSGV 9606 19593530 t 10383393: We demonstrate that both phosphorylated sHsps and the triple mutant Hsp27-S15D,S78D,S82D show significantly decreased abilities to act as molecular chaperones suppressing thermal denaturation and facilitating refolding of citrate synthase in vitro. lperfetto Purified pkg isoforms ia, ib, and ii all caused incorporation of phosphate in recombinant hsp27 at ser-78, ser-82, and thr-143, but not ser-15.These Studies indicate that hsp27 is a genuine substrate for pkg and that pkg may mediate inhibition of platelet aggregation through phosphorylation of hsp27 and subsequent prevent of actin polymerization SIGNOR-186796 0.2 C3 convertase complex complex SIGNOR-C310 SIGNOR C3 protein P01024 UNIPROT up-regulates activity cleavage Arg671 QPAARRRrSVQLTEK 31331124 t lperfetto This forms the C4b2a complex, which is a classical pathway C3 convertase. C4b2a cleaves C3, which is the central component of the complement cascade, to C3a, and anaphylatoxin, and C3b results in the activation of the lytic pathway SIGNOR-263449 0.547 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LTC4S protein Q16873 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001433 12574384 f miannu activation of NF-kappaB and p50/p65 overexpression down-regulated the LTC(4) synthase gene. LPS down-regulates cysteinyl LT release and LTC(4) synthase gene expression in mononuclear phagocytes by an NF-kappaB-mediated mechanism. SIGNOR-254799 0.259 LYN protein P07948 UNIPROT IRF5 protein Q13568 UNIPROT down-regulates activity phosphorylation Tyr313 PSDKQRFyTNQLLDV 9606 BTO:0002181 27521268 t miannu Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity. SIGNOR-277247 0.333 CXCL8 protein P10145 UNIPROT CXCR1 protein P25024 UNIPROT up-regulates binding 9606 11350788 t gcesareni Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades. SIGNOR-107920 0.776 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT up-regulates activity phosphorylation Ser245 KPGALSNsESIPTID 9534 BTO:0000298 11483516 t llicata BMP type I receptor activation stimulates AMSH phosphorylation | The exact position of phosphoserine residues in four phosphopeptides was identified by Edman degradation analysis; spot a for Ser243, Ser245 and Ser247, spot b for Ser2, and spots c and d for Ser48. To confirm the position of the phosphoserine residues, the serine residue(s) in each phosphopeptide was replaced by alanine residues. Then, each mutant as well as wild‐type AMSH was transfected into COS7 cells in the absence or presence of caALK6, and tryptic phosphopeptide mapping of each mutant was performed. As seen in Figure 7, each spot corresponding to the phosphopeptide containing phosphoserine disappeared in the tryptic phosphopeptide mapping. | Thus, AMSH promotes BMP signaling by negatively regulating the function of I‐Smads. SIGNOR-250598 0.292 OGDC complex SIGNOR-C397 SIGNOR succinyl-CoA(5-) smallmolecule CHEBI:57292 ChEBI up-regulates quantity chemical modification 9606 15953811 t miannu The Œ±-ketoglutarate‚Äìdehydrogenase complex is a complex including multiple copies of three proteins: E1k (Œ±-ketoglutarate dehydrogenase), E2k (dihydrolipoyl succinyltransferase), and E3 (dihydrolipoamide dehydrogenase) (Fig. 2). The consecutive action of the three catalytic components of KGDHC results in oxidative decarboxylation of 2-oxoglutarate, preserving the energy in the form of succinylCoA and NADH. SIGNOR-266258 0.8 ATF4 protein P18848 UNIPROT YARS2 protein Q9Y2Z4 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269432 0.2 sorafenib chemical CHEBI:50924 ChEBI KDR protein P35968 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258285 0.8 CDK4 protein P11802 UNIPROT GATA4 protein P43694 UNIPROT down-regulates quantity by destabilization phosphorylation Ser105 AYTPPPVsPRFSFPG 9606 BTO:0000567 21447557 t miannu Finally, CDK4 phosphorylated GATA4 directly, which promoted the degradation of GATA4 in cultured cells. SIGNOR-276317 0.362 RAB5C protein P51148 UNIPROT EEA1 protein Q15075 UNIPROT up-regulates activity binding -1 12493736 t Federica The Rab5 effector early endosome antigen 1 (EEA1) is a parallel coiled coil homodimer with an N-terminal C(2)H(2) Zn(2+) finger and a C-terminal FYVE domain. Rab5 binds to independent sites at the N and C terminus of EEA1.|The results demonstrate that the C(2)H(2) Zn(2+) finger is both essential and sufficient for the N-terminal interaction with Rab5. SIGNOR-261266 0.828 phosphatidic acid smallmolecule CHEBI:16337 ChEBI SOS1 protein Q07889 UNIPROT up-regulates chemical activation 9606 17486115 t gcesareni Phosphatidic acid interacts with a defined site in the sos ph domain with high affinity and specificity SIGNOR-154676 0.8 ZBTB16 protein Q05516 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 BTO:0002882 9710637 f fcortellessa PLZF overexpression leads to apoptosis. SIGNOR-261686 0.7 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t The effect has been demonstrated using Q01196-8. gcesareni Phosphorylation of ser-48, ser-303, and ser-424 by cyclin-dependent kinases (cdks) increases runx1 trans-activation activity without perturbing p300 interaction. SIGNOR-138920 0.345 L-tryptophan smallmolecule CHEBI:16828 ChEBI 5-hydroxy-L-tryptophan smallmolecule CHEBI:17780 ChEBI up-regulates quantity precursor of 9606 31024440 t brain lperfetto In serotonergic neurons Trp serves as the precursor for 5-HT. The 5-HT metabolic pathway is initiated by Trp being hydroxylated to the intermediate 5-hydroxytryptophan (5-HTP), which is subsequently decarboxylated to become 5-HT|Thus, the rate limiting step in the biosynthesis of 5-HT is the hydroxylation of Trp which is catalyzed by the enzyme tryptophan hydroxylase (TPH) (Figure 1). This enzyme is specific for 5-HT producing cells, however, it is present in two different isoforms, TPH1 and TPH2 [reviewed in (22, 23)]. SIGNOR-264185 0.8 cabozantinib chemical CHEBI:72317 ChEBI RET protein P07949 UNIPROT down-regulates activity chemical inhibition 9606 21606412 t miannu XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. SIGNOR-259321 0.8 TM9SF4 protein Q92544 UNIPROT MTOR protein P42345 UNIPROT down-regulates activity binding 9606 BTO:0000007 29125601 t miannu TM9SF4 inhibited mTOR activity in HEK293 cells. Under nutrient starvation, TM9SF4 functions to facilitate mTOR inactivation, resulting in an enhanced autophagic flux, which serves to protect cells from apoptotic cell death. SIGNOR-266703 0.2 SRC protein P12931 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Tyr236 FYDETYDyGGFTMMF 9606 12052863 t lperfetto We show that hnrnp k and the c-src kinase specifically interact with each other, leading to c-src activation and tyrosine phosphorylation of hnrnp k in vivo and in vitro. c-src-mediated phosphorylation reversibly inhibits the binding of hnrnp k to the differentiation control element (dice) of the lox mrna 3' untranslated region in vitro and specifically derepresses the translation of dice-bearing mrnas in vivo.We confirmed that tyr 230, 234, 236, and 380 are phosphorylated and identified two additional targets of c-src, tyr 72 and tyr 225 (data not shown). SIGNOR-88911 0.607 HDAC3 protein O15379 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR up-regulates binding 9606 23213415 t lperfetto Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes. SIGNOR-217358 0.449 RAD23B protein P54727 UNIPROT XPA protein P23025 UNIPROT up-regulates activity binding 24086043 t lperfetto GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo SIGNOR-275697 0.765 TTBK2 protein Q6IQ55 UNIPROT KIF2A protein O00139 UNIPROT down-regulates activity phosphorylation Ser135 SSAQQNGsVSDISPV 9534 26323690 t Manara TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A SIGNOR-260926 0.413 PI4KA protein P42356 UNIPROT 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI down-regulates quantity chemical modification 9606 10101268 t miannu The enzymes PtdIns 4-kinase (PI4K, for nomenclature see [3]) and PtdIns(4)P 5-kinase (PI4P5K) catalyse the phosphorylation of PtdIns at the D4 and consecutively at the D5 position. SIGNOR-269095 0.8 BMI1 protein P35226 UNIPROT PTEN protein P60484 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000785 19884659 f gcesareni Chromatin immunoprecipitation assays revealed the bmi-1 transcriptionally downregulated expression of the tumor suppressor pten in tumor cells through direct association with the pten locus. SIGNOR-189040 0.561 Kindlin proteinfamily SIGNOR-PF48 SIGNOR AD/b2 integrin complex SIGNOR-C172 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259028 0.408 ADRA1B protein P35368 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257079 0.604 PRKCZ protein Q05513 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates quantity by stabilization phosphorylation Ser345 RGDGSGFsL 9606 BTO:0002181 23249950 t miannu APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation. SIGNOR-276433 0.838 GARS1 protein P41250 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 24898252 t miannu Aminoacyl-tRNA synthetases are an ancient enzyme family that specifically charges tRNA molecules with cognate amino acids for protein synthesis. Glycyl- tRNA synthetase (GlyRS) is one of the most intriguing aminoacyl-tRNA synthetases due to its divergent quaternary structure and abnormal charging properties. . In this study we report crystal structures of wild type and mutant hGlyRS in complex with tRNA and with small substrates and describe the molecular details of enzymatic recognition of the key tRNA identity elements in the acceptor stem and the anticodon loop. SIGNOR-270479 0.8 SF3A2 protein Q15428 UNIPROT U2 snRNP complex complex SIGNOR-C479 SIGNOR form complex binding 9606 30765414 t lperfetto The major spliceosomal building blocks are the U1, U2, U4/U6, and U5 small nuclear ribonucleoproteins (snRNPs). Each consists of a small nuclear RNA (snRNA) (or two, in the case of U4/U6), seven Sm proteins that form a ring (or seven Lsm proteins in the case of U6), and a variable number of snRNP-specific proteins (Fig. 1F) (Will and Lührmann 2011). Under splicing conditions, the U4/U6 and U5 snRNPs form a 25S U4/U6.U5 tri-snRNP, in which the U4 and U6 snRNAs are base-paired, forming a three-way junction. SIGNOR-270667 0.812 SEMA3A protein Q14563 UNIPROT PLXNA2 protein O75051 UNIPROT up-regulates binding 9606 10679438 t gcesareni Plexins form stable complexes with neuropilin-1 or -2. SIGNOR-75168 0.855 PRKCH protein P24723 UNIPROT ANXA1 protein P04083 UNIPROT up-regulates phosphorylation Ser27 EYVQTVKsSKGGPGS 9606 24103589 t lperfetto The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization. SIGNOR-202792 0.2 GSK3B protein P49841 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates quantity by destabilization phosphorylation Ser114 EEDHVDLsLSCTLVP 9606 BTO:0000093 17283049 t lperfetto Glycogen synthase kinase 3beta phosphorylates p21waf1/cip1 for proteasomal degradation after uv irradiationhere, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3beta (gsk-3beta) is required for its degradation in response to uv irradiation SIGNOR-152941 0.407 PRKACG protein P22612 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 10949026 t gcesareni Ser-155 is the major phosphoacceptor site for pka on bad, but that pka also phosphorylates ser-112 and ser-136. Phosphorylated bad appears to be the inactive moiety. These results implicate pkac as the candidate kinase for s112 phosphorylation in vivo. SIGNOR-81157 0.418 palmitoyl-CoA smallmolecule CHEBI:15525 ChEBI 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity precursor of 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267880 0.8 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 1939237 t lperfetto Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. The identification of myelin basic protein (phosphorylation at -pro-arg-thr-pro-) as a substrate for the erk kinases (fig. 1) demonstrates that there are other determinants important for substrate recognition than those present in the originally identified consensus sequence. SIGNOR-22424 0.511 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10375532 t miannu Isolated SCF(Skp2) contained an E3 ubiquitin ligase activity towards p27. Our data thus suggest that SCF(Skp2) specifically targets p27 for degradation during cell-cycle progression.Immunodepletion of components of the complex - Cul-1, Skp1, or Skp2 - from the extract abolished p27 degradation, while addition of purified SCF(Skp2) to Skp2- depleted extract restored the capacity to degrade p27.  SIGNOR-272933 0.688 TNFRSF1B protein P20333 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates activity 20887952 f These results indicate that TNF-a-activated p38 pathway negatively controls the expansion of PAX7-positive SCs SIGNOR-253603 0.304 SMAD7 protein O15105 UNIPROT TAB2 protein Q9NYJ8 UNIPROT up-regulates binding 9606 BTO:0001253 17384642 t lperfetto The formation of smad7-tab2 and smad7-tab3 complexes resulted in the suppression of tnf signaling SIGNOR-153917 0.558 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid chemical CHEBI:91366 ChEBI AURKA protein O14965 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258250 0.8 ANKRD11 protein Q6UB99 UNIPROT RAB13 protein P51153 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000142 29274743 t miannu Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.  SIGNOR-266738 0.2 MAPK8 protein P45983 UNIPROT STAT3 protein P40763 UNIPROT up-regulates activity phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0002923 23255093 t lperfetto Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3, SIGNOR-235704 0.579 RAD18 protein Q9NS91 UNIPROT PCNA protein P12004 UNIPROT up-regulates ubiquitination 9606 19706603 t gcesareni Rad5 interacts with the e3 ligase rad18, which is initially required to monoubiquitinate pcna SIGNOR-187705 0.842 CNR2 protein P34972 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256979 0.251 TOLLIP protein Q9H0E2 UNIPROT IRAK1 protein P51617 UNIPROT down-regulates activity binding 9606 BTO:0000007 10854325 t lperfetto Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs) SIGNOR-251980 0.795 MEF2C protein Q06413 UNIPROT CDKL5 protein O76039 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 20513142 f Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression|In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. SIGNOR-254031 0.355 WASH complex complex SIGNOR-C258 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261006 0.2 GSK3B protein P49841 UNIPROT MUC1 protein P15941 UNIPROT down-regulates activity phosphorylation Ser1227 PPSSTDRsPYEKVSA BTO:0000567 9819408 t lperfetto GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo. SIGNOR-249356 0.464 CSNK1E protein P49674 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250806 0.348 PCDH19 protein Q8TAB3 UNIPROT GABRA5 protein P31644 UNIPROT up-regulates quantity by stabilization binding 10116 BTO:0003102 SIGNOR-C335 29360992 t miannu Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.  SIGNOR-267219 0.26 CSNK1A1 protein P48729 UNIPROT AGO2 protein Q9UKV8 UNIPROT down-regulates activity phosphorylation Thr830 DSAEGSHtSGQSNGR 9606 BTO:0001109 28114302 t miannu Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression. SIGNOR-276510 0.374 ANXA1 protein P04083 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0004136 17464329 f miannu We next focused on the pro-apoptotic function of ANXA1 in AML1-ETO-expressing AML cells. In this regard, FK228 was found to increase the protein levels of both the full-length and 33 kDa N-terminal cleavage products of ANXA1, which led to the localization of ANXA1 on the plasma membrane. Conversely, the inhibition of ANXA1 function (by ANXA1 neutralizing antibody, which blocked ANXA1 localization on the plasma membrane) or expression (by siRNA) significantly reduced FK228-induced apoptosis, indicating that ANXA1 is involved in apoptosis induction in response to FK228. SIGNOR-261689 0.7 PLCB1 protein Q9NQ66 UNIPROT GNA11 protein P29992 UNIPROT up-regulates binding 9606 1322796 t miannu Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11 SIGNOR-17239 0.613 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 9606 BTO:0000527 19941816 t gcesareni It has been shown that the c-terminal domains of ck2? Are phosphorylated by cdc2 and interact with the peptidyl-prolyl isomerase pin1 in a cell cycle-dependent manner SIGNOR-161843 0.358 XRCC3 protein O43542 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates quantity by stabilization binding 9606 23438602 t miannu XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation. SIGNOR-262667 0.741 MAP2K4 protein P45985 UNIPROT RXRA protein P19793 UNIPROT down-regulates phosphorylation Tyr249 VEPKTETyVEANMGL 9606 10938283 t miannu Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1. SIGNOR-80619 0.2 CDK1 protein P06493 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser251 MIQFAINsTERKRMT 9606 SIGNOR-C17 19737929 t lperfetto A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1the phosphorylation at ser-251 is critical for the activation of foxm1. SIGNOR-187876 0.756 SNX5 protein Q9Y5X3 UNIPROT IGF1R protein P08069 UNIPROT down-regulates quantity binding 9606 BTO:0000567 32150533 t miannu Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures. SIGNOR-269444 0.271 JQ1 chemical CHEBI:137113 ChEBI BRD2 protein P25440 UNIPROT down-regulates activity chemical inhibition -1 20871596 t lperfetto Enantiomerically pure (+)-JQ1 bound with a Kd of about 50 nM and 90 nM to the first and second bromodomains of BRD4, respectively (Fig. 1c, Supplementary Table 3). Comparable binding to both domains of BRD3 was observed, whereas the first bromodomains of BRDT and BRD2 revealed about 3-fold weaker binding.|Here, we present a first, thoroughly characterized inhibitor of the BET-family of bromodomains. SIGNOR-261987 0.8 RELB protein Q01201 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 26385063 f miannu We have shown here for the first time the role of RelB on lymphocyte development in humans. In the absence of RelB, B cells development is arrested, resulting in poor production of immunoglobulins and specific antibodies. SIGNOR-263655 0.7 ACO2 protein Q99798 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI up-regulates quantity chemical modification 9606 24068518 t miannu Citrate is converted to cis-aconitate. This is catalyzed by aconitase. Cis-aconitate is an intermediate and is further converted to isocitrate by aconitase. Aconitase is involved in both reactions. In which first dehydration and then rehydration occur and as a result final product isocitrate is obtained. SIGNOR-266246 0.8 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 17053147 t gcesareni Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation. SIGNOR-150140 0.2 SAV1 protein Q9H4B6 UNIPROT STK3 protein Q13188 UNIPROT up-regulates binding 9606 21084559 t Sav1 interacts with Mst1/2 through the SARAH domains present in both Sav1 and Mst1/2. gcesareni Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst. SIGNOR-169829 0.829 CASP1 protein P29466 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates activity cleavage Asp329 EMEEDSYdSFGEPSY -1 10069390 t lperfetto In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329. SIGNOR-261748 0.323 ASTN2 protein O75129 UNIPROT Neuron_migration phenotype SIGNOR-PH67 SIGNOR up-regulates 9606 BTO:0000142 28506896 f miannu The role of astrotactin and Brinp proteins has been partially characterized, with ASTN1 and ASTN2 demonstrated to facilitate glial-guided neuronal migration during brain development SIGNOR-269814 0.7 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT up-regulates quantity by stabilization phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 t miannu Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis SIGNOR-267472 0.376 MAP3K20 protein Q9NYL2 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates activity phosphorylation 9606 12220515 t gcesareni This result suggests that ZAK activates JNK/SAPK mediated by downstream target, MKK7 SIGNOR-243342 0.2 ADAM17 protein P78536 UNIPROT EREG protein O14944 UNIPROT up-regulates activity cleavage 9606 26284334 t miannu ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF SIGNOR-259843 0.555 OXSR1 protein O95747 UNIPROT SLC12A2 protein P55011 UNIPROT up-regulates phosphorylation Thr212 TNTYYLRtFGHNTMD 9606 16669787 t miannu We have identified three residues in nkcc1 (thr175/thr179/thr184 in shark or thr203/thr207/thr212 in human) that are phosphorylated by spak and osr1 / exposure of hek-293 (human embryonic kidney) cells to osmotic stress, which leads to phosphorylation and activation of nkcc1, increased phosphorylation of nkcc1 at the sites targeted by spak/osr1 SIGNOR-146521 0.534 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Ser2032 CRMGIKTsEGTPGFR 9606 BTO:0000938 20595391 t lperfetto Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2. SIGNOR-166466 0.2 NDN protein Q99608 UNIPROT CDKN2A protein P42771 UNIPROT up-regulates 9606 24392140 f lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253383 0.281 PTPN2 protein P17706 UNIPROT GJA1 protein P17302 UNIPROT up-regulates dephosphorylation Tyr247 VKGKSDPyHATSGAL 9606 BTO:0000671 24849651 t lperfetto Tc-ptp dephosphorylates cx43 residues y247 and y265, dephosphorylation maintained cx43 gap junctions at the plaque and partially reversed the channel closure caused by v-src-mediated phosphorylation of cx43. SIGNOR-205097 0.329 RPS6KA3 protein P51812 UNIPROT CREB1 protein P16220 UNIPROT up-regulates activity phosphorylation Ser119 EILSRRPsYRKILND 9606 8688081 t lperfetto MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression SIGNOR-248951 0.72 SOD1 protein P00441 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI down-regulates quantity chemical modification 9606 29301787 t lperfetto Oxidative stress contributes to diabetes mellitus (DM)–induced endothelial dysfunction, which is one of the most common causes of cardiovascular morbidity and mortality.1,2 The major cellular defense against superoxide (O2•−) is SODs (superoxide dismutases), which consists of the SOD1 (cytoplasmic copper zinc SOD [Cu/ZnSOD]), the SOD2 (mitochondrial MnSOD), and the SOD3 (extracellular Cu/ZnSOD). SIGNOR-272285 0.8 PTPRC protein P08575 UNIPROT JAK1 protein P23458 UNIPROT down-regulates activity dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11201744 t CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling|these results show that CD45 dephosphorylates functionally important tyrosine residues. It should be noted that, as with our phosphatase assays in vitro, Tyr 1022 and Tyr 1023 of JAK1, Tyr 1007 and Tyr 1008 of JAK2, and Tyr 1054 and Tyr 1055 of Tyk2 are indeed hyperphosphorylated in cd45-deficient cells SIGNOR-248355 0.461 ATG3 protein Q9NT62 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates activity binding -1 16303767 t lperfetto Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme) SIGNOR-141926 0.871 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates activity phosphorylation Ser63 GILARRPsYRKILKD 10090 BTO:0000452 11909979 t lperfetto Using embryonic fibroblasts derived from these mice we were able to demonstrate an important role for these enzymes in the activation of CREB and the closely related transcription factor ATF1. | Our results clearly demonstrate that MSK1 and MSK2 are the major, if not the only, protein kinases that mediate the phosphorylation of CREB at Ser133 and of ATF1 at Ser63 in fibroblasts SIGNOR-249145 0.606 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu68 VEETCSYeEAFEALE -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263681 0.661 GSK3B protein P49841 UNIPROT SPAG5 protein Q96R06 UNIPROT up-regulates phosphorylation Thr937 ADEEPEStPVPLLGS 9606 18055457 t lperfetto Astrin acts as a substrate for gsk3beta and is phosphorylated at thr-111, thr-937 ((s/t)p motif) and ser-974/thr-978 ((s/t)xxx(s/t)-p motif;p is a phosphorylatable residue). Inhibition of gsk3beta impairs spindle and kinetochore accumulation of astrin and spindle formation at mitosis, suggesting that astrin association with the spindle microtubule and kinetochore may be dependent on phosphorylation by gsk3beta SIGNOR-159582 0.273 CDK8 protein P49336 UNIPROT STAT1 protein P42224 UNIPROT up-regulates activity phosphorylation Ser727 TDNLLPMsPEEFDEV 29239838 t lperfetto We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. SIGNOR-273179 0.398 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 f miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255185 0.382 HP protein P00738 UNIPROT HBA1 protein P69905 UNIPROT down-regulates quantity binding 9606 9315856 t Regulation of binding miannu Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers. SIGNOR-251816 0.736 ACVR1 protein Q04771 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 9748228 t fspada Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2 SIGNOR-60171 0.753 TJP1 protein Q07157 UNIPROT ARVCF protein O00192 UNIPROT up-regulates activity binding 9615 BTO:0000837 15456900 t Regulation of binding miannu We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. E-cadherin, ZO-1, and ARVCF are recruited to sites of initial cell-cell contact. Binding of the ZO-1 PDZ domains per se does not facilitate membrane recruitment of ARVCF, indicating a requirement for the intact ZO-1 and possibly its association with membrane proteins and/or the cytoskeleton for this process. SIGNOR-252121 0.461 NPBWR1 protein P48145 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256675 0.419 PRKCA protein P17252 UNIPROT PPP1R14A protein Q96A00 UNIPROT up-regulates activity phosphorylation Thr38 QKRHARVtVKYDRRE 9606 32471307 t lperfetto A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225]. SIGNOR-96692 0.511 MAPK1 protein P28482 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR down-regulates activity phosphorylation 9606 12809513 t inferred from family member llicata We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay. SIGNOR-270303 0.432 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates activity binding 9606 BTO:0000567 14565952 t llicata MKL2 binds to and activates SRF similar to myocardin and MKL1. SIGNOR-237671 0.2 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 12692549 f lperfetto The transcription factors interferon regulatory factor 3 (IRF3) and NF-B are required for the expression of many genes involved in the innate immune response. SIGNOR-216319 0.7 MAPK3 protein P27361 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates activity phosphorylation Ser284 RRDYDDMsPRRGPPP 9606 11231586 t lperfetto Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353. SIGNOR-105238 0.349 TFEB protein P19484 UNIPROT GNS protein P15586 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276792 0.315 gamma-secretase complex SIGNOR-C98 SIGNOR APP protein P05067 UNIPROT up-regulates activity cleavage 9606 BTO:0000590 19958215 t lperfetto The production and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer's disease (AD). A multi-subunit enzyme complex, referred to as gamma (gamma) secretase, plays a pivotal role in the generation of Abeta from its parent molecule, the amyloid precursor protein (APP). SIGNOR-251576 0.593 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr791 LAQAPPVyLDVLG 9606 9099755 t gcesareni In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785 SIGNOR-47183 0.2 MAPK1 protein P28482 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates activity phosphorylation 9534 BTO:0004055 14993270 t lperfetto We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling. SIGNOR-244916 0.748 DTX1 protein Q86Y01 UNIPROT TCF3 protein P15923 UNIPROT down-regulates 9606 BTO:0000776 9528794 f gcesareni Our experiments indicate that deltex expression alone is suffcient to inhibit e47. SIGNOR-56141 0.277 miR-495 mirna URS000075C517_9606 RNAcentral Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 10090 26344767 t Luana To further determine whether MeCP2 regulates the expression of miR-199a, we also re-expressed MeCP2 in MeCP2-KO neurons. As expected, this restored the level of mature-miR-199a expression to that in WT neurons SIGNOR-264545 0.4 PRKCB protein P05771 UNIPROT NRGN protein Q92686 UNIPROT up-regulates activity phosphorylation Ser36 AAAKIQAsFRGHMAR -1 8080473 t lperfetto Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM. SIGNOR-248914 0.365 HES1 protein Q14469 UNIPROT PTGDS protein P41222 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002605 15743775 f miannu knock-down of Hes-1 mRNA by RNA interference significantly enhanced the L-PGDS mRNA level, indicating that the L-PGDS gene expression is repressed by the Notch-Hes signaling. SIGNOR-255424 0.2 BLOC-3 complex SIGNOR-C253 SIGNOR RAB32 protein Q13637 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 23174301 t lperfetto HPS1/HPS4 was active exclusively for RAB32 and RAB38. Moreover, when overexpressed with HPS1 in HeLa cells, a mitochondrially restricted form of HPS4 preferentially recruited GFP-tagged RAB32 or RAB38 – but not the related RAB7 or RAB9 – to mitochondria. Activity in both assays required both HPS1 and HPS4. Finally, depletion of HPS1 or HPS4 by siRNA in a pigmented human melanoma cell line, MNT-1, resulted in the mislocalization of RAB32. These data provide strong evidence that BLOC-3 is a selective GEF for RAB32 and RAB38  SIGNOR-260693 0.553 PRKCH protein P24723 UNIPROT ITGB2 protein P05107 UNIPROT unknown phosphorylation Ser745 FEKEKLKsQWNNDNP 9606 BTO:0000751 11700305 t lperfetto Here, we identify catalytic domain fragments of protein kinase C (PKC) delta and PKCbetaI/II as the major protein kinases in leukocyte extracts that phosphorylate a peptide corresponding to the cytoplasmic tail of the integrin CD18 chain. The sites phosphorylated in vitro were identified as Ser-745 and Thr-758. PKCalpha and PKCeta also phosphorylated these residues, and PKCalpha additionally phosphorylated Thr-760. Ser-745, a novel site, was shown to become phosphorylated in T cells in response to phorbol ester stimulation. | SIGNOR-249118 0.348 noradrenaline smallmolecule CHEBI:33569 ChEBI adrenaline smallmolecule CHEBI:33568 ChEBI up-regulates quantity precursor of 9606 7961964 t brain lperfetto In the adrenal medulla NA (noradrenaline) is N-methylated by the enzyme phenylethanolamine N-methyl transferase (PNMT, EC 2.1.1.28) to form A (adrenaline). SIGNOR-264183 0.8 CAPRIN2 protein Q6IMN6 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by stabilization post transcriptional regulation 9606 BTO:0000007 35051932 t lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|Altogether, the data indicate that CAPRIN2 binds Oxt mRNA |Therefore, we propose that CAPRIN2 facilitates post-transcriptional modifications that increase Oxt transcript stability. SIGNOR-268556 0.2 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 16151013 t Cytosolic p53 amattioni P53 also accumulates in the cytoplasm where it directly activates bax to promote mitochondrial outer membrane permeabilization. SIGNOR-140242 0.747 Kindlin proteinfamily SIGNOR-PF48 SIGNOR A8/b1 integrin complex SIGNOR-C165 SIGNOR up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259019 0.405 RARG protein P13631 UNIPROT RXRB protein P28702 UNIPROT up-regulates binding 9606 1310351 t gcesareni Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins. SIGNOR-16662 0.705 Monobutylphthalate chemical CHEBI:88522 ChEBI PPARA protein Q07869 UNIPROT up-regulates activity chemical activation 9606 BTO:0000816 16326050 t miannu Mono(2-ethylhexyl)phthalate and mono-n-butyl phthalate activation of peroxisome proliferator activated-receptors alpha and gamma in breast SIGNOR-268750 0.8 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT down-regulates activity phosphorylation Ser85 ELLHFQAsQREEKEF 9606 SIGNOR-C14 SIGNOR-C14 17977820 t lperfetto In this study we analyze the ikkbeta-mediated phosphorylation of the ikk-binding domain of nemo. In vitro, ikkbeta phosphorylates three serine residues in the domain of nemo at positions 43, 68, and 85. However, mutational analysis revealed that only the phosphorylation of serine 68 in the center of the ikk-binding domain plays an essential role for the formation and the function of the ikk complex. Thus, ser(68) phosphorylation attenuates the amino-terminal dimerization of nemo as well as the ikkbeta-nemo interaction. I SIGNOR-158663 0.962 PTPN6 protein P29350 UNIPROT TRPV1 protein Q8NER1 UNIPROT down-regulates activity dephosphorylation 10116 25790452 t miannu Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia. SIGNOR-277129 0.2 cetirizine chemical CHEBI:3561 ChEBI HRH1 protein P35367 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 7925364 t miannu The human H1-receptor cDNA was transfected into Chinese hamster ovary cells (CHO) via an eukaryotic expression vector; the receptor protein present on cell membranes specifically bound [3H]mepyramine with a Kd of 3.7 nM. The binding was displaced by H1-histamine-receptor antagonists and histamine. Affinity of histamine and selected histamine antagonists for human H, receptors expressed in CHO cells (CHO H,-30) and a comparison with HI receptors found in guinea pig cerebellum. SIGNOR-258868 0.8 PTPRB protein P23467 UNIPROT SRC protein P12931 UNIPROT down-regulates activity dephosphorylation 9606 27314562 t miannu Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2. SIGNOR-277132 0.454 SESN2 protein P58004 UNIPROT GATOR2 complex SIGNOR-C193 SIGNOR down-regulates activity binding 10090 BTO:0002572 25457612 t We describe AMPK-independent mechanism of mTORC1 regulation by the Sestrins, in which the Sestrins inhibit mTORC1 localization to the lysosomes in a Rag-dependent manner through an interaction with GATOR2 SIGNOR-253560 0.712 CTCF protein P49711 UNIPROT BCL6 protein P41182 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001690 20733034 f miannu Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. SIGNOR-253824 0.28 S1PR1 protein P21453 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates 9606 9488656 f gcesareni Edg-1 is known to activate the mitogen-activated protein (map) kinase known as extracellular signal-regulated kinase 2 (erk-2) through pertussis toxin (ptx)sensitive giprotein SIGNOR-54770 0.49 IL10 protein P22301 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity binding 9606 BTO:0000801 26260587 t lperfetto IL10 is a classic anti-inflammatory cytokine and its molecular signalling pathway has been well characterized in macrophages and T lymphocytes. Secreted IL10 cytokine binds to the IL10 receptor 1 (IL10R1) on membrane surfaces, and IL10R1 dimerizes with IL10R2 to exert its downstream effects. SIGNOR-249544 0.912 STX11-SNAP23 SNARE complex complex SIGNOR-C272 SIGNOR Platelet_degranulation phenotype SIGNOR-PH138 SIGNOR up-regulates 9606 BTO:0000782 22767500 f lperfetto Coimmunoprecipitation experiments showed that syntaxin-11 can form SNARE complexes with both VAMP-8 and SNAP-23. |The SNAREs form transmembrane complexes that mediate membrane fusion and granule cargo release. SIGNOR-261901 0.7 CDK2 protein P24941 UNIPROT ZBTB16 protein Q05516 UNIPROT down-regulates phosphorylation Ser197 SFGLSAMsPTKAAVD 9606 BTO:0001271 18246121 t llicata Here we show that the main cyclin-dependent kinase involved at the g(1) to s transition (cdk2) phosphorylates plzf at two consensus sites found within pest domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of plzf, which impairs plzf transcriptional repression ability and antagonizes its growth inhibitory effects. SIGNOR-160626 0.284 MACF1 protein Q9UPN3 UNIPROT LRP6 protein O75581 UNIPROT up-regulates 9606 BTO:0000938 16815997 f flangone Macf1 appeared to be involved in the translocation and subsequent binding of the axin complex to lrp6 at the cell membrane. SIGNOR-147457 0.3 PPM1G protein O15355 UNIPROT SNRPN protein P63162 UNIPROT up-regulates quantity by stabilization dephosphorylation 9606 17984321 t lperfetto Dephosphorylation of survival motor neurons (SMN) by PPM1G and PP2Cgamma governs Cajal body localization and stability of the SMN complex.|This indicates that the catalytic activity of PPM1G promotes accumulation of the SMN complex in CBs and suggests that PPM1G is a major determinant of the SMN-complex localization in the nucleus. SIGNOR-277021 0.2 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser376 LKSKKGQsTSRHKKL 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269328 0.442 SAGA complex complex SIGNOR-C465 SIGNOR H3-5 protein Q6NXT2 UNIPROT down-regulates activity acetylation Lys15 ARKSTGGkAPRKQLA 9606 34811519 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14. SIGNOR-269642 0.2 MAPK1 protein P28482 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser104 FPPLNSVsPSPLMLL 9606 BTO:0000567 17615152 t gcesareni In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity SIGNOR-156848 0.663 lovastatin chemical CHEBI:40303 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0000318 9727070 t miannu The antihypercholesterolemic drug lovastatin also activated hPXR as did phenobarbital and the organochlorine pesticide transnonachlor (Fig. 4 A). Thus, hPXR is activated by a remarkably diverse group of synthetic compounds that are known to induce CYP3A4 gene expression (Fig. 4 C). SIGNOR-258828 0.8 ROCK1 protein Q13464 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 19386264 t lperfetto Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide SIGNOR-185567 0.726 MAP1LC3C protein Q9BXW4 UNIPROT ATG3 protein Q9NT62 UNIPROT up-regulates activity binding 10090 BTO:0002572 22170151 t lperfetto Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-191552 0.777 ETV2 protein O00321 UNIPROT SPI1 protein P17947 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 24583263 f irozzo We also identify Spi1 as a common downstream target gene of Etv2 and Gata2. We provide evidence that Etv2 and Gata2 bind to the Spi1 promoter in vitro and in vivo. Etv2 and Gata2 synergistically transactivate Spi1 gene expression. SIGNOR-256006 0.261 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis. SIGNOR-165216 0.7 DZIP3 protein Q86Y13 UNIPROT ATXN1 protein P54253 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000567 24326307 t miannu HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation. SIGNOR-272078 0.491 SHANK3 protein Q9BYB0 UNIPROT GRIA3 protein P42263 UNIPROT up-regulates quantity binding 9606 BTO:0000938 28179641 t miannu SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3). SIGNOR-264603 0.2 NCBP3 protein Q53F19 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268364 0.8 MAPK1 protein P28482 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser668 INTKALQsPKRPRSP 9606 10648599 t lperfetto Tfii-i can be phosphorylated in vitro by erk and mutation of consensus map kinase substrate sites at serines 627 and 633 impairs the phosphorylation of tfii-i by erk and its activity on the c-fos promoter. These results suggest that erk regulates the activity of tfii-i by direct phosphorylation. SIGNOR-74296 0.369 FYN protein P06241 UNIPROT NMT1 protein P30419 UNIPROT unknown phosphorylation Tyr180 YTLLNENyVEDDDNM -1 11594778 t Human NMT was found to be phosphorylated by non-receptor tyrosine kinase family members of Lyn, Fyn and Lck. Tyr100 is the principle phosphorylation site on hNMT for Lyn and Fyn. The significance of a phosphorylation-dependent interaction between NMT and a tyrosine kinase is not known at present. SIGNOR-251179 0.387 ER stress stimulus SIGNOR-ST9 SIGNOR PRNP protein F7VJQ1 UNIPROT up-regulates 9606 BTO:0000007 21478263 f ER stress specifically increases the synthesis of AltPrP from PrP cDNA. SIGNOR-253609 0.7 TRIM23 protein P36406 UNIPROT TBK1 protein Q9UHD2 UNIPROT up-regulates activity binding 9606 BTO:0000007 28871090 t miannu TRIM23 interacts with TBK1 and p62. TRIM23 GTPase activates TBK1 to phosphorylate p62. Biochemical characterization showed that TRIM23 binds with its C-terminal ARF domain to the N-terminal KD of TBK1, and that GTP hydrolysis activity of the ARF stimulates TBK1-mediated phosphorylation of p62 at S403 in its ubiquitin-associated (UBA) domain, which was shown to promote cargo recruitment and autophagic flux SIGNOR-266654 0.529 CBFA2T3/ZNF651 complex SIGNOR-C197 SIGNOR ZNF652 protein Q9Y2D9 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000007 20116376 t Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes. Here we show that ZNF651 is a ZNF652 paralogue that shares a common DNA binding sequence with ZNF652 and represses target gene expression through the formation of a CBFA2T3-ZNF651 corepressor complex. SIGNOR-253955 0.519 TNRC6B protein Q9UPQ9 UNIPROT AGO2 protein Q9UKV8 UNIPROT up-regulates activity binding -1 17891150 t miannu The assay showed that full-length TNRC6B binds full-length human AGO2. We have identified and molecularly dissected important sequence and structure features in the conserved Ago hooks of S. pombe Tas3 and human TNRC6B. The effect of Ago hook peptides from the shuttling P-body component TNRC6B in our miRNA-mediated translational repression assay (Fig. 5b), in particular, hints at a novel regulatory role of Ago hooks in miRNA-mediated gene repression mechanisms. SIGNOR-269680 0.791 MT-ND1 protein P03886 UNIPROT Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR form complex binding 30030361 t lperfetto Thus, we now know the complete mammalian cI structure [22,23] and how the subunits are organized in six modules (N, Q, ND1, ND2, ND4 and ND5)|The Q-module is built through the association of NDUFA5, NDUFS2 and NDUFS3 plus NDUFS7 and NDUFS8. The chaperones NDUFAF3/C3ORF60 and NDUFAF4/C6ORF66 [36,37] remain bound to this module until the final assembly steps [34]. NDUFAF6/C8ORF38 [38] also seems to participate in the assembly of the Q-module [24,39]. NDUFAF3, 4 and 6, are necessary to maintain normal MT-ND1 synthesis [40,41]. NDUFAF5 adds a hydroxyl group to Arg73 of NDUFS7 [42] and NDUFAF7 dimethylates NDUFS2 in Arg85 [43], an essential modification for cI assembly [44]. NUBPL/IND1 delivers [4Fe–4S] clusters specifically to the N- and Q-module subunits [45,46]. SIGNOR-262143 0.808 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000776 10207047 t lperfetto The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation. SIGNOR-235881 0.965 GPR17 protein Q13304 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256835 0.37 LYN protein P07948 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276186 0.2 HIF-1 complex complex SIGNOR-C418 SIGNOR PDK1 protein Q15118 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 16517405 t miannu Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. SIGNOR-267446 0.416 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004958; BTO:0002648 9182762 f Giulio Giuliani Indeed, we identified Osf2/Cbfa1 binding sites in the promoter of four genes expressed only (the Osteocalcin genes) or highly (Œ±1(I) collagen, Bsp, and Osteopontin) in osteoblasts. Each of these elements was able to bind Osf2/Cbfa1. SIGNOR-255408 0.589 DVL2 protein O14641 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity 9606 19279717 t areggio Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin SIGNOR-258979 0.27 DLX5 protein P56178 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity transcriptional regulation 9606 19497851 t gcesareni Here we demonstrate by luciferase assay that the MYC promoter is specifically activated by overexpression of DLX5 and that two DLX5 binding sites in the MYC promoter are important for transcriptional activation of MYC. We also show that DLX5 binds to the MYC promoter both in vitro and in vivo and that transfection of a DLX5 expression plasmid promotes the expression of MYC in a dose-dependent manner in mammalian cells SIGNOR-241914 0.277 estramustine chemical CHEBI:4868 ChEBI ESR1 protein P03372 UNIPROT up-regulates activity chemical activation 9606 14755680 t miannu A variety of new estrogenic/anti‐estrogenic/selective estrogen receptor modulator (SERM)‐like compounds, including 2‐methoxyestradiol, genistein, resveratrol, licochalcone, Raloxifene, ICI 182,780, and estramustine are being evaluated for their potential in the next generation of PCa therapies. SIGNOR-259296 0.8 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 9606 19914161 t lpetrilli Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3 SIGNOR-161617 0.74 KCNC3 protein Q14003 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI down-regulates quantity relocalization 9606 11506885 t miannu Kv3 currents are activated specifically during action potential repolarization. Analysis of the Kv3 subfamily of K+ channel subunits has lead to the discovery of a new class of neuronal voltage-gated K+ channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height SIGNOR-265587 0.8 (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI up-regulates quantity precursor of 9606 21876188 t lperfetto In this pathway, 5,10-methyleneTHF, a one-carbon donor, is generated from serine by SHMT and used for the conversion of dUMP to dTMP in a reaction catalyzed by TYMS. The TYMS-catalyzed reaction generates dihydrofolate, which is converted to THF in an NADPH-dependent manner by DHFR. SIGNOR-268233 0.8 SLITRK1 protein Q96PX8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 19640509 f miannu Phosphorylation of SLITRK1 on the CK2 phosphorylation site modulated SLITRK1-enhanced neurite outgrowth. SIGNOR-273658 0.7 MTR protein Q99707 UNIPROT homocysteine smallmolecule CHEBI:17230 ChEBI down-regulates quantity chemical modification 9606 10520212 t lperfetto Methionine synthase is a vitamin B12-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. SIGNOR-253142 0.8 PKA proteinfamily SIGNOR-PF17 SIGNOR MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation 9606 BTO:0000887 20151718 t inferred from 70% family members miannu Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation.7, 8 phosphorylation by pka is essential for proper cardiac function /for the human isoform, three pka sites were previously identified (ser275, ser284, and ser304) /our results indicate that pka phosphorylates up to four sites in both the murine and human m-domains including a novel site not previously described for either protein (ser307 for mouse and ser311 for human). SIGNOR-270128 0.2 Host translation inhibitor nsp1 protein P0C6X7-PRO_0000037309 UNIPROT JUN protein P05412 UNIPROT down-regulates activity 9606 BTO:0000007 17715225 f miannu SARS-CoV nsp1 inhibits c-Jun expression and phosphorylation. SIGNOR-262505 0.2 USF1 protein P22415 UNIPROT CTSD protein P07339 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000093 9731700 f miannu Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. These experiments suggest a model for ER stimulation of the CD promoter in which recruitment of USF-1/2 to the promoter is required for activation of transcription. SIGNOR-255595 0.396 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR -1 9677319 t llicata CKII phosphorylate multiple C-terminal serine residues, including Ser214, Ser257, Ser273, Ser290 and Ser299. | However, phosphorylation of Rad by PKC and CKII abolishes the interaction of Rad with calmodulin. SIGNOR-250947 0.315 Mitochondrial respiratory chain complex I complex SIGNOR-C277 SIGNOR Respiratory electron transport chain phenotype SIGNOR-PH141 SIGNOR up-regulates 30030361 f lperfetto The oxidative phosphorylation system (OXPHOS) of the mitochondrial inner membrane is composed of five enzymes (complexes I–V; cI–V). In mammals, they are all multimeric and, except for cII, have subunits encoded both in the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). SIGNOR-262141 0.7 PRKCB protein P05771 UNIPROT IBTK protein Q9P2D0 UNIPROT down-regulates phosphorylation Ser1203 LHSVSSKsFRDFLLE 9606 BTO:0000776 21482705 t llicata We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane. SIGNOR-173387 0.331 G3BP1 protein Q13283 UNIPROT DDX58 protein O95786 UNIPROT down-regulates activity binding 9606 BTO:0002181 30804210 t SARA G3BP1 binds RIG-I and that this interaction involves the C-terminal RGG domain of G3BP1, G3BP1 significantly enhances RIG-I-induced ifn-b mRNA synthesis. SIGNOR-260980 0.343 GSK3B protein P49841 UNIPROT DPYSL3 protein Q14195 UNIPROT up-regulates activity phosphorylation Thr514 TTTPKGGtPAGSARG 10116 16611631 t lperfetto Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro SIGNOR-146015 0.461 PRR5 protein P85299 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR form complex binding 9606 25628925 t lperfetto Depending on their binding partners and sensitivities to rapamycin, mtor resides in at least two distinct complexes, termed mtor complex 1 (mtorc1, containing raptor, fkbp12, pras40 and mlst8) and mtor complex 2 (mtorc2, containing rictor, sin1, protor and mlst8) SIGNOR-205621 0.671 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI up-regulates quantity precursor of 9606 31422819 t miannu This is a pyridoxal 5‚Ä≤-phosphate (PLP)-dependent enzyme that exists as cytosolic (GOT1) and intramitochondrial (GOT2) isoforms. Both isoforms catalyze the reversible interconversion of oxaloacetate and glutamate into aspartate and Œ±-ketoglutarate. These enzymes are part of the malate-aspartate shuttle (MAS), a key player in intracellular NAD(H) redox homeostasis (Figure 1). SIGNOR-267515 0.8 CSNK2A2 protein P19784 UNIPROT MYCN protein P04198 UNIPROT unknown phosphorylation Ser261 TSGEDTLsDSDDEDD -1 1425701 t llicata Analysis of phosphorylation sites in synthetic peptides of this acidic region identified the major sites phosphorylated by CKII as Ser261 and Ser263. SIGNOR-251014 0.372 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 20086174 t inferred from 70% of family members lperfetto We determined that mst2 phosphorylation by akt limits mst2 activity in two ways: first, by blocking its binding to rassf1a and by promoting its association into the raf-1 inhibitory complex, and second, by preventing homodimerization of mst2, which is needed for its activation. we identified t117 and t384 as akt phosphorylation sites in mst2. SIGNOR-269944 0.403 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT down-regulates activity phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0000007 27065328 t miannu Cep76 is phosphorylated by cyclin A/CDK2 at a single site S83. These data suggest that the phosphomimetic mutant is functional and that phosphorylation at S83 is critical for Cep76 to suppress centriole amplification. SIGNOR-262603 0.303 CCNH protein P51946 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 t lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269321 0.96 MAPK3 protein P27361 UNIPROT NUP153 protein P49790 UNIPROT unknown phosphorylation Ser529 SPMFKFSsPIVKSTE 9606 19767751 t llicata These results indicate that phosphorylation of nup153 and nup214 by erk strongly reduces their affinity for importin-. nup153 depletion caused a strong inhibition of nuclear accumulation of gfp?importin-beta in both erk-inhibited and erk-activated cells (fig. 8b,c), indicating that nup153 is essential for the efficient importin-beta transport. SIGNOR-188143 0.396 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates quantity by destabilization dephosphorylation Ser688 QFHSPVGsPLKSIQA 9606 20236090 t Reciprocally, we found that the phosphatases Cdc14A and Cdc14B (Cdc is cell-division cycle) bind to ERK3 and reverse its C-terminal phosphorylation in mitosis. Importantly, alanine substitution of the four C-terminal phosphorylation sites markedly decreased the half-life of ERK3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.|In vitro phosphorylation of a series of ERK3-deletion mutants by mitotic cell extracts revealed that phosphorylation is confined to the unique C-terminal extension of the protein. Using MS analysis, we identified four novel phosphorylation sites, Ser684, Ser688, Thr698 and Ser705, located at the extreme C-terminus of ERK3. SIGNOR-248831 0.632 ARHGDIA protein P52565 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity guanine nucleotide exchange factor 10116 BTO:0000526 20696765 t miannu Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma. SIGNOR-268436 0.807 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120252 0.319 CDK13 protein Q14004 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1868 SPTSPKYsPTSPKYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273037 0.55 MAPK3 protein P27361 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1944 GSTYSPTsPGYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120256 0.319 ARHGEF10 protein O15013 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260535 0.513 TNIP1 protein Q15025 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT up-regulates activity relocalization 21885437 t lperfetto ABIN1 interacted with the A20 regulatory molecule TAX1BP1 and was essential for the recruitment of TAX1BP1 and A20 to the noncanonical IkappaB kinases TBK1 and IKKi in response to poly(I:C) transfection. ABIN1 and TAX1BP1 together disrupted the interactions between the E3 ubiquitin ligase TRAF3 and TBK1/IKKi to attenuate lysine 63-linked polyubiquitination of TBK1/IKKi. SIGNOR-275735 0.458 PRTN3 protein P24158 UNIPROT AGT protein P01019 UNIPROT up-regulates activity cleavage Phe41 DRVYIHPfHLVIHNE -1 11747312 t miannu Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen. SIGNOR-256314 0.26 IKBKB protein O14920 UNIPROT IKBKG protein Q9Y6K9 UNIPROT unknown phosphorylation Ser31 QDVLGEEsPLGKPAM 9606 SIGNOR-C14 SIGNOR-C14 12657630 t IKKbeta phosphorylates human IKKgamma at Ser-31, Ser-43, and Ser-376. IKK≈í‚⧠mediates IKK≈í‚â• phosphorylation under physiologic signaling conditions. IKK≈í‚â• is chronically phosphorylated in cells expressing the HTLV1 Tax oncoprotein, which interfaces directly with the I≈í‚à´B kinase complex.both Tax and TNF induce phosphorylation of human IKK≈í‚â• at Ser-31, Ser-43, and Ser-376. SIGNOR-251285 0.962 AKT proteinfamily SIGNOR-PF24 SIGNOR ZNF322 protein Q6U7Q0 UNIPROT up-regulates activity phosphorylation Thr262 IVHQRVHtGEKPYKC 9606 BTO:0002552 31399647 t miannu We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased ADD1 promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. SIGNOR-276753 0.2 2-hydroxyglutarate smallmolecule CHEBI:132941 ChEBI FOXP3 protein Q9BZS1 UNIPROT down-regulates activity chemical inhibition 9606 33114536 f Luana Moreover, glutamate oxaloacetate transaminase 1 (GOT1), an enzyme involved in glutamine metabolism, exerts pro-inflammatory effects by producing 2-hydroxyglutarate, which hinders the expression of FOXP3 and thus blocks the formation of Tregs. SIGNOR-268042 0.8 MAP1LC3A protein Q9H492 UNIPROT O-phosphoethanolamine smallmolecule CHEBI:17553 ChEBI up-regulates binding 9606 22170151 t gcesareni Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe SIGNOR-191546 0.8 NMDA receptor_2B complex SIGNOR-C348 SIGNOR Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264133 0.7 LLGL2 protein Q6P1M3 UNIPROT Scribble_complex_DLG2-LLGL2_variant complex SIGNOR-C503 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270879 0.554 CYP11A1 protein P05108 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI down-regulates quantity chemical modification 9606 BTO:0000048 33117906 t lperfetto The steroidogenic acute regulatory protein (StAR) assists in the transport of cholesterol from the cytosol to the inner mitochondria membrane to be converted into pregnenolone using the P450 side-chain cleavage (P450scc) enzyme. SIGNOR-268633 0.8 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11101851 t gcesareni Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1. SIGNOR-84827 0.922 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates activity phosphorylation Ser82 HSISYTLsRAQTVVV -1 19264966 t miannu The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites. SIGNOR-276139 0.761 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT down-regulates quantity by destabilization phosphorylation Ser279 VLKRPERsQEESPPG 9606 12676583 t Phosphorylation is the signal for ubiquitination gcesareni We show that ir-induced destruction of cdc25a requires both atm and the chk2-mediated phosphorylation of cdc25a on serine 123. the basal turnover of cdc25a operating in unperturbed s phase required chk1-dependent phosphorylation of serines 123, 178, 278, and 292. Ir-induced acceleration of cdc25a proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of chk1 and chk2 kinases. SIGNOR-99729 0.84 DAP3 protein P51398 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261459 0.754 PRKAA1 protein Q13131 UNIPROT KCNA5 protein P22460 UNIPROT down-regulates activity phosphorylation Ser559 VQRKVSGsRGSFCKA 9606 BTO:0000007 30279167 t miannu Thus, AMPK directly phosphorylates the  subunit of KV1.5 at Ser592 and, to a lesser extent, at Ser559 SIGNOR-277799 0.2 MEF2C protein Q06413 UNIPROT MYH1 protein P12882 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 15728583 t lperfetto Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation SIGNOR-238754 0.389 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser346 RAPSRKDsLESDSST 9606 23337587 t gcesareni Interestingly, sufu stability is regulated via dual phosphorylation at ser342/ser346 by pka and gsk3, and blocking sufu phosphorylation either by mutating ser346 to ala or by treating cultured cells with pka inhibitors attenuates sufu ciliary accumulation, whereas phospho-mimetic forms of sufu exhibits increased ciliary localization SIGNOR-119099 0.453 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR NEFL protein P07196 UNIPROT down-regulates activity binding 9606 23230147 t inferred from 70% family members miannu These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments. SIGNOR-269953 0.2 dexamethasone chemical CHEBI:41879 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 20956975 t fspada Glucocorticoids, such as dexamethasone, have been used as in vitro inducers of adipogenesis. However, the roles of the glucocorticoid receptor (gr) in adipogenesis have not been well characterized yet. Here, we show that inhibition of gr activity using the gr antagonist ru486 prevents human mesenchymal stem cell and mouse embryonic fibroblast (mef) differentiation into adipocytes SIGNOR-168562 0.8 BMPR1A protein P36894 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR up-regulates activity phosphorylation 10090 19620713 t ggiuliani The expression of CA-BMPr1A and CA-BMPr1B mRNA was confirmed by RT-PCR using appropriate primers to distinguish expression of the constitutively active receptors from endogenous BMP receptors; specific antibodies for these receptors were not available. However, the functional effects of their expression, i.e., phosphorylation of Smad1/5/8 and p38 MAPK, verify overexpression of the constitutively active receptors (Fig. 3B). Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway (Fig. 3B) (16, 17). SIGNOR-255786 0.694 ABL1 protein P00519 UNIPROT PDGFRB protein P09619 UNIPROT up-regulates activity phosphorylation Tyr934 AHASDEIyEIMQKCW -1 19275932 t miannu C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.  SIGNOR-276141 0.515 HIF-1 complex complex SIGNOR-C418 SIGNOR Hexokinase proteinfamily SIGNOR-PF76 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 27692180 t miannu HIF-1 promotes glycolysis by transcriptionally upregulating GLUT1, GLUT3, HK1, and HK2. HIF-1 also suppresses oxidative phosphorylation by the upregulation of gene expression of BNIP3, BNIP3L, LDHA, and PDK1. In addition, HIF-1 can inhibit apoptosis by suppressing the expression of BID. SIGNOR-267500 0.36 DUSP7 protein Q16829 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 20626350 t gcesareni The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues SIGNOR-166577 0.655 TOP2A protein P11388 UNIPROT Chromosome_segregation phenotype SIGNOR-PH44 SIGNOR up-regulates 9606 20562910 f lperfetto Topoisomerase IIalpha (topoIIalpha) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis. SIGNOR-242530 0.7 MAPK1 protein P28482 UNIPROT PCBP2 protein Q15366 UNIPROT up-regulates quantity by stabilization phosphorylation Ser173 MLETLSQsPPKGVTI 9606 17475908 t miannu We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B). SIGNOR-262910 0.322 RBBP8 protein Q99708 UNIPROT ATM protein Q13315 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001130 22832221 f gcesareni Brca1/e2f1/ctipbinding to atm promoter activates atm transcription. SIGNOR-198473 0.825 EP300 protein Q09472 UNIPROT KRT16 protein P08779 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12954631 f miannu these results suggest that Sp1 and AP1 sites in the essential promoter region are critical for EGF response, and Sp1 showed a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of EGF-induced keratin 16 gene expression. The coactivators p300/CBP could collaborate with Sp1 and c-Jun in the activation of keratin 16 promoter. SIGNOR-253904 0.2 APC protein P25054 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates quantity binding 9606 22083140 t amattioni Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)]. SIGNOR-177230 0.919 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation Ser403 DLAHSSEsQETISSM 9606 16943424 t lperfetto Recently we showed that atm- and hdm2-dependent ubiquitination and subsequent degradation of hdmx following dsb induction are mediated by phosphorylation of hdmx on s403, s367, and s342, with s403 being targeted directly by atm. SIGNOR-149300 0.73 RANBP2 protein P49792 UNIPROT TNPO1 protein Q92973 UNIPROT up-regulates activity binding 9606 BTO:0001938 32161167 t lperfetto Nup358(806–1306), but not other regions, efficiently recruits importin β and transportin 1 SIGNOR-262111 0.462 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates activity phosphorylation Ser14 PFSCHYPsRLRRDPF 9606 BTO:0000887 11342557 t lperfetto Hsp22 is phosphorylated by protein kinase c (at residues ser(14) and thr(63)) and by p44 mitogen-activated protein kinase (at residues ser(27) and thr(87)). Concerning the possible function of hsp22, no definitive conclusions can be drawn with the available data, although its function might be to bind to and modulate the activity of hsp27.Some Studies claimed that phosphorylation is required for the translocation SIGNOR-107684 0.31 RIMBP3 protein Q9UFD9 UNIPROT RIMS2 protein Q9UQ26 UNIPROT down-regulates activity binding 10116 BTO:0001009 11988172 t miannu SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins. SIGNOR-264365 0.363 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT down-regulates dephosphorylation 9606 17386267 t gcesareni These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt / phlpp1 specifically modulates the phosphorylation of hdm2 and gsk-3alpha through akt2, whereas phlpp2 specifically modulates the phosphorylation of p27 through akt3 SIGNOR-153935 0.613 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates quantity transcriptional regulation 9606 30017632 t miannu The downstream molecules including mad2, smad3, smad4 and smad7 are involved in TGF-β1-induced EMT,while Smad7 blocks the smad3 expression SIGNOR-260437 0.603 RUNX1 protein Q01196 UNIPROT BAALC protein Q8WXS3 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22493267 f miannu We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. SIGNOR-255077 0.334 CTBP1 protein Q13363 UNIPROT BRCA1 protein P38398 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 23303449 f irozzo Our findings suggest an important role of CtBP1 in the transcriptional control of p16INK4a and Brca1[.]. Breast Cancer Susceptibility Gene 1(Brca1), a core protein in DNA damage repair, was repressed by CtBP1 in melanoma cells. SIGNOR-259194 0.592 DUSP1 protein P28562 UNIPROT JUN protein P05412 UNIPROT down-regulates activity dephosphorylation 9606 26734995 t miannu However, adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown.|The results suggested that HDACI-induced MKP-1 contributes to inactivation of JNK instead of ERK, consistent with the previous reports in other cell types SIGNOR-277102 0.463 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT up-regulates activity phosphorylation Tyr1190 DIYETDYyRKGGKGL -1 2449432 t lperfetto We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151; SIGNOR-106518 0.2 CAMK2G protein Q13555 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates phosphorylation 9606 12482967 t gcesareni Camkii interacts with and phosphorylates tak1. SIGNOR-96422 0.2 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser171 RILNHDTsFAKTFVG 9606 17197699 t gcesareni Enzymatic activity, induced; SIGNOR-151755 0.2 mTORC1 complex SIGNOR-C3 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates activity 10090 BTO:0002314 25047835 f Knockdown (KD) of either mTORC or its subunit Raptor delayed SC activation without influencing the differentiation program. SIGNOR-256273 0.7 PRKACA protein P17612 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates phosphorylation Ser1248 HGRAREGsFESRYQQ 9606 BTO:0000782;BTO:0000661 1370476 t llicata The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl. SIGNOR-17901 0.2 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 BTO:0000590 12226093 t The effect has been demonstrated using P10636-8 lperfetto Phosphopeptide mapping revealed enhanced phosphorylation of ser(202)/thr(205) residues by p25-cdk5 considering the fact that phosphorylation of ser(202)/thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-cdk5 may play a pivotal role in neuronal cell death in alzheimer's disease. SIGNOR-251600 0.699 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT down-regulates quantity by destabilization phosphorylation Ser51 LRPSTSRsLYASSPG -1 2500966 t lperfetto We reported that stoichiometric phosphorylation by either cAMP-dependent protein kinase or protein kinase C induces disassembly of vimentin filaments. In the present work, we attempted to identify the sites of vimentin phosphorylated by each protein kinase. Sequential analysis of the purified phosphopeptides, together with the known primary sequence, revealed that Ser-8, Ser-9, Ser-20, Ser-25, Ser-33, and Ser-41 were specifically phosphorylated by protein kinase C, whereas Ser-46 was phosphorylated preferentially by cAMP-dependent protein kinase. Both kinases reacted with Ser-6, Ser-24, Ser-38, Ser-50, and Ser-65. SIGNOR-248883 0.287 trichostatin A chemical CHEBI:46024 ChEBI HDAC5 protein Q9UQL6 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-258010 0.8 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates quantity by destabilization phosphorylation Ser206 SSSTYPHsPTSSDPG 9606 19914161 t lpetrilli Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3. SIGNOR-189137 0.388 MAPK11 protein Q15759 UNIPROT MAPK11 protein Q15759 UNIPROT down-regulates activity phosphorylation Ser243 MEVVGTPsPEVLAKI -1 26976637 t miannu P38β Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261 SIGNOR-277215 0.2 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates activity phosphorylation Ser77 PGPFATRsPLFIFMR 12818176 t miannu JNKs specifically phosphorylate BIMEL at Ser55, 65, and/or 73. several observations demonstrate that the phosphorylation of BIMEL is a physiologically important mechanism for enhancing its proapoptotic activity. SIGNOR-250135 0.628 N-(2,6-dimethylphenyl)-5,6-dihydro-4H-1,3-thiazin-2-amine chemical CHEBI:92386 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258922 0.8 CAMK2B protein Q13554 UNIPROT SCN8A protein Q9UQD0 UNIPROT up-regulates activity phosphorylation Thr642 RSVKRNStVDCNGVV 9606 BTO:0000938 32611770 t lperfetto CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability|mmobilized peptide arrays and nanoflow LC-electrospray ionization/MS of Nav1.6 reveal potential sites of CaMKII phosphorylation, specifically Ser-561 and Ser-641/Thr-642 within the first intracellular loop of the channel. SIGNOR-275789 0.274 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 9606 BTO:0000150 10550055 t gcesareni However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci. SIGNOR-72083 0.505 GSK3B protein P49841 UNIPROT MITF protein O75030 UNIPROT up-regulates quantity by stabilization phosphorylation Ser405 QARAHGLsLIPSTGL 9606 25605940 t miannu We also show that the MITF protein was stabilized by Wnt signaling, through the novel C-terminal GSK3 phosphorylations identified here. SIGNOR-276475 0.442 FYN protein P06241 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates activity phosphorylation Tyr446 DQSRQMKyQSFNEYR -1 24970799 t miannu We report that FYN phosphorylates human COX2 on Tyr 446, and while corresponding phospho-mimetic COX2 mutation promotes COX2 activity, the phosphorylation blocking mutation prevents FYN-mediated increase in COX2 activity. FYN and LYN kinases phosphorylate COX2 on two distinct residues in vitro. SIGNOR-276644 0.395 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr536 LPLNTDAyLSLQELQ -1 10214954 t Recombinant p56(lck) phosphorylates in vitro tyrosine residues within the IL-2Rbeta chain. p56(lck) phosphorylates tyrosine residues 355, 358 and 361 but not 338 of the IL-2Rbeta chain acidic subdomain. p56(lck) also phosphorylates very efficiently the two tyrosines present in the IL-2Rbeta chain C-terminal region, Tyr-392 and Tyr-510. SIGNOR-251379 0.635 ULK2 protein Q8IYT8 UNIPROT DENND3 protein A2RUS2 UNIPROT up-regulates activity phosphorylation Ser490 ELAPRNSsLRLTDTA 9606 25925668 t lperfetto ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. SIGNOR-264733 0.2 AURKB protein Q96GD4 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates phosphorylation Thr117 KNKIAKEtNNKKKEF 9606 17457057 t lperfetto Phosphorylation by aurora-b negatively regulates survivin function . hat survivin is phosphorylated at t117 during mitosis, and once phosphorylated, dephosphorylation is crucial for chromosome congression and progression into anaphaseduring mitosis SIGNOR-154569 0.789 SGK3 protein Q96BR1 UNIPROT SCN5A protein Q14524 UNIPROT up-regulates activity phosphorylation Ser664 GARQRALsAVSVLTS 9606 BTO:0000938 33410863 t lperfetto Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5 SIGNOR-275768 0.278 dexamethasone chemical CHEBI:41879 ChEBI NR3C2 protein P08235 UNIPROT down-regulates activity chemical inhibition 9534 BTO:0001538 8282004 t miannu The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. aldosterone shows a higher functional sensitivity for the human mineralocorticoid receptor than deoxycorticosterone (higher affinity) or cortisol (similar affinity). Moreover, the very high binding affinity of the human mineralocorticoid receptor for progesterone (k i < 0.0l nM) in combination with the very low agonistic activity indicates that progesterone may act as a potent human mineralocorticoid receptor antagonist that is even more effective than spironolactone (k~ = 5.7 nM), which displays no partial agonistic activity (fig. 4). SIGNOR-258710 0.8 RPS6KA4 protein O75676 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 16055710 t lperfetto Serine 374 and serine 362 are the primary sites targeted by Erk1/2 and the mitogen-activated protein kinase-activated kinases Rsk1/2 (12, 13, 37, 38, 41), respectively. Their phosphorylation leads to protein stabilization (3, 13, 20, 41). Threonine 325 and threonine 331 are secondary targets of Erk1/2; their modification occurs only when serines 362 and 374 are phosphorylated and Erk1/2 activation is sufficiently sustained (37, 38). This enhances the transcriptional activity of c-Fos SIGNOR-263000 0.397 EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000782 20506119 f miannu In T lymphocytes EGR2 and EGR3 have been shown to inhibit NAB2 expression. SIGNOR-253885 0.587 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser487 AAISRELsEITTAEA 9606 BTO:0000150 17693255 t gcesareni Here we show that ikkbeta, a major downstream kinase in the tnfalpha signaling pathway, physically interacts with and phosphorylates tsc1 at ser487 and ser511, resulting in suppression of tsc1phosphorylation of tsc2 (by akt and erk;refs. 28, 29) and tsc1(by ikkbeta;ref. 30) results in the disruption of the tsc1/2 complex, and thereby activates the oncogenic mtor signaling contributing to tumor progression. SIGNOR-157296 0.633 PRKCA protein P17252 UNIPROT AQP1 protein P29972 UNIPROT up-regulates phosphorylation Thr157 VLCVLATtDRRRRDL 9606 BTO:0000671 17522053 t llicata Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc). SIGNOR-155102 0.2 PRKCA protein P17252 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation Ser209 DTATKSGsTTKNRFV 10090 8662663 t lperfetto Phosphorylation of eIF-4E on serine 209 by protein kinase C is inhibited by the translational repressors, 4E-binding proteins.[..] This suggests a two-step model for the phosphorylation (and activation) of eIF4E by growth factors and hormones: first, dissociation of eIF4E . SIGNOR-248945 0.387 CUL3 protein Q13618 UNIPROT RHOA protein P61586 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 19782033 t miannu BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. SIGNOR-264238 0.402 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT unknown phosphorylation Tyr409 TDGLGLSyLSSHIAN -1 10210201 t llicata Gelsolin phosphorylation by c-Src in the presence of lysophosphatidic acid also revealed Tyr438 as the most prominent site. Additional minor sites were found using the anti-phosphotyrosine bead immunoprecipitation method followed by MALDI-MS and PSD analysis. These sites, representing approximately 5% of the total phosphate incorporation, were identified as Tyr59, Tyr382, Tyr576, and Tyr624. SIGNOR-250780 0.574 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0006413 32917631 t Ser2 in CTD of PolII lperfetto Together, these studies demonstrate the important, yet largely redundant, role for CDK12 and CDK13 for the regulation of POLII CTD phosphorylation at multiple residues, as well as the global role for both of these kinases in regulating POLII occupancy across the genome.|CDK12 and CDK13 are thus evolutionarily related and structurally similar kinases, and biochemical assays have demonstrated that both have POLII C-terminal domain (CTD) kinase activity and the ability to phosphorylate the Ser2 residue of the repetitive CTD heptad sequence SIGNOR-273094 0.749 MRPS21 protein P82921 UNIPROT 28S mitochondrial small ribosomal subunit complex SIGNOR-C266 SIGNOR form complex binding 9606 25838379 t miannu The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. . We report here the identification of 28 S small subunit proteins. SIGNOR-261486 0.663 perfluorododecanoic acid chemical CHEBI:90633 ChEBI PPARD protein Q03181 UNIPROT up-regulates activity chemical activation -1 31332417 t miannu In the present study, we demonstrated PFASs bound to and activated human PPARb/d-LBD directly. The PPARb/d binding potency and transcriptional activity of PFASs were all related to the carbon chain length and the terminal functional group. SIGNOR-268759 0.8 BMPR2 protein Q13873 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding 10090 10712517 t ggiuliani Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand. SIGNOR-255781 0.621 RLIM protein Q9NVW2 UNIPROT LDB1 protein Q86U70 UNIPROT down-regulates quantity by destabilization polyubiquitination 10029 BTO:0000246 11882901 t miannu Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.  SIGNOR-272617 0.578 (RS)-Ppcc chemical CID:16726095 PUBCHEM SIGMAR1 protein Q99720 UNIPROT up-regulates activity chemical activation 9606 17328523 t Federica We suggest that 4b may act as a ơ1/ơ2 agonist and that the ơ ligands may modulate TG-2 differently. SIGNOR-261107 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NPM1 protein P06748 UNIPROT down-regulates activity phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 12058066 t lperfetto Both subtypes of B23 proteins were phosphorylated during mitosis by cyclin B/cdc2. The RNA binding activity of B23.1 was repressed through cyclin B/cdc2-mediated phosphorylation at specific sites in B23. Thus, the RNA binding activity of B23.1 is stringently modulated by its phosphorylation and subtype association. SIGNOR-216749 0.414 PRKCD protein Q05655 UNIPROT HNRNPK protein P61978 UNIPROT down-regulates phosphorylation Ser302 GRGGRGGsRARNLPL 9606 10329716 t lperfetto Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment SIGNOR-67515 0.348 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 23898330 t lperfetto In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation SIGNOR-249505 0.707 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK2 protein O96017 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206841 0.8 DYNLT1 protein P63172 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates activity binding 9606 BTO:0002181 29089450 t miannu Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules. SIGNOR-277369 0.291 ARNT protein P27540 UNIPROT CYP1B1 protein Q16678 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001033 16115918 f miannu Expressions of CYP1B1 mRNA and protein were increased in prostate cancer. The aryl hydrocarbon receptor (AhR)/AhR nuclear translocator (ARNT) heterodimer complex activates gene transcription by binding to the DREs of CYP1B1. SIGNOR-253740 0.407 SIRT1 protein Q96EB6 UNIPROT XBP1 protein P17861-2 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 20955178 t miannu P300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity.. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. SIGNOR-260430 0.385 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser721 TPRLRSVsSYGNIRA 9606 SIGNOR-C3 18722121 t llicata Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-252774 0.2 C9 protein P02748 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263441 0.476 CDK1 protein P06493 UNIPROT MAP2K1 protein Q02750 UNIPROT down-regulates phosphorylation Thr292 ETPPRPRtPGRPLSS 9606 8114697 t gcesareni P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well SIGNOR-36116 0.482 HRH1 protein P35367 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257425 0.443 HOXD12 protein P35452 UNIPROT MAFB protein Q9Y5Q3 UNIPROT down-regulates activity binding -1 11036080 t miannu Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf. SIGNOR-221896 0.382 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR ST7 protein Q9NRC1 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0004297 30945288 t miannu We found that both CUL4A and CUL4B can form an E3 complex with DNA damage-binding protein 1 (DDB1) and DDB1-CUL4-associated factor 4 (DCAF4). In vitro and in vivo ubiquitination analyses indicate that CRL4DCAF4 E3 ligase specifically directs degradation of ST7 (suppression of tumorigenicity 7). SIGNOR-272309 0.2 JNK proteinfamily SIGNOR-PF15 SIGNOR ATN1 protein P54259 UNIPROT down-regulates activity phosphorylation 9606 BTO:0000142 12812981 t inferred from 70% family members lperfetto Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-jun nh2-terminal kinase. serine 734 of the drpla protein is a phospho-acceptor site by jnk. The phosphorylation may be coupled to the activation of a protease. The molecular size of drpla protein detected in the rat brain with the specific phosphopeptide antibody was 150_kda, which was slightly smaller than that expected from the sequence and the results with the human protein. The phosphorylated forms of ha-tagged human drpla gradually disappeared after osmotic treatment, SIGNOR-269978 0.2 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT up-regulates phosphorylation Tyr599 VDFREYEyDLKWEFP 9606 BTO:0001271 11971190 t lperfetto Previously we reported that flt3 with itd (flt3/itd) formed a homodimer and was autophosphorylated on tyrosine residuewe examined the role of tyr residues (y589, y591, y597 and y599) in the jm domain in the activation of flt3. In wt-flt3, these tyr residues were important for the fl-dependent activation SIGNOR-117583 0.2 DGC complex SIGNOR-C217 SIGNOR GABA-A (a3-b1-g2) receptor complex SIGNOR-C332 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265434 0.2 CARM1 protein Q86X55 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0000725 24332853 f miannu PRMT4 blocks myeloid differentiation of human hematopoietic stem/progenitor cells While PRMT4 promotes differentiation in several biological systems including T cell, adipocyte and muscle development, it blocks differentiation in the hematopoietic system, allowing HSPCs to maintain stemness.  SIGNOR-261968 0.7 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Thr336 GGPGPERtPGSGSGS 10090 BTO:0000944 7889942 t lperfetto We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erki phosphorylates five c-terminal sites in elk-i (s324,t336, s383, s389 and s422) with varying degrees of efficiency. SIGNOR-235467 0.551 oxaprozin chemical CHEBI:7822 ChEBI PTGS2 protein P35354 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132;BTO:0003652 9650852 t miannu We used human platelets cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 for measuring cyclooxygenase selectivity. The presence of the enzymes was confirmed by immunoblotting and immunoprecipitation analysis, and by the reverse transcriptase-polymerase chain reaction. Mean IC50 values (microM) for human platelet cyclooxygenase-1 and interleukin-1beta-stimulated human synovial cell cyclooxygenase-2 and cyclooxygenase-1/-2 IC50 ratio of various NSAIDs were as follows: aspirin, 3.2, 26, 0.12; diclofenac, 0.037, 0.00097, 38; etodolac, 122, 0.68, 179; ibuprofen, 3.0, 3.5, 0.86; indomethacin, 0.013, 0.044, 0.30; loxoprofen (active metabolite), 0.38, 0.12, 3.2; NS-398, 12, 0.0095, 1263; oxaprozin, 2.2, 36, 0.061; zaltoprofen, 1.3, 0.34, 3.8; respectively. SIGNOR-258930 0.8 GGCX protein P38435 UNIPROT PROZ protein P22891 UNIPROT up-regulates activity carboxylation 9606 28125048 t lperfetto Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z SIGNOR-265926 0.495 DAPK2 protein Q9UIK4 UNIPROT DAPK2 protein Q9UIK4 UNIPROT down-regulates activity phosphorylation Ser318 VRRRWKLsFSIVSLC 9606 BTO:0000007;BTO:0000356 11230133 t llicata Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. | It comprises a single autophosphorylation event mapped to Ser308 within the CaM regulatory domain. SIGNOR-251084 0.2 IFNL2 protein Q8IZJ0 UNIPROT IFNLR1 protein Q8IU57 UNIPROT up-regulates binding 9606 12469119 t gcesareni Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha. SIGNOR-96206 0.704 MAPK14 protein Q16539 UNIPROT JUNB protein P17275 UNIPROT up-regulates phosphorylation Ser79 QGSDTGAsLKLASSE 9606 15308641 t lperfetto These results clearly demonstrate that phosphorylation by p38 kinase is essential for the regulation of dmp1 transcription by junb and p300. phosphorylation of junb at ser-79 was found to be essential for its interaction with p300. SIGNOR-127545 0.496 EGR2 protein P11161 UNIPROT NAB2 protein Q15742 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000848 20506119 f miannu In melanoma and carcinoma cells EGR1 activates NAB2 expression. we investigated the influence of EGR2 and EGR3 on NAB2 expression in melanoma and carcinoma cells. Here, we show that like EGR1, EGR2 and EGR3 induced NAB2 expression in these cells. EGR1 and EGR3 act in concert on the NAB2 promoter and are more potent activators of NAB2 transcription than EGR2. SIGNOR-253883 0.587 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Thr850 EAKRMKLtFSEAIRN -1 10366608 t lperfetto In addition, we identified threonine 830 as a potential PKC phosphorylation site. SIGNOR-249017 0.558 MYO10 protein Q9HD67 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 27580874 f miannu Myosin X is required for filopodia formation and extension. myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles. Myosin X facilitates initiation and elongation of filopodia, which implies favouring formation of parallel bundled F-actin filaments. SIGNOR-268283 0.7 CSNK2A1 protein P68400 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Ser485 QPDNSSDsDYDLHGA 9606 9834084 t lperfetto In this study, we use jurkat t cell transfectants of cd5 cytoplasmic tail mutants to reveal phosphorylation sites relevant to signal transduction. Our results show that casein kinase ii (ckii) is responsible for the constitutive phosphorylation of cd5 molecules at a cluster of three serine residues located at the extreme c terminus (s458, s459, and s461) SIGNOR-62311 0.346 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1626 SPSYSPTsPSYSPTS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248736 0.731 GPKOW protein Q92917 UNIPROT DHX16 protein O60231 UNIPROT up-regulates quantity binding 25296192 t miannu In this report, we showed that GPKOW interacted directly with the DHX16/hPRP2 and with RNA. Immuno-depletion of GPKOW from HeLa nuclear extracts resulted in an inactive spliceosome that still bound DHX16. SIGNOR-266300 0.845 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT up-regulates activity phosphorylation Tyr1172 ISLDNPDyQQDFFPK 10090 BTO:0002882 16122376 t Dimerization mediated by a beta hairpin, which protudes from the S1 domains of each ligand bound monomer lperfetto EGFR possesses three major and two minor tyrosine autophosphorylation sites located at Y1068, Y1148, Y1173, and at Y992 and Y1086 respectively. In addition, EGFR Y1114 is preceded by glutamic acid (Figure 1), which should be preferred by the EGFR kinase as indicated in previous work SIGNOR-236531 0.2 CAV1 protein Q03135 UNIPROT ANXA3 protein P12429 UNIPROT up-regulates quantity relocalization 9606 BTO:0000608 26095609 f miannu There has been no study regarding the route of entry of exogenous ANXA3 in any cell type thus far. We found exogenous ANXA3 to be internalized into HCC cells through caveolin-1-mediated, but not HSPG-mediated, endocytosis. SIGNOR-262215 0.294 FBXW11 protein Q9UKB1 UNIPROT BTRC protein Q9Y297 UNIPROT down-regulates quantity by destabilization binding 9606 BTO:0002419 31406304 t miannu Glucose deprivation activates AMPK kinase to phosphorylate β-TrCP1 and promotes the subsequent ubiquitination and degradation of β-TrCP1 by β-TrCP2, but does not promote β-TrCP2 degradation by β-TrCP1.  SIGNOR-277476 0.579 PPP2CB protein P62714 UNIPROT PRKCD protein Q05655 UNIPROT down-regulates activity dephosphorylation Ser664 QSAFAGFsFVNPKFE 10090 BTO:0000944 11959144 t PP2A(c) displayed the highest specific activity towards PKCdelta. The role of PP2A(c) in the dephosphorylation of PKCdelta in cells was supported by the demonstration that these proteins could be co-immunoprecipitated from NIH3T3 cells.|In conclusion, the evidence here indicates that PKCdelta de-phosphorylation and hence inactivation is effected by PP2A with which it forms a complex SIGNOR-248596 0.302 ERAP1 protein Q9NZ08 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 31810556 t scontino While peptides loaded onto MHC class I molecules are 8‚Äì11 amino acid residues long (a restriction based on the size and conformation of the peptide-binding groove of MHC class I molecules), peptides translocated by TAP can be significantly longer. These peptides will be trimmed to the correct length by ERAP-1. SIGNOR-267771 0.8 RAB14 protein P61106 UNIPROT RUFY1 protein Q96T51 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 20534812 t Giulio Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn. SIGNOR-261279 0.621 MK-2461 chemical CID:44137946 PUBCHEM MERTK protein Q12866 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-194381 0.8 FBXW7 protein Q969H0 UNIPROT DAB2IP protein Q5VWQ8 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27858941 t miannu DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1 SIGNOR-254774 0.33 DGC complex SIGNOR-C217 SIGNOR GABA-A (a4-b3-d) receptor complex SIGNOR-C327 SIGNOR up-regulates quantity binding 9606 BTO:0000938;BTO:0002606 22626542 t miannu  In brain, the DGC is involved in the organisation of GABA(A) receptors (GABA(A)Rs) and aquaporin-4 (AQP4)-containing protein complexes in neurons and glia, respectively. DGC-like complexes function in the postsynaptic clustering and stabilisation of GABAARs in a subset of inhibitory GABAergic synapses. SIGNOR-265437 0.2 RNF216 protein Q9NWF9 UNIPROT TLR4 protein O00206 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15107846 t miannu Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling.  SIGNOR-271504 0.393 GTP smallmolecule CHEBI:15996 ChEBI Translation release factor ERF1-ERF3 complex SIGNOR-C494 SIGNOR form complex binding 9606 29735640 t miannu Termination of mRNA translation occurs when a stop codon enters the A site of the ribosome, and in eukaryotes is mediated by release factors eRF1 and eRF3, which form a ternary eRF1/eRF3-guanosine triphosphate (GTP) complex. SIGNOR-275394 0.8 CTTNBP2 protein Q8WZ74 UNIPROT CTTN protein Q14247 UNIPROT up-regulates activity binding 10116 BTO:0000938 22262902 t miannu Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines. SIGNOR-269703 0.52 CDH8 protein P55286 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0000567 17938208 t gianni CHD8 binds to histone H3 di- and trimethylated on lysine 4. It resides on the human U6 promoter as well as the mRNA IRF3 promoter in vivo and contributes to efficient transcription from both these promoters SIGNOR-266898 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR UBTF protein P17480 UNIPROT up-regulates phosphorylation Ser389 INKKQATsPASKKPA 9606 11698641 t lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity SIGNOR-217304 0.367 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates activity phosphorylation Thr476 EANYVPMtPGTFDFS 10029 BTO:0000246 15379552 t lperfetto Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal SIGNOR-249400 0.591 PRKCD protein Q05655 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser284 AGGGRRIsDSHEDTG 9606 BTO:0000562 17075052 t gcesareni The triple aspartic acid mutation shows greater distance between the two thick myosin filaments (affects the steric arrangement of the filament distances) in heart tissue. Mutation is cardioprotective during stress (ischemia-reprofusion injury) against apoptosis similar to isoproterenol treatment. SIGNOR-150351 0.2 NFIB protein O00712 UNIPROT ID3 protein Q02535 UNIPROT down-regulates quantity transcriptional regulation 10090 31838646 t Gianni By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development SIGNOR-268879 0.252 GRK2 protein P25098 UNIPROT SNCG protein O76070 UNIPROT down-regulates activity phosphorylation Ser124 EVAEEAQsGGD -1 10852916 t GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser124 dramatically inhibits γ-synuclein phosphorylation by GRK2 SIGNOR-251204 0.2 CSNK2A1 protein P68400 UNIPROT CDC25B protein P30305 UNIPROT up-regulates activity phosphorylation Ser187 AGSGAASsSGEDKEN -1 12527891 t llicata Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. | Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. SIGNOR-250837 0.341 ATIC protein P31939 UNIPROT IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity chemical modification 9606 33179964 t miannu The last two steps in the pathway are catalyzed by the bifunctional AICAR transformylase/IMP cyclohydrolase (ATIC). The transformylase domain of the enzyme first catalyzes the conversion of AICAR to formylaminoimida zole-4-carboxamide ribonucleotide (FAICAR) using the N10-formyltetrahydrofolate. Then, the cyclohydrolase domain closes the purine ring to form IMP. SIGNOR-267329 0.8 WYE-687 chemical CID:25229450 PUBCHEM MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;ATP-competitive inhibitor mTOR gcesareni SIGNOR-207818 0.8 Norbinaltorphimine chemical CHEBI:81529 ChEBI OPRM1 protein P35372 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258821 0.8 NCOR2 protein Q9Y618 UNIPROT AR protein P10275 UNIPROT down-regulates acetylation 9606 BTO:0000150;BTO:0001130 12771131 t gcesareni In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases. SIGNOR-101286 0.572 GART protein P22102 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI down-regulates quantity chemical modification 9606 33179964 t miannu The second enzyme in the DNPB pathway is trifunc tional GART (TGART), whose domains and activities include: glycinamide ribonucleotide synthase (GARS) that catalyzes the ATP-dependent process that uses 5- PRA and Gly to make glycinamide ribonucleotide (GAR); glycinamide ribonucleotide transformylase (GART) that transfers the formyl group of N10-formyltetrahydrofolate to GAR, generating formylglycinamide ribonucleotide (FGAR); and aminoimidazole ribonucleotide synthase (AIRS) that converts formylglycinamidine ribonucleotide (FGAM) to aminoimidazole ribonucleotide (AIR) in an ATP-dependent manner. SIGNOR-267314 0.8 EEF1A1 protein P68104 UNIPROT Phe-tRNA(Phe) smallmolecule CHEBI:29153 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269520 0.8 SF3B6 protein Q9Y3B4 UNIPROT SF3b complex SIGNOR-C442 SIGNOR form complex binding 9606 32140746 t lperfetto Characterization of the purified SF3b complex indicated that it consists of seven proteins with a molecular size ranging from 10 to 155 kDa [10–12] (Fig. 1a). Due to methodological differences in identifying SF3b components in human and yeast, a number of names have been designated for these proteins across different species. In this review, I will use SF3b1-7 for consistency and clarity (Fig. 1a). SIGNOR-268408 0.86 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser519 SGYSSPGsPGTPGSR 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249343 0.733 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates activity phosphorylation Ser1150 LERGRKVsIVSKPVL 9534 BTO:0000298 19103606 t miannu these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells SIGNOR-276177 0.421 RUNX2 protein Q13950 UNIPROT RUNX2/EP300 complex SIGNOR-C211 SIGNOR form complex binding 10116 BTO:0002648 12697832 t Giulio Giuliani More interestingly, the bone-specific transcriptionfactor Runx2/Cbfa1 is present in the immunoprecipitated material, strongly indicating that in osteoblastic cells expressing OC, p300 and Runx2/Cbfa1 are components of the same nuclear protein complex. SIGNOR-255419 0.46 CLK1 protein P49759 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Thr735 DTEWRSVtLPRDLQS 9606 18794806 t lperfetto Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3 SIGNOR-181031 0.26 TLK1 protein Q9UKI8 UNIPROT MAPKAPK5 protein Q8IW41 UNIPROT up-regulates activity phosphorylation Ser386 HENGAEDsNVALEKL 9606 BTO:0000007 35064619 t miannu We established that TLK1 phosphorylates MK5 on three residues (S160, S354 and S386), resulting in MK5 activation, and additionally, mobility shifts of MK5 also supported its phosphorylation by TLK1 in transfected HEK 293 cells. SIGNOR-276747 0.2 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT down-regulates activity phosphorylation Ser641 YRYPRPAsVPPSPSL -1 6772446 t Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-. SIGNOR-253005 0.678 HTR1F protein P30939 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256673 0.435 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH22 protein Q9UJ99 UNIPROT up-regulates activity chemical activation 9606 22535893 t miannu Cadherins are Ca(2+)-dependent cell-cell adhesion molecules that play critical roles in animal morphogenesis. SIGNOR-265838 0.8 CASP8 protein Q14790 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity cleavage 9606 21295084 t amattioni Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction. SIGNOR-171767 0.718 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR isoleucine smallmolecule CHEBI:24898 ChEBI down-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270421 0.8 PLCG1 protein P19174 UNIPROT 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI up-regulates chemical modification 9606 21918248 t gcesareni Phospholypase c is an enzyme which catalyzes the hydrolysis of phosphatidylinositol-4,5-biphosphate (p(4,5)p(2)) into second messangers inositol-1,4,5-triphosphate (ins(1,4,5)p3) and dag. SIGNOR-176609 0.8 CFI complex complex SIGNOR-C388 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates quantity cleavage 9606 8626397 t lperfetto Purification and characterization of human cleavage factor Im involved in the 3' end processing of messenger RNA precursors|Gel retardation experiments confirmed the results obtained by UV cross-linking. In addition, we could show that CF Im stabilizes the binding of the cleavage and polyadenylation specificity factor (CPSF) to pre-mRNA and that CPSF and CF Im together form a slower migrating complex with pre-mRNA than the single protein factors. SIGNOR-266125 0.8 PTPN11 protein Q06124 UNIPROT SYK protein P43405 UNIPROT down-regulates activity dephosphorylation 9606 23182168 t miannu Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively. SIGNOR-277085 0.533 Caspase 8 complex complex SIGNOR-C231 SIGNOR CASP7 protein P55210 UNIPROT up-regulates cleavage 9606 18073771 t amattioni Active caspase-8 then proteolytically processes and activates caspase-7 SIGNOR-256454 0.734 THRAP3 protein Q9Y2W1 UNIPROT SFPQ protein P23246 UNIPROT down-regulates binding 9606 20932480 t miannu Here we demonstrate that in resting tcells psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. Upon tcell activation, reduced gsk3 activity leads to reduced psf phosphorylation, releasing psf from trap150 and allowing it to bind cd45 splicing regulatory elements and repress exon inclusion. SIGNOR-168441 0.443 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT down-regulates activity phosphorylation Ser303 DPDAKGLsDPGKIKR -1 12740371 t miannu Here we demonstrate that AMPK directly phosphorylates HNF4alpha and represses its transcriptional activity. AMPK-mediated phosphorylation of HNF4alpha on serine 304 had a 2-fold effect, reducing the ability of the transcription factor to form homodimers and bind DNA and increasing its degradation rate in vivo. SIGNOR-263106 0.31 KDM6A protein O15550 UNIPROT HOXC4 protein P09017 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 24561908 t miannu Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters. SIGNOR-260030 0.453 SCAF11 protein Q99590 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates activity cleavage Asp333 DTVAENDdGGFSEEW -1 10069390 t lperfetto Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis. SIGNOR-261742 0.296 FBXW11 protein Q9UKB1 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates ubiquitination 9606 11359933 t gcesareni Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3. SIGNOR-108240 0.263 9-cis-retinoic acid chemical CHEBI:50648 ChEBI RARA protein P10276 UNIPROT up-regulates activity chemical activation 9606 18321241 t miannu Alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid, capable of binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma, and RXR-alpha, -beta, -gamma). SIGNOR-259234 0.8 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT down-regulates activity phosphorylation Tyr628 PKVAYHPyPEDYGDI -1 9195949 t Tyr624 and Tyr628 are involved in the interaction between the IR and the KRLB domain of IRS-2, including tyrosine phosphorylation, and Tyr628 seems to be more important than Tyr624 in this process. the binding between the insulin receptor and the KRLB domain of IRS-2 results in tyrosine phosphorylation of the KRLB domain, and this leads to decreased binding of IRS-2 to the insulin receptor. SIGNOR-251318 0.752 NUMA1 protein Q14980 UNIPROT TUBA1B protein P68363 UNIPROT up-regulates binding 9606 11956313 t miannu Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. SIGNOR-116472 0.265 CHUK protein O15111 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000567 SIGNOR-C13 10469655 t lperfetto All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391). SIGNOR-70453 0.741 SRC protein P12931 UNIPROT GIT1 protein Q9Y2X7 UNIPROT up-regulates activity phosphorylation Tyr284 EELAMDVyDEVDRRE 9534 BTO:0000298 24699139 t miannu Tyrosines 246 and 293 are required to hold GIT1 in a closed conformation.Hyperphosphorylation of GIT1-N by Src and pervanadate does not affect its binding in vitro to full length GIT1 proteins. Mutations Y246E and Y293E of GIT1 enhance binding to paxillin. SIGNOR-276627 0.553 GSK3B protein P49841 UNIPROT RBM38 protein Q9H0Z9 UNIPROT down-regulates phosphorylation Ser195 DQYPYAAsPATAASF 9606 24142875 t lperfetto Here, we showed that rnpc1 is phosphorylated at ser195 by glycogen synthase kinase 3 (gsk3). We also provided evidence that ser195 phosphorylation converts rnpc1 from a repressor to an activator of p53. SIGNOR-203011 0.2 GSK3B protein P49841 UNIPROT NFATC2 protein Q13469 UNIPROT down-regulates phosphorylation 9606 15276472 t lperfetto Gsk3 was previously shown to directly phosphorylate the n-terminal regulatory domain of nfatc1, thus antagonizing the action of calcineurin and inhibiting nuclear shuttling of nfat. SIGNOR-179784 0.55 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Ser385 RYSDTTDsDPENEPF 9606 BTO:0001938 15987703 t lperfetto We provide evidence suggesting that LKB1 phosphorylates PTEN at residue S385 in combination either with S380, T382 or T383 SIGNOR-247446 0.616 HIF1A protein Q16665 UNIPROT Metabolism phenotype SIGNOR-PH77 SIGNOR up-regulates 9606 17415528 f HIF-1 has been known as a major transcription factor for the induction of virtually all genes encoding glucose transporters and glycolytic enzymes, which allows hypoxic tumor cells to take up glucose more efficiently and metabolize pyruvate to lactate SIGNOR-256591 0.7 PDPK1 protein O15530 UNIPROT AKT2 protein P31751 UNIPROT up-regulates activity phosphorylation Ser474 RTHFPQFsYSASIRE 9606 15743829 t lperfetto Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation. SIGNOR-134481 0.723 FGF3 protein P11487 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni Using fgf 1 as an internal standard we have determined the relative activity of all the other members of the fgf family. These data should serve as a biochemical foundation for determining developmental, physiological, and pathophysiological processes that involve fgf signaling pathways SIGNOR-42374 0.762 FGA protein P02671 UNIPROT Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 16418530 f lperfetto In response to agonist stimulation, the αIIbβ3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. SIGNOR-253372 0.7 PRKCZ protein Q05513 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser359 EERQTQRsKPQPAVP 9606 BTO:0000130 12056906 t lperfetto Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. SIGNOR-89280 0.399 propranolol chemical CHEBI:8499 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9205951 t miannu The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. SIGNOR-258614 0.8 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t inferred from 70% family members gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus SIGNOR-270137 0.2 EIF2AK2 protein P19525 UNIPROT KDM4C protein Q9H3R0 UNIPROT down-regulates quantity by destabilization phosphorylation Ser918 MFDDGSFsRDTFPED 9606 BTO:0003016 31888886 t miannu In the absence of Wnt3a, protein kinase R phosphorylated KDM4C at Ser918, inducing KDM4C ubiquitination and degradation. SIGNOR-277497 0.2 TGFb proteinfamily SIGNOR-PF5 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates 9606 SIGNOR-C9 12524424 f fspada Because tgf-beta inhibits adipogenesis by signaling through smad3, we examined physical and functional interactions of smad3 and smad4 with c/ebpbeta, c/ebpdelta, and ppargamma2. SIGNOR-97123 0.2 RAD23B protein P54727 UNIPROT PAX3 protein P23760 UNIPROT down-regulates activity binding -1 17662948 t llicata Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B. SIGNOR-237667 0.296 HECW2 protein Q9P2P5 UNIPROT TP73 protein O15350 UNIPROT up-regulates quantity by stabilization ubiquitination 9534 BTO:0000298 12890487 t miannu P73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability. SIGNOR-269457 0.375 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity phosphorylation Ser11 TKQTARKsTGGKAPR 9606 12588998 t Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory). gcesareni Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. SIGNOR-98289 0.2 NMUR2 protein Q9GZQ4 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257352 0.419 EFR3A protein Q14156 UNIPROT KRAS protein P01116 UNIPROT up-regulates quantity binding 9606 BTO:0000007 34504076 t miannu EFR3A directly binds to active KRAS through its C-terminus. EFR3A promotes the localization and nanoclustering of KRAS at the plasma membrane. SIGNOR-269094 0.2 PTPN6 protein P29350 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates activity dephosphorylation Tyr380 TDSEEQPyLEMDLSS 9606 18086677 t Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. SIGNOR-248477 0.358 SMO protein Q99835 UNIPROT MBP protein P02686 UNIPROT up-regulates quantity transcriptional regulation 10090 35082605 f Non-canonical pathway (Gli1-indipendent): SMO/AMPK SimoneGraziosi We show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMPactivated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. SIGNOR-269226 0.2 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT up-regulates activity phosphorylation Thr471 PIKPLIStPPVSSQP 9606 BTO:0000567 30021153 t lperfetto Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1. Knockdown of WAC compromises Plk1 activity and delays mitotic entry. SIGNOR-265034 0.2 AIIB/b3 integrin complex SIGNOR-C173 SIGNOR PTK2 protein Q05397 UNIPROT up-regulates activity 9606 15688067 f miannu Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin. SIGNOR-257717 0.559 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT up-regulates activity carboxylation Glu63 LERECVEeTCSYEEA -1 10556651 t lperfetto We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood. SIGNOR-263680 0.661 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr341 GQRDSSYyWEIEASE 9606 12551923 t gcesareni We also show that phosphorylation of raf-1 on serine 338 by pak1 and tyrosines 340 and 341 by src relieves autoinhibition and that this occurs through a specific decrease in the binding of the raf-1 regulatory domain to its catalytic domain. SIGNOR-97639 0.594 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR USP7 protein Q93009 UNIPROT up-regulates activity phosphorylation Tyr243 NQLRKAVyMMPTEGD 24317448 t lperfetto In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity.|The HAUSP Y243F mutant showed significantly reduced BCR-ABL-induced HAUSP phosphorylation, which in turn was completely abrogated by imatinib treatment SIGNOR-276532 0.2 SRC protein P12931 UNIPROT PTEN protein P60484 UNIPROT up-regulates activity phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 BTO:0002035 11948419 t miannu MMAC/PTEN is tyrosine phosphorylated. U251 glioblastoma cells were cotransfected with MMAC/PTEN and either Src Lck expression plasmids.Reduced tyrosine phosphorylation of MMAC/PTEN was observed when tyrosine 240 or 315 mutants were mutated to nonphosphorylated residues (Figure 1e). SIGNOR-275982 0.547 PF-04691502 chemical CID:25033539 PUBCHEM AKT1 protein P31749 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck;inhibitor of phosphorylation of AktT308 and AktS473 gcesareni SIGNOR-252631 0.8 GPR55 protein Q9Y2T6 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256670 0.2 PRKDC protein P78527 UNIPROT HSP90AA1 protein P07900 UNIPROT unknown phosphorylation Thr7 tQDQPMEE 9606 BTO:0000567 2507541 t lperfetto Here we show that the dsDNA-activated protein kinase from human HeLa cells phosphorylates 2 threonine residues in the sequence PEETQTQDQPME at the amino terminus of human hsp90 alpha. SIGNOR-248888 0.434 ponatinib chemical CHEBI:78543 ChEBI FGFR4 protein P22455 UNIPROT down-regulates activity chemical inhibition 9606 23468082 t miannu Ponatinib is an oral multitargeted kinase inhibitor that potently inhibits all 4 members of the FGFR family. SIGNOR-259280 0.8 TNF protein P01375 UNIPROT SCN11A protein Q9UI33 UNIPROT up-regulates activity 10090 BTO:0004102 26112872 f miannu TNF-α increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons. TNF-α increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. SIGNOR-253492 0.2 5-[(Z)-(5-Fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-3H-pyrrole-3-carboxamide chemical CID:73755145 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates activity chemical inhibition -1 22037378 t llicata Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258288 0.8 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 15735019 t miannu Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates SIGNOR-134212 0.639 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0001321 15659650 t lperfetto CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37 SIGNOR-217795 0.775 HDAC8 protein Q9BY41 UNIPROT TP53 protein P04637 UNIPROT down-regulates activity deacetylation 10090 BTO:0002882 26387755 t HDAC8 mediates CM-induced deacetylation of p53.Collectively, these results indicate that although binding to p53 and HDAC8 occurs through distinct regions of the CM protein, simultaneous interaction with HDAC8 and p53 is required for aberrant deacetylation and inactivation of p53. SIGNOR-255738 0.463 JAK2 protein O60674 UNIPROT EPOR protein P19235 UNIPROT up-regulates activity phosphorylation Tyr454 PTPPHLKyLYLVVSD 12441334 t JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2 SIGNOR-251350 0.808 ZEB2 protein O60315 UNIPROT VDR protein P11473 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11432806 t Luisa ZEB, a Krüppel-type transcription factor known to repress the transcription of several genes, binds to two sites within the VDR promoter and activates the transcription of this receptor in a cell-specific manner. Transfection of ZEB into SW620 colon carcinoma cells results in an up-regulation of the expression of endogenous VDR, confirming the role of ZEB in the transcriptional activation of the VDR gene. SIGNOR-268954 0.2 PRKCD protein Q05655 UNIPROT CHAT protein P28329 UNIPROT up-regulates quantity phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000930 15381704 t lperfetto Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity. SIGNOR-249271 0.313 2-[[7-(3,4-dimethoxyphenyl)-5-imidazo[1,2-c]pyrimidinyl]amino]-3-pyridinecarboxamide chemical CHEBI:91426 ChEBI SYK protein P43405 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000793 30744170 t lperfetto The Selective SYK Inhibitor BAY 61-3606 Enhances the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells SIGNOR-262020 0.8 MARCHF9 protein Q86YJ5 UNIPROT FCGR2B protein P31994 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0001522 19457934 t miannu MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.  SIGNOR-271541 0.2 PRKDC protein P78527 UNIPROT PRKAG1 protein P54619 UNIPROT up-regulates activity phosphorylation Ser192 KPEFMSKsLEELQIG -1 31983282 t miannu PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity.  SIGNOR-277503 0.2 KIF5C protein O60282 UNIPROT Plus-end directed sliding movement phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 19773780 f In general, N-kinesins and C-kinesins drive microtubule plus end- and minus end-directed motilities, respectively, and M-kinesins depolymerize microtubules1,9 (Box 1).|Forty-five genes that encode kinesin superfamily proteins (also known as KIFs) have been discovered in the mouse and human genomes.|KIFs are molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs, along the microtubule system. SIGNOR-272518 0.7 RUNX1 protein Q01196 UNIPROT MECOM protein Q03112 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 22689058 f irozzo Our results suggest that RUNX1 and EVI1 could be regulating each other. RUNX1 would activate EVI1 transcription, and when highly expressed, EVI1 could bind to RUNX1 at protein level, inhibiting its activity as a transcription factor, acting in a negative feedback. SIGNOR-255715 0.515 CDK5 protein Q00535 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Thr498 KTPPAPKtPPSSGEP 9606 BTO:0000590 12387894 t lperfetto We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235. SIGNOR-249326 0.758 JAK1 protein P23458 UNIPROT IL10RA protein Q13651 UNIPROT up-regulates activity phosphorylation Tyr496 PPALAKGyLKQDPLE 10433356 t Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). SIGNOR-251339 0.804 OTX2 protein P32243 UNIPROT BEST1 protein O76090 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 20530484 f miannu BEST1 promoter activity was increased by SOX9 overexpression and decreased by siRNA-mediated SOX9 knockdown. SOX9 physically interacted with MITF and OTX2 and orchestrated synergistic activation of the BEST1 promoter with the paired SOX site playing essential roles. SIGNOR-255186 0.356 PAK1 protein Q13153 UNIPROT NET1 protein Q7Z628 UNIPROT down-regulates activity phosphorylation Ser539 LTAQRRAsTVSSVTQ -1 15684429 t miannu In this work we show that the Rac/Cdc42hs-regulated protein kinase PAK1 down-regulates the activity of the RhoA-specific guanine nucleotide exchange factor NET1. Specifically, PAK1 phosphorylates NET1 on three sites in vitro: serines 152, 153, and 538. Replacement of serines 152 and 153 with glutamate residues down-regulates the activity of NET1 as an exchange factor in vitro and its ability to stimulate actin stress fiber formation in cells. Using a phospho-specific antibody that recognizes NET1 phosphorylated on serine 152, we show that PAK1 phosphorylates NET1 on this site in cells and that Rac1 stimulates serine 152 phosphorylation in a PAK1-dependent manner. SIGNOR-263018 0.251 CREB5 protein Q02930 UNIPROT DGKG protein P49619 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002810 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253803 0.2 CABIN1 protein Q9Y6J0 UNIPROT HIRA complex 1 complex SIGNOR-C461 SIGNOR form complex binding 9606 30285846 t miannu H3.3 is an ancient and conserved H3 variant and plays essential roles in transcriptional regulation. HIRA complex, which is composed of HIRA, UBN1 or UBN2, and Cabin1, is a H3.3 specific chaperone complex. In this study, we demonstrate that the UBN1 or UBN2 subunit is mainly responsible for specific recognition and direct binding of H3.3 by the HIRA complex. SIGNOR-269435 0.689 PRKACA protein P17612 UNIPROT PHKA1 protein P46020 UNIPROT up-regulates activity phosphorylation 9606 10487978 t miannu Phosphorylation of the alpha and beta subunits by the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) also relieves inhibition of the gamma subunit and thereby activates the enzyme. SIGNOR-267411 0.423 CLOCK protein O15516 UNIPROT PER1 protein O15534 UNIPROT up-regulates quantity by expression transcriptional regulation 22750052 f Mammalian clocks are primarily based on a transcription and translation feedback loop in which a heterodimeric complex of the transcription factors CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle Arnt-like protein 1) activates the expression of its own repressors, the period (PER1-3) and cryptochrome (CRY1,2) proteins. SIGNOR-253633 0.724 ANGPT1 protein Q15389 UNIPROT TIE1 protein P35590 UNIPROT up-regulates binding 9606 11172728 t gcesareni We reasoned that there may be cooperative interactions among the angiopoietins (i.e., ligands for tie2) and tie1, the orphan receptor. SIGNOR-105199 0.46 MID1 protein O15344 UNIPROT PPP2CA protein P67775 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0004725 11685209 t miannu MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation SIGNOR-271467 0.46 SELPLG protein Q14242 UNIPROT SELE protein P16581 UNIPROT up-regulates binding 9606 BTO:0000130 9024699 t gcesareni PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro. SIGNOR-46330 0.767 CKM complex complex SIGNOR-C406 SIGNOR NOTCH1 protein P46531 UNIPROT down-regulates quantity by destabilization phosphorylation -1 25344755 t lperfetto Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues SIGNOR-273160 0.381 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation Tyr332 ILAIHDSyKPEFHSD 10029 12907755 t PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates SIGNOR-248418 0.487 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC7 protein Q8WUI4 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257980 0.8 (S)-adrenaline smallmolecule CHEBI:40751 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258453 0.8 C8A protein P07357 UNIPROT Membrane attack complex complex SIGNOR-C313 SIGNOR form complex binding -1 30552328 t lperfetto The human MAC pore was formed on liposomes from individual complement proteins. |The maps were further subdivided into three components: an asymmetric region (C5b, C6, C7, and C8), a hinge region (C7, C8, and two C9 molecules), and a C9 oligomer SIGNOR-263445 0.586 TSHB protein P01222 UNIPROT SLC5A5 protein Q92911 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 14623893 t miannu I– uptake is stimulated by TSH, the master hormone for thyroid gland regulation. TSH stimulation results, at least in part, from the cAMP-mediated increase in NIS biosynthesis. TSH not only stimulates NIS transcription and biosynthesis but is also required for modulating the NIS phosphorylation pattern, maintaining its half-life, and retaining NIS at the thyrocyte plasma membrane SIGNOR-251995 0.386 TBK1 protein Q9UHD2 UNIPROT IKBKB protein O14920 UNIPROT up-regulates binding 9606 14743216 t fstefani A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway. SIGNOR-121576 0.409 p38 proteinfamily SIGNOR-PF16 SIGNOR DROSHA protein Q9NRR4 UNIPROT down-regulates activity phosphorylation Ser300 RHRDNRRsPSLERSY 9606 BTO:0000007 25699712 t lperfetto Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.  SIGNOR-264847 0.2 CDK1 protein P06493 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates activity phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12202491 t gcesareni Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity. SIGNOR-151799 0.564 PPP1CA protein P62136 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 12840032 t gcesareni P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3) SIGNOR-103152 0.453 RXRB protein P28702 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10882139 t lperfetto The nuclear receptor ppargamma/rxralpha heterodimer regulates glucose and lipid homeostasis SIGNOR-78907 0.658 AE/b7 integrin complex SIGNOR-C186 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269030 0.7 PRKCZ protein Q05513 UNIPROT ADD2 protein P35612 UNIPROT down-regulates phosphorylation Ser713 KKKFRTPsFLKKSKK 9606 16116087 t gcesareni We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta. SIGNOR-139914 0.277 VEZF1 protein Q14119 UNIPROT EDN1 protein P05305 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0004294 11504723 t miannu Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone SIGNOR-266884 0.279 selumetinib chemical CHEBI:90227 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates chemical inhibition 9606 Other t Selleck lperfetto SIGNOR-244823 0.8 ESR1 protein P03372 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000150 16169518 t gcesareni Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k. SIGNOR-140470 0.618 MIB1 protein Q86YT6 UNIPROT SMN1 protein Q16637 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 23615451 t lperfetto The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein SIGNOR-253112 0.326 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR XBP1 protein P17861 UNIPROT down-regulates quantity by destabilization phosphorylation Ser181 QQVQAQLsPLQNISP 9606 BTO:0001109 23277279 t miannu Phosphorylation of XBP-1u by ERK is critical for the increased interaction of XBP-1u and FoxO1. SIGNOR-276439 0.2 KDM3B protein Q7LBC6 UNIPROT H3C1 protein P68431 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. SIGNOR-266634 0.2 BRK1 protein Q8WUW1 UNIPROT NHS protein Q6T4R5 UNIPROT up-regulates activity binding 9606 20332100 t miannu We show that the WHD of NHS interacts with the Abi family of proteins, HSPC300, Nap1 and Sra1, and is important for the localization of NHS to the leading edge. SIGNOR-253574 0.2 GEM protein P55040 UNIPROT CACNB2 protein Q08289 UNIPROT down-regulates activity binding 9606 14701738 t miannu Two functions for Gem have been demonstrated, including inhibition of voltage-gated calcium channel activity and inhibition of Rho kinase-mediated cytoskeletal reorganization, such as stress fiber formation and neurite retraction. These functions for Gem have been ascribed to its interaction with the calcium channel Β subunit and Rho kinase Β, respectively. SIGNOR-261710 0.2 PGM2 protein Q96G03 UNIPROT D-ribofuranose 5-phosphate(2-) smallmolecule CHEBI:78346 ChEBI up-regulates quantity chemical modification 9606 17804405 t miannu Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses. The role of phosphopentomutase is to utilize ribose 1-phosphate and deoxyribose 1-phosphate, which are formed by purine nucleoside phosphorylase and uridine phosphorylase. Using catalytic efficiency as a criterion, PGM2 acted more than 10-fold better as a phosphopentomutase (both on deoxyribose 1-phosphate and on ribose 1-phosphate) than as a phosphoglucomutase. SIGNOR-267076 0.8 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MAP1LC3B protein Q9GZQ8 UNIPROT down-regulates activity phosphorylation Thr50 QLPVLDKtKFLVPDH -1 31857374 t done miannu LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1). SIGNOR-273905 0.2 NTRK1 protein P04629 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 10092678 t gcesareni The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation SIGNOR-65955 0.773 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 9606 15381704 t The effect has been demonstrated using P28329-3 gcesareni Finally, basal chat phosphorylation in neurons is mediated predominantly by pkc at ser-476, with pkc activation increasing phosphorylation at ser-440 and enhancing chat activity. SIGNOR-129340 0.29 CSNK1D protein P48730 UNIPROT KIR3DL1 protein P43629 UNIPROT up-regulates phosphorylation Ser388 RTANSEDsDEQDPEE 9606 17911614 t gcesareni In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover. SIGNOR-158125 0.2 SP3 protein Q02447 UNIPROT LORICRIN protein P23490 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12200429 f miannu Loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. SIGNOR-254537 0.2 RPL3L protein Q92901 UNIPROT 60S cytosolic large ribosomal subunit complex SIGNOR-C287 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262494 0.758 Cap-binding complex complex SIGNOR-C440 SIGNOR messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates relocalization 9606 32873578 t lperfetto The largely nuclear cap-binding complex (CBC) binds to the 5′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression. SIGNOR-268360 0.8 MAP2K2 protein P36507 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Thr185 HDHTGFLtEYVATRW 9606 11971971 t gcesareni Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity. SIGNOR-86709 0.737 IL13 protein P35225 UNIPROT IL13RA1 protein P78552 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1. SIGNOR-100750 0.849 INSR protein P06213 UNIPROT CALM3 protein P0DP25 UNIPROT down-regulates phosphorylation Tyr100 FDKDGNGyISAAELR 9606 3415247 t miannu The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule. SIGNOR-266336 0.38 SRC protein P12931 UNIPROT TNS3 protein Q68CZ2 UNIPROT up-regulates phosphorylation Tyr1206 SHSFRGAyGLAMKVA 9606 BTO:0000150;BTO:0000551;BTO:0000848 19732724 t llicata Tyrosines in the sh2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. tensin-3 is a src substrate SIGNOR-187847 0.414 ETS2 protein P15036 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 11175361 f miannu Ets1 and Ets2 seem to play opposing roles in apoptosis. While Ets1 seems to activate pro-apoptotic pathways, Ets2 seems to inhibit apoptosis SIGNOR-259870 0.7 MAPK1 protein P28482 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni We have identified a new subfamily of murine serine/threonine kinases, whose members, map kinase-interacting kinase 1 (mnk1) and mnk2, bind tightly to the growth factor-regulated map kinases, erk1 and erk2erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity SIGNOR-48338 0.589 CSNK2A1 protein P68400 UNIPROT MECOM protein Q03112 UNIPROT up-regulates activity phosphorylation Ser726 PLKMEPQsPGEVKKL 23858473 t phosphorylation site remapping based on Fig 5 lperfetto We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. SIGNOR-273428 0.2 C5 convertase complex complex SIGNOR-C312 SIGNOR C5 protein P01031 UNIPROT up-regulates activity cleavage Arg677 KEILRPRrTLQKKIE 31331124 t lperfetto Association of C3b with C3 convertases (C3bBb or C4b2a) results in formation of C5 convertases, C3bBbC3b and C4b2aC3b, which initiate the lytic pathway by cleavage of C5 to C5a and C5b SIGNOR-263452 0.546 MAPK3 protein P27361 UNIPROT FOS protein P01100 UNIPROT up-regulates activity phosphorylation Ser374 PSSDSLSsPTLLAL 9606 12972619 t lperfetto In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. SIGNOR-118023 0.711 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates activity phosphorylation Thr176 PFISEGTtLKDLIYD -1 8576253 t giulio giuliani From our present data, it is not easy to deduce the mechanistic significance of serine 172 and threonine 176 of TŒ≤R-I in TGF-Œ≤ signaling. Although it was reported that TGF-Œ≤-induced phosphorylation of these residues was not detected in vivo(22), it is still possible that TŒ≤R-II may phosphorylate these residues as minor phosphorylation site(s). SIGNOR-255961 0.714 PRKCA protein P17252 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser464 LLKHVTQsSRKLIRA 9606 BTO:0000938 15381704 t The effect has been demonstrated using P28329-3 gcesareni We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. SIGNOR-129260 0.388 DVL2 protein O14641 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates activity binding 10029 BTO:0000457 23132247 t gcesareni Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions. SIGNOR-243999 0.271 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1616 TPQSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248734 0.731 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser407 SNGVESKsLTPALCR 9606 16216881 t lperfetto We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase. SIGNOR-141006 0.2 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT up-regulates activity phosphorylation Ser380 PEQIKEDsLSEESAD -1 21880710 t miannu Here, we report that the atypical protein kinase Rio2 is a novel substrate of Plk1 and can be phosphorylated by Plk1 at Ser-335, Ser-380, and Ser-548. Overexpression of Rio2 causes a prolonged mitotic exit whereas knockdown of Rio2 accelerates mitotic progression, suggesting that Rio2 is required for the proper mitotic progression. SIGNOR-262938 0.437 IKBKE protein Q14164 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates quantity by destabilization phosphorylation 9606 BTO:0000801 20717897 t lperfetto The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation. SIGNOR-167524 0.492 POLR3E protein Q9NVU0 UNIPROT RNA Polymerase III complex SIGNOR-C389 SIGNOR form complex binding 9606 BTO:0000567 12391170 t lperfetto In this article, we use this proposed nomenclature for the S. cerevisiae subunits as the guide to refer to the human RNA polymerase III subunits, as indicated in Table ​Table1,1, and consequently the numbering of the human subunits does not always correspond to their decreasing apparent molecular weights. SIGNOR-266129 0.847 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t gcesareni The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-184591 0.378 PRSS1 protein P07477 UNIPROT F2RL1 protein P55085 UNIPROT up-regulates activity cleavage Lys34 QGTNRSSkGRSLIGK -1 10978167 t lperfetto PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 SIGNOR-263605 0.379 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NUP50 protein Q9UKX7 UNIPROT down-regulates phosphorylation 9606 19767751 t inferred from 70% family members gcesareni Erk phosphorylates nup50 at ser221 and ser315 erk phosphorylation of the fg repeat region of nup50 reduced its affinity for importin-beta family proteins, importin-beta and transportin. SIGNOR-270041 0.2 GPR174 protein Q9BXC1 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256900 0.2 PIP3 smallmolecule CHEBI:16618 ChEBI AKT2 protein P31751 UNIPROT up-regulates activity chemical activation 9606 21779497 t lperfetto When active, pi3k converts phosphatidylinositol (4,5)-bisphosphate (pip2) into phosphatidylinositol (3,4,5)-trisphosphate (pip3). Pip3, in turn, binds the pleckstrin homology (ph) domain of akt/pkb, stimulating its kinase activity, resulting in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. SIGNOR-175247 0.8 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 SIGNOR form complex binding 9606 23397623 t miannu The Scribble polarity complex or module is one of the three polarity modules that regulate cell polarity in multiple epithelia including blood-tissue barriers. This protein complex is composed of Scribble, Lethal giant larvae (Lgl) and Discs large (Dlg), which are well conserved across species from fruitflies and worms to mammals. SIGNOR-270884 0.542 PSEN1 protein P49768 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates cleavage 9606 SIGNOR-C98 10593990 t Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface. gcesareni Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains. SIGNOR-72886 0.793 Dynorphin A smallmolecule CHEBI:4727 ChEBI OPRK1 protein P41145 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9686407 t miannu Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors. SIGNOR-258794 0.8 PRKACA protein P17612 UNIPROT NEDD4L protein Q96PU5 UNIPROT down-regulates phosphorylation Ser448 IRRPRSLsSPTVTLS 9606 15328345 t gcesareni Nedd4-2 was a substrate for phosphorylation by pka in vitro and in cells;three nedd4-2 residues were phosphorylated by pka and were required for camp to inhibit nedd4-2 (relative functional importance ser-327 > ser-221 > thr-246). SIGNOR-128429 0.2 PRKG2 protein Q13237 UNIPROT PTPN6 protein P29350 UNIPROT up-regulates activity phosphorylation Ser557 AKASRTSsKHKEDVY 9606 BTO:0002181 21177494 t miannu  PKGII directly phosphorylated and stimulated SHP-1 activity SIGNOR-276287 0.2 PTPRG protein P23470 UNIPROT LIMK1 protein P53667 UNIPROT down-regulates activity dephosphorylation Tyr507 KPDRKKRyTVVGNPY -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254711 0.262 RPS6KA1 protein Q15418 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 18722121 t lperfetto Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity SIGNOR-217553 0.467 CSNK2A1 protein P68400 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser89 KTEESPAsDEAGEKE 9606 10739259 t lperfetto Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools. SIGNOR-76274 0.2 PHF1 protein O43189 UNIPROT HOXA9 protein P31269 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 20565746 t miannu These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression. SIGNOR-260069 0.289 PRKAA1 protein Q13131 UNIPROT PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser314 IQEVRSKsDPIMLLK -1 33022274 t miannu AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex SIGNOR-276839 0.2 DCC protein P43146 UNIPROT CACNA1A protein O00555 UNIPROT up-regulates activity 9606 12827203 t miannu DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER. SIGNOR-268293 0.2 SMURF1 protein Q9HCE7 UNIPROT RABEP2 protein Q9H5N1 UNIPROT unknown ubiquitination -1 20804422 t miannu Recombinant proteins were used to profile substrate ubiquitination by the Smurf1 ubiquitin ligase on a global scale using protein microarrays. T Proteins ubiquitinated on the protein microarray were confirmed as potential substrates of the Smurf1 activity using an off chip in vitro ubiquitination assay. SIGNOR-272690 0.2 porfimer chemical CHEBI:60652 ChEBI LDLR protein P01130 UNIPROT up-regulates activity chemical activation 9606 1450993 t miannu Porphyrins are transported in blood mainly by lipoproteins, and the low density lipoprotein (LDL) receptor-mediated pathway is probably one of the important factors involved in the selective accumulation of porphyrins by tumor tissues, as cancer cells generally express much more LDL receptors than normal cells. SIGNOR-259302 0.8 quizartinib chemical CHEBI:90217 ChEBI FLT3 protein P36888 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206331 0.8 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F7 protein P08709 UNIPROT up-regulates activity cleavage Arg212 NASKPQGrIVGGKVC 9606 BTO:0000131 12524220 t lperfetto The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa. SIGNOR-263521 0.933 MAS1 protein P04201 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 23488800 f miannu The discovery that Ang-(1-7) offsets the major biological effects of Ang II has contributed to the realization that the RAS is composed of two opposing axes. The first axis is constituted by the enzyme ACE, with Ang II as the end product, and the AT1 receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to production of Ang-(1-7), with Mas receptor as the main effector conveying the vasodilator, antiproliferative, anti-inflammatory and anti-fibrotic effects of Ang-(1-7). Activation of the ACE2/Ang-(1-7)/Mas axis decreases inflammatory cell function and fibrogenesis in diverse models of human diseases. SIGNOR-260228 0.7 COPS2 protein P61201 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270772 0.921 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates activity phosphorylation Ser2624 QTRTQEGsLSARWPV -1 12186630 t lperfetto We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function. SIGNOR-249156 0.2 TP53 protein P04637 UNIPROT GMPS protein P49915 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000599;BTO:0003477;BTO:0001670 27939741 t miannu Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells. SIGNOR-267342 0.383 PIP4K2A protein P48426 UNIPROT 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) smallmolecule CHEBI:57795 ChEBI down-regulates quantity chemical modification 9606 9367159 t Gianni The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities'. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K SIGNOR-268866 0.8 HAT1 protein O14929 UNIPROT H4C1 protein P62805 UNIPROT down-regulates activity acetylation Lys13 KGGKGLGkGGAKRHR -1 28143904 t lperfetto Histone acetyltransferase 1 is the founding member of the histone acetyltransferase superfamily and catalyzes lysine acetylation of newly synthesized histone H4|Lys12 for direct attack of the acetyl group of the cofactor.| It is postulated that histone acetylation, through charge neutralization of the cationic histone tails, weakens nucleosomal electrostatic interactions with anionic DNA, thus destabilizing internucleosomal contacts and nucleosomal structure and facilitating access to the promoter region for RNA polymerase and transcription factors. SIGNOR-264790 0.2 COPS7A protein Q9UBW8 UNIPROT COP9 signalosome variant 1 complex SIGNOR-C489 SIGNOR form complex binding 9606 18850735 t miannu The COP9 signalosome (CSN) is a multiprotein complex that plays a critical role in diverse cellular and developmental processes in various eukaryotic organisms. we have performed a comprehensive proteomic analysis of the human CSN complex using a new purification method and quantitative mass spectrometry. Purification of the human CSN complex from a stable 293 cell line expressing N-terminal HBTH-tagged CSN5 subunit was achieved by high-affinity streptavidin binding with TEV cleavage elution. SIGNOR-270771 0.915 CHRM5 protein P08912 UNIPROT GNA15 protein P30679 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257351 0.368 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI up-regulates quantity precursor of 9606 34775382 t miannu 6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule. SIGNOR-268111 0.8 NHLRC1 protein Q6VVB1 UNIPROT PPP1R3B protein Q86XI6 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 18029386 t miannu Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. We show here that laforin and malin play a crucial role in the regulation of glycogen biosynthesis in FTO2B hepatoma cells. In these cells, the laforin–malin complex counteracts the glycogenic effect of PTG because it promotes its ubiquitination and degradation. SIGNOR-271728 0.405 FOXO3 protein O43524 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 BTO:0000007 14976264 f lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-267283 0.7 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Thr1097 SMIRTGEtPTKKRGI 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104695 0.846 FOXO3 protein O43524 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates activity 9606 BTO:0000007 22931788 f AMPK signaling Gianni Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process. SIGNOR-261952 0.7 PEX2 protein P28328 UNIPROT PEX5 protein P50542 UNIPROT down-regulates quantity by destabilization ubiquitination -1 19687296 t miannu Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle. SIGNOR-253021 0.591 HRH2 protein P25021 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257250 0.251 lysophosphatidic acids smallmolecule CHEBI:32957 ChEBI LATS2 protein Q9NRM7 UNIPROT down-regulates 10090 BTO:0002572 22863277 f milica Serum-borne lysophosphatidic acid (lpa) and sphingosine 1-phosphophate (s1p) act through g12/13-coupled receptors to inhibit the hippo pathway kinases lats1/2, thereby activating yap and taz transcription coactivators, which are oncoproteins repressed by lats1/2. SIGNOR-198520 0.8 ESR1 protein P03372 UNIPROT KDM4B protein O94953 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001248 20682797 f miannu Here, we show the histone demethylase JMJD2B is regulated by both ERalpha and HIF-1alpha, drives breast cancer cell proliferation in normoxia and hypoxia, and epigenetically regulates the expression of cell cycle genes such as CCND1, CCNA1, and WEE1. these data indicate that JMJD2B is a bona fide target of ERα and its expression in ER-positive breast cancer cells is mainly dependent on ERα. SIGNOR-263737 0.596 USF1 protein P22415 UNIPROT CBS protein P35520 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12427542 f miannu We previously described essential transactivating roles for specificity protein 1 (Sp1), Sp3, nuclear factor Y (NF-Y), and USF-1 in the regulation of the CBS-1b promoter. SIGNOR-254814 0.2 FOXF2 protein Q12947 UNIPROT TBP protein P20226 UNIPROT up-regulates activity binding -1 9722567 t miannu The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. SIGNOR-220373 0.414 MAPK14 protein Q16539 UNIPROT MAPT protein P10636 UNIPROT up-regulates phosphorylation 9606 20626350 t lperfetto A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins. SIGNOR-166611 0.32 CASP3 protein P42574 UNIPROT IKBKB protein O14920 UNIPROT down-regulates cleavage Asp373 PATQCISdGKLNEGH 9606 11741536 t gcesareni Ikappab kinase (ikk) beta was specifically proteolyzed by caspase-3-related caspases at aspartic acid residues 78, 242, 373, and 546 during tumor necrosis factor (tnf)-alpha-induced apoptosis. SIGNOR-112792 0.37 INS protein P01308 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000887;BTO:0001103 8250835 f gcesareni The results suggest that ser-9 phosphorylation underlies the reported gsk3 beta inhibition by insulin and that gsk3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades. SIGNOR-37220 0.465 ABL1 protein P00519 UNIPROT GLO1 protein Q04760 UNIPROT up-regulates activity phosphorylation Tyr136 GIAVPDVySACKRFE -1 34838714 t miannu We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D). SIGNOR-276187 0.2 PIK3CD protein O00329 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9534 BTO:0004055 14665640 f lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242655 0.7 LCK protein P06239 UNIPROT CD3G protein P09693 UNIPROT up-regulates activity phosphorylation 10090 BTO:0000782 2470098 t Last, we demonstrate directly that members of the CD3 complex, including the gamma, delta, and epsilon chains, as well as a putative zeta subunit, can be phosphorylated at tyrosine residues by the CD4/CD8.p56lck complex. SIGNOR-259931 0.549 EIF4G1 protein Q04637 UNIPROT eIF4F_complex complex SIGNOR-C44 SIGNOR form complex binding 9606 BTO:0000671 11408474 t miannu Eif4a interacts with a scaffold protein, eif4g, to form complexes that also contain the cap-binding protein eif4e, which binds the cap structure (m7gpppn_) at the 5_-end of the mrna. These complexes are termed eif4f. SIGNOR-108518 0.926 HNF4A protein P41235 UNIPROT G6PC1 protein P35575 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 18805788 f gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-181271 0.2 PKA proteinfamily SIGNOR-PF17 SIGNOR GRK1 protein Q15835 UNIPROT down-regulates activity phosphorylation Ser21 AFIAARGsFDGSSSQ 9606 15946941 t Luana Phosphorylation of GRK1 and GRK7 by cAMP-dependent Protein Kinase Attenuates Their Enzymatic Activities | We also determined that cAMP-dependent protein kinase (PKA) phosphorylates GRK1 at Ser(21) and GRK7 at Ser(23) and Ser(36) in vitro. These sites are also phosphorylated when FLAG-tagged GRK1 and GRK7 are expressed in HEK-293 cells treated with forskolin to stimulate the endogenous production of cAMP and activation of PKA. SIGNOR-260841 0.2 PTPRJ protein Q12913 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr1059 DIYKDPDyVRKGDAR 9606 18936167 t gcesareni The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2. SIGNOR-181676 0.692 MLL-ENL fusion protein SIGNOR-FP7 SIGNOR RUNX1 protein Q01196 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 24449215 f miannu However, the functional consequence of MLL fusions on RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. SIGNOR-260127 0.2 TRIM25 protein Q14258 UNIPROT GPI protein P06744 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 24810856 t miannu Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF. SIGNOR-272178 0.252 CARS1 protein P49589 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI down-regulates quantity chemical modification 9606 11347887 t miannu Cysteinyl-tRNA synthetase catalyzes the addition of cysteine to its cognate tRNA. Here we report the isolation of a fulllength cDNA that encodes a protein of 748 amino acids. The predicted protein sequence shows considerable similarity to other eukaryotic cysteinyltRNA synthetases in the carboxylterminus. Expression of the fulllength and alternative forms of the enzyme in E. coli generated functional proteins that were active in aminoacylation of human cytoplasmic tRNA with cysteine. SIGNOR-270471 0.8 Laminin-10 complex SIGNOR-C182 SIGNOR A6/b1 integrin complex SIGNOR-C164 SIGNOR up-regulates activity binding 12123670 t lperfetto We have developed a cell-free assay for binding of solubilized beta1 integrins to their physiologically relevant ligands using an electrochemiluminescent detection method|Binding was clearly optimal for the presumed physiological ligands, i.e., collagen IV for a1b1, collagen I for a2b1, VCAM-Ig for a4b1, fibronectin (the 120-kDa cell attachment fragment was used) for a5b1, and laminin for a6b1. SIGNOR-253222 0.557 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CD80 protein P33681 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12860928 f miannu Upon CD40 signaling, transcription of the CD80 gene is induced by the nuclear factor (NF)-kappaB transcription factor. SIGNOR-254783 0.3 ginkgolide B chemical CHEBI:5356 ChEBI PTAFR protein P25105 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-192684 0.8 PTMA protein P06454 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 BTO:0000567 12522243 t PHAP proteins promoted caspase-9 activation after apoptosome formation, whereas ProT negatively regulated caspase-9 activation by inhibiting apoptosome formation. SIGNOR-259079 0.37 PRLHR protein P49683 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256694 0.28 CDC14B protein O60729 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Thr698 KSIQATLtPSAMKSS 9606 20236090 t lperfetto Using ms analysis, we identified four novel phosphorylation sites, ser684, ser688, thr698 and ser705, located at the extreme c-terminus of erk3.alanine substitution of the four c-terminal phosphorylation sites markedly decreased the half-life of erk3 in mitosis, thereby linking phosphorylation to the stabilization of the kinase.we found that the phosphatases cdc14a and cdc14b (cdc is cell-division cycle) bind to erk3 and reverse its c-terminal phosphorylation in mitosis. SIGNOR-164483 0.56 PLK3 protein Q9H4B4 UNIPROT TOP2A protein P11388 UNIPROT up-regulates phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 18062778 t llicata The direct phosphorylation of thr(1342) of topoisomerase iialpha by plk3 was demonstrated with an in vitro kinase assay, and overexpression of plk3 induced the phosphorylation of thr(1342) in cellular topoisomerase iialpha. it is possible that plk3 regulates the activity of topoisomerase iia by phosphorylation in a cell-cycle dependent manner. Another possibility is that plk3 regulates the activity of topoisomerase iia when the checkpoint is activated. SIGNOR-159596 0.27 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 9922370 t gcesareni The jip proteins function by aggregating components of a map kinase module (including mlk, mkk7, and jnk) and facilitate signal transmission by the protein kinase cascade. Overexpression of jip1 deactivates the jnk pathway selectively by cytoplasmic retention of jnk and thereby inhibits gene expression mediated by jnk, which occurs in the nucleus SIGNOR-64175 0.879 RPS6KB1 protein P23443 UNIPROT MXD1 protein Q05195 UNIPROT down-regulates phosphorylation Ser145 IERIRMDsIGSTVSS 9606 18451027 t llicata Both rsk and s6k phosphorylate serine 145 of mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of mad1 accelerates the ubiquitination and degradation of mad1 through the 26s proteasome pathway, which in turn promotes the transcriptional activity of myc. SIGNOR-178590 0.307 STUB1 protein Q9UNE7 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates quantity by destabilization polyubiquitination -1 12239347 t miannu We now show that the chaperone-binding ubiquitin ligase CHIP efficiently ubiquitinates and down-regulates ErbB2. CHIP expression shortens the half-life of both nascent and mature ErbB2 protein. In vitro ubiquitination assay shows that CHIP serves as a ubiquitin ligase for ErbB2, and both exogenously expressed and endogenous CHIP coprecipitate with the kinase.  SIGNOR-272586 0.617 RAC1 protein P63000 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates activity 9606 23151663 f gcesareni Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization. SIGNOR-199539 0.651 PTP4A2 protein Q12974 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation 9606 14643450 t amattioni Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity SIGNOR-119478 0.2 CIB1 protein Q99828 UNIPROT AIIB/b3 integrin complex SIGNOR-C173 SIGNOR down-regulates activity binding 9606 BTO:0000132 16418530 t lperfetto In response to agonist stimulation, the alphaIIbbeta3 integrin on platelets is converted to an active conformation that binds fibrinogen and mediates platelet aggregation. This process contributes to both normal hemostasis and thrombosis. Activation of alphaIIbbeta3 is believed to occur in part via engagement of the beta3 cytoplasmic tail with talin; however, the role of the alphaIIb tail and its potential binding partners in regulating alphaIIbbeta3 activation is less clear. We report that calcium and integrin binding protein 1 (CIB1), which interacts directly with the alphaIIb tail, is an endogenous inhibitor of alphaIIbbeta3 activation; overexpression of CIB1 in megakaryocytes blocks agonist-induced alphaIIbbeta3 activation, whereas reduction of endogenous CIB1 via RNA interference enhances activation. CIB1 appears to inhibit integrin activation by competing with talin for binding to alphaIIbbeta3, thus providing a model for tightly controlled regulation of alphaIIbbeta3 activation. SIGNOR-253357 0.413 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263814 0.8 MYCT1 protein Q8N699 UNIPROT CASP3 protein P42574 UNIPROT up-regulates activity 9606 30283340 f miannu Herein, we observed that overexpression of MYCT1 induced apoptosis in HL-60 and KG-1a cells, and upregulated Bax, downregulated Bcl-2, and enhanced cleavage of caspase-3 and -9. Similar proapoptotic role of MYCT1 was also found in the AML cell xenografts. These results suggest that MYCT1 affects AML cell apoptosis by modulating the endogenous apoptotic pathways. SIGNOR-261942 0.2 CSNK2A1 protein P68400 UNIPROT CEBPD protein P49716 UNIPROT up-regulates activity phosphorylation Ser57 PAMYDDEsAIDFSAY -1 25680545 t miannu Here, we have identified the CCAAT/enhancer binding protein δ (C/EBPδ) as a new substrate for CK2. Using point mutants of C/EBPδ the major phosphorylation site for CK2 was mapped to serine 57, which is located within the transactivation domain of C/EBPδ. For proper functioning as a transcription factor C/EBPδ has to be translocated into the nucleus where it forms heterodimers with other members of the C/EBP family of proteins and ATF4. Here, we found that CK2 phosphorylation does neither influence the subcellular localization of C/EBPδ nor its interaction with C/EBPβ, but rather does CK2 phosphorylation modulate the transcriptional activity of C/EBPδ.  SIGNOR-276886 0.2 CSNK2A1 protein P68400 UNIPROT CERS6 protein Q6ZMG9 UNIPROT up-regulates activity phosphorylation Ser341 KVSKDDRsDIESSSD 9606 BTO:0000007 26887952 t miannu Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing itsVmaxvalue.  SIGNOR-273990 0.2 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT down-regulates activity phosphorylation Ser7326 RAGSRASsRRGSDAS 9606 BTO:0004905 21295697 t lperfetto We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. SIGNOR-264434 0.442 bis(2-ethylhexyl) phthalate chemical CHEBI:17747 ChEBI NR1I2 protein O75469 UNIPROT up-regulates activity chemical activation 9534 BTO:0001538 27551952 t miannu We discovered that di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP), two of the highest volume production agents, were potent activators of human CAR2 (hCAR2), a unique human CAR splice variant and, to a lesser degree, human PXR (hPXR). SIGNOR-268774 0.8 RAD51AP1 protein Q96B01 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates activity binding 9606 17996711 t miannu Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand-pairing step in HR. RAD51 associated protein 1 (RAD51AP1) is a RAD51-interacting protein whose function has remained elusive. Biochemical and cytological results show that RAD51AP1 functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Purified RAD51AP1 binds both dsDNA and a D loop structure and, only when able to interact with RAD51, greatly stimulates the RAD51-mediated D loop reaction. SIGNOR-261962 0.765 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser104 GKGSQPPsPPSPAPS 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164617 0.568 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates activity acetylation Lys19 VKRLLGWkKSAGGSG 9606 17074756 t lperfetto Acetylation of the short isoform of Smad2 improves its DNA binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity. Smad2(FL) and Smad2(_E3) were also acetylated by P/CAF in vivo and the acetylation of both proteins was lost following mutation of Lys19 (Fig. 2D), suggesting that Lys19 in Smad2 is also targeted by P/CAF. SIGNOR-217607 0.623 VAV1 protein P15498 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 BTO:0000725 9151714 t Barakat In summary, we demonstrate here that Y315 in ZAP-70 is required to interact with the Vav SH2 domain, and is critical for ZAP-70–mediated gene activation. SIGNOR-274150 0.835 CSNK1A1L protein Q8N752 UNIPROT GLIS2 protein Q9BZE0 UNIPROT up-regulates 9606 17289029 f gcesareni We decided to focus on the interaction between _-catenin and glis2. the critical role of the first zinc finger motif was confirmed by the observation that a point mutation in the first zinc finger motif, that destroys its tetrahedral configuration, abolished the interaction. _-catenin contains several functional domains, the amino terminus interacts with gsk3_ and casein kinase i_ (ck1) binding sites while its 12 armadillo repeats provides an interface for tcf/lefs, the co-activator cbp, and several other proteins SIGNOR-152962 0.2 RNA Polymerase I complex SIGNOR-C390 SIGNOR rRNA_transcription phenotype SIGNOR-PH145 SIGNOR up-regulates 22260999 f lperfetto In eukaryotic cells, the RNA polymerase Pol I synthesizes the rRNA precursor, Pol II transcribes mRNAs and small non-coding RNAs (such as small nuclear RNAs), and Pol III produces tRNAs and other small RNAs. Pol I, II and II contain 14, 12 and 17 polypeptide subunits, respectively (Table 1).  SIGNOR-266177 0.7 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates activity phosphorylation Tyr666 GWMEDYDyVHLQGKE 9606 11604500 t lperfetto The loss of activity in the cas-f668/f670 mutant is consistent with the notion that src, once initially bound by its sh3 domain, phosphorylates the tyr668/670 site to further stabilize its interaction by sh2 binding. SIGNOR-111060 0.799 serotonin smallmolecule CHEBI:28790 ChEBI HTR2C protein P28335 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264283 0.8 EN2 protein P19622 UNIPROT FGF8 protein P55075 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0003560 10026229 t miannu Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. SIGNOR-265801 0.424 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 9130707 t gcesareni We demonstrate here that elk-1 is barely activated by a third subclass of map kinases (p38), most likely because the critical residues ser383 and ser389 are poorly phosphorylated by p38 map kinase. SIGNOR-47634 0.513 pictrelisib chemical CHEBI:65326 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 BTO:0000149 21876152 t gcesareni Currently, several pi3k inhibitors, including gdc0941 (genentech) and bez235 (novartis pharmaceuticals), have entered phase i clinical trials, and in addition, isoform-specific compounds are being developed SIGNOR-176295 0.8 DOK1 protein Q99704 UNIPROT A6/b1 integrin complex SIGNOR-C164 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257675 0.318 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT up-regulates activity phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 10521487 t gcesareni Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b. SIGNOR-71419 0.2 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Thr718 KEDLPVItIDPASPQ 9606 11604491 t llicata Trophic factor withdrawal: p38 mitogen-activated protein kinase activates nhe1, which induces intracellular alkalinization. activated p38 mapk directly phosphorylated the c terminus of nhe1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on nhe1, thr 717, ser 722, ser 725, and ser 728. SIGNOR-111051 0.559 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 10318843 t lperfetto Phosphopeptide encompassing the motif harboring tyr319, ysdp, interacted with lcksh2;tyr319-mediated binding of the sh2 domain of lck is crucial for zap-70 activation and consequently for the propagation of the signaling cascade leading to t-cell activation SIGNOR-67443 0.608 SIRT1 protein Q96EB6 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity deacetylation 9606 BTO:0000007 14976264 t lperfetto Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress SIGNOR-252994 0.91 GDNF protein P39905 UNIPROT ALCAM protein Q13740 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002881 15212950 f miannu We characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells.Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. SIGNOR-252177 0.2 AP 23573 chemical CHEBI:79700 ChEBI MTOR protein P42345 UNIPROT down-regulates chemical inhibition 9606 BTO:0000887 20554235 t gcesareni Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mtor inhibitors. SIGNOR-166186 0.8 CSNK2B protein P67870 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-251054 0.288 NLRP3 inflammasome complex SIGNOR-C225 SIGNOR Pyroptosis phenotype SIGNOR-PH105 SIGNOR up-regulates 9606 30166988 f miannu Once activated by a ligand, inflammasomes lead to the activation of a caspase. Activated caspases allow the release of mature forms of interleukin-1β and interleukin-18 and trigger a specific pro-inflammatory cell death termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1, and AIM2, are involved in the generation of tissue damage and immune dysfunction after trauma. SIGNOR-260356 0.7 PTPA protein Q15257 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 21159657 t gcesareni Consistent with previous reports (2830), we found that expression of sv40st, suppression of either pp2a c or b resulted in elevated levels of akt phosphorylation (ser473) SIGNOR-170699 0.2 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT up-regulates activity phosphorylation Ser213 TRKLMEFsEHCAIIL 9606 BTO:0002181 9155023 t lperfetto Here we show that TbetaRII kinase is regulated intricately by autophosphorylation on at least three serine residues. Ser213, in the membrane-proximal segment outside the kinase domain, undergoes intra-molecular autophosphorylation which is essential for the activation of TbetaRII kinase activity, activation of TbetaRI and TGF-beta-induced growth inhibition. SIGNOR-236087 0.2 HES1 protein Q14469 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates quantity by repression transcriptional regulation 10090 BTO:0000938 30030829 f lperfetto The basic-helixloop-helix factors HES1 and HES5 repress the expression of the proneural genes (Ascl1, Atoh1, Neurog1 and Neurog2) and thereby inhibit NSCs differentiation and neuron production SIGNOR-265146 0.448 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 17466630 t gcesareni Here, we show that the apoptotic initiator protease caspase-9 is regulated during the cell cycle through periodic phosphorylation at an inhibitory site, thr125. This site is phosphorylated by cdk1/cyclin b1 during mitosis and in response to microtubule poisons that arrest cells at this stage of the cell cycle. SIGNOR-154626 0.437 SPOP protein O43791 UNIPROT HDAC6 protein Q9UBN7 UNIPROT down-regulates quantity ubiquitination 9606 BTO:0000007 28599312 t Gianni Cullin3 SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6 SIGNOR-268862 0.2 SERPING1 protein P05155 UNIPROT F12 protein P00748 UNIPROT down-regulates activity binding 9606 BTO:0000131 26707513 t lperfetto C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1). SIGNOR-263517 0.636 ITCH protein Q96J02 UNIPROT GLI1 protein P08151 UNIPROT down-regulates ubiquitination 9606 BTO:0001573 17115028 t gcesareni The consequent activation of_ itch, together with the recruitment of gli1 through direct binding with_ numb, allows gli1 to enter into the complex, resulting in gli1 ubiquitination and degradation. we demonstrate that the hedgehog transcription factor gli1 is targeted by numb for itch-dependent ubiquitination, which suppresses hedgehog signals, thus arresting growth and promoting cell differentiation SIGNOR-150847 0.567 ARAP2 protein Q8WZ64 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity gtpase-activating protein 9606 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260453 0.501 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Thr68 SSLETVStQELYSIP -1 16481012 t miannu Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.  SIGNOR-276053 0.832 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KAT5 protein Q92993 UNIPROT up-regulates activity phosphorylation Ser90 LPGSRPGsPEREVPA 9606 BTO:0000567 12468530 t llicata Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylatedin vitro by the cyclin B/Cdc2 complex. SIGNOR-250642 0.424 AMBRA1 protein Q9C0C7 UNIPROT HUWE1 protein Q7Z6Z7 UNIPROT up-regulates activity relocalization 9606 BTO:0000567 phosphorylation:Ser1043 CRPEALNsGVEYYWD 30217973 t lperfetto AMBRA1 regulates mitophagy at two critical steps. Upon mitophagy stimulation, AMBRA1 mediates the HUWE1 E3 ubiquitin ligase translocation from cytosol to mitochondria (light blue). AMBRA1 acts as a cofactor for HUWE1 E3 ubiquitin ligase activity, favouring its binding to its substrate MFN2 (and maybe other OMM substrates) and targeting it to the proteasome SIGNOR-272962 0.2 CDK1 protein P06493 UNIPROT FANCG protein O15287 UNIPROT up-regulates phosphorylation Ser387 PRFSPPPsPPGPCMP 9606 15367677 t gcesareni S387a mutant abolished fancg fusion protein phosphorylation by cdc2. SIGNOR-129061 0.358 SYK protein P43405 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr783 EGRNPGFyVEANPMP 9606 8657103 t lperfetto Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. SIGNOR-246576 0.768 CDK4 protein P11802 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 SIGNOR-C18 21902831 t gcesareni In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms. SIGNOR-176527 0.521 MAPK3 protein P27361 UNIPROT KARS1 protein Q15046 UNIPROT up-regulates phosphorylation Ser207 PYEITLLsPCLHMLP 9606 19524539 t gcesareni Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus. SIGNOR-186125 0.2 HRH2 protein P25021 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256777 0.439 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT up-regulates activity phosphorylation Tyr1108 TYVNTTLyEKFTYAG 9606 BTO:0001176 20973951 t miannu This phosphorylation requires a kinase competent Tie2 as well as intact tyrosines 1100 and 1106 (Y1100 and Y1106) on the receptor. This suggests that Y1100 and Y1106 on Tie2 play a role in Grb14 mediated signal transduction downstream of this receptor. SIGNOR-259833 0.2 SHC3 protein Q92529 UNIPROT GRB2 protein P62993 UNIPROT up-regulates relocalization 9606 16829981 t gcesareni In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation. SIGNOR-147865 0.814 RBM8A protein Q9Y5S9 UNIPROT Exon junction complex complex SIGNOR-C369 SIGNOR form complex binding -1 16923391 t miannu The EJC is deposited onto mRNA during splicing and is transported to the cytoplasm where it influences translation, surveillance, and localization of the spliced mRNA. The complex is formed by the association of four proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP. SIGNOR-265242 0.916 JUN protein P05412 UNIPROT FOSL1 protein P15407 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004603 13679379 t Luana Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.  SIGNOR-261604 0.823 atropine chemical CHEBI:16684 ChEBI CHRM4 protein P08173 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 2704370 t miannu In order to investigate the pharmacological properties of the individual muscarinic receptors, we have transfected each of these genes into Chinese hamster ovary cells (CHO-K1) and have established stable cell lines expressing each receptor. In the present study we have examined the antagonist binding properties of each muscarinic receptor. Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, AF-DX 116, methoctramine, dicyclomine, hexohydrodifenidol, hexahydrosiladifenidol, hexocyclium, and silahexocyclium. SIGNOR-258390 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni Cbp/p300 and pcaf are coactivators for myod and mef-2c during myogenic commitment and differentiation SIGNOR-83840 0.708 CDK1 protein P06493 UNIPROT NDUFA12 protein Q9UI09 UNIPROT up-regulates activity phosphorylation Thr142 QEWIPPStPYK 24746669 t lperfetto Here, we show that a fraction of cyclin B1/Cdk1 proteins localizes to the matrix of mitochondria and phosphorylates a cluster of mitochondrial proteins, including the complex I (CI) subunits in the respiratory chain. Cyclin B1/Cdk1-mediated CI phosphorylation enhances CI activity, whereas deficiency of such phosphorylation in each of the relevant CI subunits results in impairment of CI function.|These results were confirmed by generating phosphorylation defective forms of the five CI subunits through substitutions of S/T residues with Alanine (A) on either Cdk1 optimal or minimal consensus motifs (T383 on NDUFV1, S105 on NDUFV3, S364 on NDUFS2, S55/S29/T5 on NDUFB6, and T142/T120 on NDUFA12). The mutation of Cdk1 consensus motifs severely diminished their phosphorylation SIGNOR-275587 0.2 PERP protein Q96FX8 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity ubiquitination 9606 25860612 t We identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling SIGNOR-255843 0.2 AMPK complex SIGNOR-C15 SIGNOR DNMT1 protein P26358 UNIPROT down-regulates activity phosphorylation Ser714 DNIPEMPsPKKMHQG -1 28143904 t lperfetto Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK decreased DNMT1 activity SIGNOR-264788 0.29 ADRB3 protein P13945 UNIPROT GNAL protein P38405 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256896 0.44 PAK1 protein Q13153 UNIPROT NLRP3 protein Q96P20 UNIPROT up-regulates activity phosphorylation Thr659 KIEINLStRMDHMVS 9606 BTO:0002181 33432150 t miannu Pak1 phosphorylates NLRP3 to promote inflammasome activation. SIGNOR-277547 0.2 INTS11 protein Q5TA45 UNIPROT Integrator complex complex SIGNOR-C265 SIGNOR form complex binding 7227 26220997 t lperfetto Integrator is a metazoan-specific multisubunit, multifunctional protein complex composed of 14 subunits named Int1–Int14 (Integrator subunits)  SIGNOR-261462 0.2 ADAM17 protein P78536 UNIPROT MUC1 protein P15941 UNIPROT down-regulates cleavage 9606 12441351 t gcesareni These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase. SIGNOR-95630 0.312 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser706 ARIIGEKsFRRSVVG 9606 12058027 t gcesareni Thus, pkd2 is likely to be a novel downstream target of specific pkcs upon the stimulation of ags-b cells with gastrin. Our data suggest a two-step mechanism of activation of pkd2 via endogenously produced diacylglycerol and the activation of pkcs. SIGNOR-89423 0.2 RNF216 protein Q9NWF9 UNIPROT TLR9 protein Q9NR96 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 15107846 t miannu Here we describe how a RING finger protein, Triad3A, acts as an E3 ubiquitin-protein ligase and enhances ubiquitination and proteolytic degradation of some TLRs. Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling.  SIGNOR-271505 0.412 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT up-regulates activity phosphorylation Tyr526 LRADENYyKAQTHGK 9606 BTO:0000776 9820500 t lperfetto These represented sites of tyrosine phosphorylation previously identified from the study of in vitro autophosphorylated Syk. Phosphorylation was observed on peptides corresponding to Tyr130, Tyr317, Tyr342, Tyr346, Tyr519, and Tyr520 SIGNOR-246621 0.2 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT down-regulates quantity by destabilization phosphorylation Ser1724 SPSYSPTsPSYSPTS 9606 14662762 t lperfetto Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-269334 0.721 SEPTIN9 protein Q9UHD8 UNIPROT ARHGEF18 protein Q6ZSZ5 UNIPROT down-regulates binding 9606 15558029 t miannu In transient expression analyses, sept9b inhibited sa-rhogef-dependent rho activation in cos7 and hela cells. SIGNOR-131184 0.2 MAPK14 protein Q16539 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 15879307 t gcesareni Conversely, constitutively active mkk6 induced p38 mapk activation that recapitulated the effects of polyphenols by inducing eralpha phosphorylation and downstream activation of akt, and enos. The key role of eralpha ser-118 phosphorylation was confirmed in enos-transfected cos-7 cells SIGNOR-136950 0.616 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 19426560 t amattioni Crk can interact directly with tyrosine kinase receptors and can transmit signals downstream SIGNOR-185667 0.598 CD36 protein P16671 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252270 0.7 TNFRSF6B protein O95407 UNIPROT TNFSF15 protein O95150 UNIPROT down-regulates binding 9606 BTO:0000782 11911831 t amattioni Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a SIGNOR-116256 0.723 ACTL6B protein O94805 UNIPROT SWI/SNF ACTL6B varian complex SIGNOR-C476 SIGNOR form complex binding 9606 30397315 t miannu Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodelers that modulate genomic architecture and DNA accessibility, enabling timely and appropriate control of gene expression. They are combinatorially assembled from the products of 29 total genes into three final-form complexes: canonical BAF, PBAF (polybromo-associated BAF complexes), and a newly-defined non-canonical BAF (ncBAF), with specific subunits specifying distinct complexes, such as PBRM1, ARID2, and BRD7 in PBAF complexes, ARID1A/ARID1B and DPF2 in canonical BAF (cBAF) complexes, and GLTSCR1/GLTSCR1L and BRD9 in ncBAF complexes SIGNOR-270600 0.689 DOK1 protein Q99704 UNIPROT A4/b1 integrin complex SIGNOR-C162 SIGNOR down-regulates activity binding 9606 19118207 t miannu Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation SIGNOR-257673 0.318 RPS6KA3 protein P51812 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 9606 19282669 t lperfetto The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival. SIGNOR-184595 0.39 N-[2-(4-bromocinnamylamino)ethyl]isoquinoline-5-sulfonamide chemical CHEBI:47495 ChEBI PRKACA protein P17612 UNIPROT down-regulates activity chemical inhibition 10116 2156866 t Simone Vumbaca Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP. SIGNOR-261087 0.8 NOG protein Q13253 UNIPROT BMP2 protein P12643 UNIPROT down-regulates binding 9606 12700180 t lperfetto Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides SIGNOR-100657 0.807 CDK5 protein Q00535 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 t lperfetto In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3. SIGNOR-145912 0.614 CyclinK/CDK13 complex SIGNOR-C38 SIGNOR EIF4B protein P23588 UNIPROT up-regulates activity phosphorylation Ser422 RERSRTGsESSQTGT 9606 BTO:0001109 36882522 t lperfetto CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. SIGNOR-273116 0.278 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYB protein P10242 UNIPROT down-regulates phosphorylation Ser532 KIKQEVEsPTDKSGN 9606 BTO:0000661 8960373 t lperfetto Functional analysis of phosphorylation at serine 532 of human c-myb by map kinase. expression of a polypeptide containing the c-myb c-terminal domain stimulated c-myb activity. This effect is reduced upon mapk-dependent phosphorylation of serine 532. Our data suggest that the mapk-dependent state of phosphorylation modifies the cellular function of c-myb by modulating its interaction with a putative inhibitory factor SIGNOR-244569 0.2 PLEKHG5 protein O94827 UNIPROT RHOA protein P61586 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260566 0.766 CFAP53 protein Q96M91 UNIPROT Axonemal_Dynein proteinfamily SIGNOR-PF66 SIGNOR up-regulates activity binding 10090 BTO:0000379 33347437 t miannu CFAP53 associates with axonemal microtubules of tracheal cilia and interacts with dynein proteins and the docking complex (DC) SIGNOR-265547 0.2 MRPL24 protein Q96A35 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262369 0.713 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR up-regulates activity phosphorylation 10090 BTO:0004052 14500898 t irozzo This up-regulation required BCR-ABL tyrosine kinase activity and led to IL-3Rbetac/beta chain tyrosine phosphorylation in the absence of detectable IL-3 production. These results suggested that cytokine-independent IL-3 receptor activation could be a dominant signaling component in BCR-ABL-induced leukemogenesis. However, the IL-3Rβc/β chain could act as a cofactor in BCR-ABL-induced leukemogenesis by activation of its many known oncogenic signaling pathways. SIGNOR-256123 0.2 TRIM26 protein Q12899 UNIPROT IRF3 protein Q14653 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 25763818 t miannu TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.  SIGNOR-272440 0.664 copper(1+) smallmolecule CHEBI:49552 ChEBI SOD3 protein P08294 UNIPROT up-regulates activity chemical activation 1542024 t lperfetto Copper as a cofactor and regulator of copper,zinc superoxide dismutase SIGNOR-272301 0.8 NLGN4X protein Q8N0W4 UNIPROT DLG4 protein P78352 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 18923512 t brain lperfetto Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions. SIGNOR-264192 0.749 PP2B proteinfamily SIGNOR-PF18 SIGNOR MAPT protein P10636 UNIPROT up-regulates dephosphorylation Ser579 NVKSKIGsTENLKHQ 9606 BTO:0000142 20308788 t The effect has been demonstrated using P10636-8 lperfetto Among the sites studied, thr205, thr212, ser214, and ser262 were the most favorable sites, and ser199 and ser404 were the least favorable sites for pp2a in vitro. SIGNOR-164663 0.2 GRK5 protein P34947 UNIPROT SNCA protein P37840 UNIPROT down-regulates activity phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 16957079 t llicata Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein. SIGNOR-149372 0.627 MAPKAPK3 protein Q16644 UNIPROT HSPB1 protein P04792 UNIPROT unknown phosphorylation Ser78 PAYSRALsRQLSSGV -1 8774846 t miannu MAPKAP kinase-3 and MAPKAP kinase-2 phosphorylated peptide substrates with similar kinetic constants and phosphorylated the same serine residues in HSP27 at the same relative rates.The three serine residues in HSP27 phosphorylated by MAPKAPK2 were also phosphorylated at the same relative rates by MAPKAP-K3 (Ser-82>>Ser-78 >Ser-15) SIGNOR-250160 0.677 SUFU protein Q9UMX1 UNIPROT GLI3 protein P10071 UNIPROT down-regulates activity relocalization 10090 10433919 t lperfetto Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling SIGNOR-129068 0.887 HOXA9 protein P31269 UNIPROT MYCN protein P04198 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 21261500 f miannu HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. SIGNOR-254213 0.291 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates activity phosphorylation Ser469 AHEENPEsILDEHVQ -1 17318175 t lperfetto Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling. SIGNOR-249192 0.78 HIF1A protein Q16665 UNIPROT ALDOA protein P04075 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 8955077 f miannu we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1. SIGNOR-254422 0.341 YAP1 protein P46937 UNIPROT FSTL3 protein O95633 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni In our analysis bmp4 (bone morphogenetic protein 4) and fstl3 (follistatin-related protein 3) increased their expression in response to hyap1 s127a overexpression. SIGNOR-199072 0.2 TEK protein Q02763 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity binding 9534 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242634 0.525 CAMK2A protein Q9UQM7 UNIPROT ATP2A2 protein P16615 UNIPROT up-regulates activity phosphorylation Ser38 KLKERWGsNELPAEE 9606 BTO:0000007 7929371 t llicata SERCA2 and SERCA2 mutants S38A, S167A, and S531A were expressed in HEK-293 cells and tested for phosphorylation with CaM kinase. Mutant S38A was not phosphorylated, while mutants S167A and S531A were phosphorylated, suggesting that Ser38 is the site of CaM kinase phosphorylation in SERCA2. This conclusion was supported by the observation that phosphorylation of SERCA2 and mutants S167A and S531A by CaM kinase increased the Vmax for Ca2+ transport, while the Vmax for Ca2+ transport by mutant S38A was unaffected by exposure to a phosphorylation reaction mix. SIGNOR-250616 0.402 chloride smallmolecule CHEBI:17996 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR down-regulates 9606 BTO:0000227 18790874 f miannu GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-264989 0.7 CCT2 protein P78371 UNIPROT TRiC complex SIGNOR-C539 SIGNOR form complex binding 9606 36185250 t miannu Mammalian cells contain an evolutionarily conserved type II chaperonin called chaperonin containing tailless complex polypeptide 1 (CCT) or tailless complex polypeptide 1 ring complex (TRiC). The CCT complex is composed of eight subunits [CCT1-8 (yeast) or CCTα-θ (mammals)] and folds substrates needed for cell invasion and proliferation, such as actin, tubulin, and cell division cycle protein 20 homolog (cdc20), as well as oncoproteins like signal transducer and activator of transcription 3 (STAT3), Kirsten rat sarcoma viral oncogene homolog (KRAS), and Myelocytomatosis (MYC). SIGNOR-272860 0.751 SAE1/SAE2 complex complex SIGNOR-C294 SIGNOR MBD4 protein O95243 UNIPROT up-regulates activity sumoylation Lys377 HLHTDILkRGSEMDN 31476572 t lperfetto MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro. SIGNOR-275681 0.2 MFGE8 protein Q08431 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR down-regulates 10116 31958465 f miannu We demonstrated that Milk fat globule-EGF factor8 (MFGE8) is protective against Ang-II-induced atrial fibrosis and atrial fibrillation. In vitro, silencing of MFGE8 by small interfering RNA significantly increased Ang-II-induced atrial fibrosis, whereas administration of recombinant human MFGE8 (rhMFGE8) attenuated the atrial fibrosis. SIGNOR-260646 0.7 SRC protein P12931 UNIPROT UGT2B7 protein P16662 UNIPROT up-regulates phosphorylation Tyr438 RVINDPSyKENVMKL 9606 19289110 t gcesareni Overexpression of regular or active src, but not dominant-negative src, in 2b7-transfected cos-1 cells increased 2b7 activity and phospho-y438-2b7 by 50% SIGNOR-184613 0.348 MAX protein P61244 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240357 0.303 WAS protein P42768 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000567 20498093 t lperfetto Members of the Wiskott-Aldrich syndrome protein (WASP) family, which includes WASP, N-WASP, WAVE (1–3), WHAMM, JMY, and WASH, control actin cytoskeletal dynamics throughout biology. They act in large part by regulating the actin nucleating activity of the ubiquitous Arp2/3 complex. WASP proteins stimulate Arp2/3 complex using a conserved C-terminal VCA (Verprolin homologous, central hydrophobic, and acidic) region. They contain distinct N-terminal elements, which facilitate integration into unique macromolecular complexes. SIGNOR-261001 0.806 Papain-like proteinase protein P0C6X7-PRO_0000037311 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT down-regulates activity deubiquitination 9606 31226023 t miannu Also, SARS-CoVPLPro catalyzed deubiquitination ofTNF-receptor-associatedfactor3(TRAF3)and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist SIGNOR-260248 0.2 CEBPB protein P17676 UNIPROT PPARG protein P37231 UNIPROT up-regulates quantity transcriptional regulation 10090 7557387 t Andrea Cerquone Perpetuini  Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes SIGNOR-255730 0.723 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR IL1B protein P01584 UNIPROT up-regulates quantity transcriptional regulation 9606 BTO:0001412 8021507 t In these studies, we show that NF-kappa B induces transcription from the human pro-IL-1 beta (IL-1 beta) gene. SIGNOR-255938 0.576 regorafenib chemical CHEBI:68647 ChEBI NTRK1 protein P04629 UNIPROT down-regulates activity chemical inhibition 9606 24756792 t miannu In biochemical in vitro or cell-based assays, Regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET,VEGFR 1-3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations that can be achieved clinically. SIGNOR-259212 0.8 RAI1 protein Q7Z5J4 UNIPROT PER2 protein O15055 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 22578325 f miannu Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. SIGNOR-266840 0.312 PRKCD protein Q05655 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser304 GAPPRRSsIRNAHSI 9606 12056906 t esanto Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?. SIGNOR-89221 0.454 AMP smallmolecule CHEBI:456215 ChEBI adenosine smallmolecule CHEBI:16335 ChEBI up-regulates quantity precursor of -1 18940592 t Luana Specifically, PAP dephosphorylates extracellular adenosine monophosphate (AMP) to adenosine and activates A1-adenosine receptors in dorsal spinal cord. SIGNOR-269738 0.8 IL15 protein P40933 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 11418623 t gcesareni The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, and il-15 as well as il-2. Here we show that the gamma(c) is also shared with the il-21r complex. SIGNOR-108815 0.85 KHDRBS1 protein Q07666 UNIPROT CREBBP protein Q92793 UNIPROT down-regulates activity binding 9606 BTO:0000093 12496368 t miannu These results suggest that Sam68 and CBP interact in vivo in a manner dependent on the FXE/DXXXL motif. Sam68 Represses CBP-dependent Transcriptional Activation SIGNOR-266202 0.383 H2AC4 protein P04908 UNIPROT CENP-A nucleosome complex SIGNOR-C321 SIGNOR form complex binding -1 23324462 t miannu In vitro assembly of both yeast and human CENP-A nucleosomes yields standard octameric structures containing two copies each of CENP-A, H2A, H2B and H4 histones. Human CENP-A also produces rigidified homotypic CENP-A/H4 tetramers in vitro. SIGNOR-263700 0.2 PROS1 protein P07225 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 t gcesareni We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function. SIGNOR-34483 0.473 IL15 protein P40933 UNIPROT IL15RA protein Q13261 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2 SIGNOR-157415 0.865 PI-103 chemical CHEBI:90524 ChEBI PIK3CB protein P42338 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-206166 0.8 PRKACA protein P17612 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT down-regulates phosphorylation Ser557 SGKFRRGsGSACSLL 9606 17988215 t llicata The stimulatory effect of h89 on mcoln1 function was not observed when ser(557) and ser(559) were mutated to alanine residues, indicating that these two residues are essential for pka-mediated negative regulation of mcoln1. SIGNOR-158946 0.2 MYCT1 protein Q8N699 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30283340 f miannu MYCT1 overexpression significantly inhibited cell proliferation, arrested cell cycle at G0/G1 phase, and downregulated the expression of cyclins D and E. Moreover, MYCT1 overexpression triggered apoptosis in AML cells, which was accompanied by enhanced cleavage of caspase-3 and -9, upregulated expression of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), and downregulated Bcl-2. SIGNOR-261734 0.2 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates activity phosphorylation Ser385 MARVGGAsSLENTVD -1 18440553 t lperfetto Virus-induced phosphoactivation of irf-3, thought to be mediated directly or indirectly by ikkepsilon And/or tbk1 occurs in the c-terminal region of irf-3 at seven ser/thr residues, 385sslentvdlhisnshplslts405 (fig. 1a).Within This region, irf-3 has two phosphorylation sites: site 1 includes ser385 and ser386, whereas site 2 includes ser396, ser398, ser402, ser405, and thr404. SIGNOR-178363 0.736 KDM3B protein Q7LBC6 UNIPROT H3-4 protein Q16695 UNIPROT down-regulates activity demethylation Lys10 RTKQTARkSTGGKAP 9534 16603237 t miannu We have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 demethylation and transcriptional activation. Thus, our work identifies a histone demethylase and links its function to hormone-dependent transcriptional activation. SIGNOR-266635 0.2 ARHGAP20 protein Q9P2F6 UNIPROT RAC1 protein P63000 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260473 0.421 P2RY11 protein Q96G91 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257060 0.2 1D-myo-inositol 1,4,5-trisphosphate smallmolecule CHEBI:16595 ChEBI GSN protein P06396 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000132 12788695 t lperfetto We further measured the ability of ppIs phosphorylated in positions D-3 and D-4 to release the F-actin capping proteins CapZ and gelsolin from OG-permeabilized platelets (Fig. 7A). Ten percent of platelet CapZ and gelsolin is found in the OG-insoluble fraction (4). PI3,4,5P3 and PI3,4P2 release both CapZ and gelsolin from these preparations. SIGNOR-261840 0.8 SMAD7 protein O15105 UNIPROT SMAD7/HDAC1/E2F-1 complex SIGNOR-C12 SIGNOR form complex binding 9606 23213415 t gcesareni Furthermore, smad7 caused hdac-1 bind to e2f-1 to form a ternary complex on chromosomal dna containing an e2f-binding motif and leading to repression in the activity of the e2f target genes SIGNOR-199970 0.451 SH3GL2 protein Q99962 UNIPROT Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 9606 25517094 f miannu Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin-mediated endocytosis. SIGNOR-263883 0.7 sumatriptan chemical CHEBI:10650 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 BTO:0000567 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258340 0.8 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT up-regulates activity phosphorylation Ser231 GTENTFPsPKAIPNG 10090 12796778 t llicata Three specific phosphorylation sites (Ser198, Thr219 and Ser231) and two weak phosphorylation sites (Ser242 and Thr245) for CDK5/p35 are located in this region of NUDEL | Each single or double mutant compromised,and the triple mutant completely eliminated, interaction with 14-3-3ε. | 14-3-3ε sustains NUDEL phosphorylation and protects it from phosphatase.e dynein motor function. SIGNOR-250676 0.767 AMPK complex SIGNOR-C15 SIGNOR CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 21331044 t lperfetto Here we show that both ampk and calcineurin modulate longevity exclusively through post-translational modification of crtc-1, the sole c. elegans crtc. We demonstrate that crtc-1 is a direct ampk target. SIGNOR-216529 0.287 ALK protein Q9UM73 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr160 QVPQQPTyVQALFDF 9606 BTO:0000007 20554525 t lperfetto Two phosphorylation sites on Grb2 have been identified thus far at position Tyr209 in BCR-ABL-expressing cells (16) and Tyr160 by pp60c-src (18)Previous reports suggested an inhibitory role of Grb2 Tyr7, Tyr37, Tyr52, and Tyr209 phosphorylation in receptor tyrosine kinase signaling (16) (43). Instead, in our system Grb2 Tyr160 mutation was not show to have a role in ALCL proliferation. SIGNOR-247142 0.474 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 9187659 t gcesareni We have determined the nmr structure of a ligand-binding domain of the granulocyte colony-stimulating factor (g-csf) receptor comparisons between the spectra of the 15n-labelled domain with and without g-csf indicate that the major ligand-recognition site is on the fg loop just upstream of the wsxws sequence. SIGNOR-49126 0.854 TIMP2 protein P16035 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR down-regulates 17326328 f lperfetto There are many naturally occurring proteins that can inhibit angiogenesis, including angiostatin, endostatin, interferon, platelet factor 4, thorombospondin, prolactin 16 kd fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3 SIGNOR-252273 0.7 MAP4K1 protein Q92918 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 8824585 f gcesareni These results demonstrated that the observed jnk1 activation was from hpk1 and not from other hpkl-associated kinases or from cross-reactive kinases precipitated by anti-hpk1 antibody. SIGNOR-43999 0.323 FRZB protein Q92765 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 BTO:0000671 9326585 t gcesareni We and others demonstrated that fzb-1 blocks wnt-1 and xwnt-8 signaling in xenopus embryos, SIGNOR-51798 0.493 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270431 0.8 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser343 TTPGPSLsQGVSVDE 9606 10802669 t gcesareni We show that atm physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (s343a) does not completely complement radiosensitivity in nbs cells. SIGNOR-77149 0.853 PTPRG protein P23470 UNIPROT ZAP70 protein P43403 UNIPROT up-regulates activity dephosphorylation Tyr319 TSVYESPySDPEELK -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254734 0.262 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr33 KFKNEDLtDELSLNK -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276204 0.386 IRF4 protein Q15306 UNIPROT FCER2 protein P06734 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000776 11342629 f IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression. SIGNOR-253933 0.269 BRAF protein P15056 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates activity phosphorylation -1 8413257 t lperfetto Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. SIGNOR-244831 0.782 NOTCH4 protein Q99466 UNIPROT HEY2 protein Q9UBP5 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 12548545 f gcesareni Herp1 appears to be important particularly in the development of vascular tissue, and herp1might be regulated by vascular-specific isoforms of ligands and receptors such as dll4 and notch4 SIGNOR-97630 0.607 WASF2 protein Q9Y6W5 UNIPROT WAVE complex complex SIGNOR-C271 SIGNOR form complex binding 9606 BTO:0000567 15070726 t lperfetto Here we purify Wave-2 from HeLa cells. Five proteins, Sra, Nap, Wave-2, Abi, and Hspc, are copurified, indicating that they form a tight complex.  SIGNOR-261871 0.908 MAPK1 protein P28482 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 20974802 t gcesareni We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription. SIGNOR-169001 0.305 NUP98 protein P52948 UNIPROT NPC complex SIGNOR-C263 SIGNOR form complex binding 27016207 t lperfetto The protein inventory of the NPC has been studied for a very diverse set of eukaryotes, including trypanosomes, fungi, plants, animals, and humans [4], [5], [6], [7], [8], [9]. In all cases, about 30 different Nups were found (Fig. 2). SIGNOR-262074 0.69 ATM protein Q13315 UNIPROT NBN protein O60934 UNIPROT up-regulates phosphorylation Ser397 EQKFRMLsQDAPTVK 9606 10839545 t lperfetto We have identified two residues of nbs1, ser 278 and ser 343 that are phosphorylated in vitro by atm and whose modification in vivo is essential for the cellular response to dna damage. This response includes s-phase checkpoint activation, formation of the nbs1/mrel1/rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. SIGNOR-78030 0.853 BRAF protein P15056 UNIPROT EEF1A1 protein P68104 UNIPROT down-regulates quantity by destabilization phosphorylation Ser21 GHVDSGKsTTTGHLI -1 22378069 t miannu Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.  SIGNOR-276404 0.264 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND2 protein P30279 UNIPROT down-regulates phosphorylation Thr280 DELDQAStPTDVRDI 9606 17486076 t lperfetto These results indicate that cyclin d2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by thr280 phosphorylation by gsk3beta or p38 SIGNOR-154672 0.2 FAS protein P25445 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 11495919 t amattioni Ask1 binds fas SIGNOR-109676 0.685 FOXP1 protein Q9H334 UNIPROT CSF1R protein P07333 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000738 15286807 t Gianni Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation. SIGNOR-269048 0.3 NKX2-5 protein P52952 UNIPROT TBX5 protein Q99593 UNIPROT up-regulates quantity by expression transcriptional regulation 15095414 f Mutation at the potential TBE-B and -C sites, and at the GC box and NKX2.5 sites significantly decreased luciferase activity, suggesting that the GC box and the potential TBE-B, -C, and NKX2.5 sites are functionally important for the activation of the promoter function. SIGNOR-253650 0.785 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr142 SVGDEDIySGLSDQI -1 10669745 t Lck recognizes preferentially the tyrosine residue of Vav located at position 174 and, with significantly less affinity, those present at positions 142 and 160. It is now clear that this posttranslational modification will be involved in the activation of Vav, in the regulation of the strength of the signals emanating from this molecule, and also in the negative regulation of its function. SIGNOR-251389 0.779 PRKACA protein P17612 UNIPROT ETV5 protein P41161 UNIPROT up-regulates activity phosphorylation Ser367 PPYQRRGsLQLWQFL 9606 BTO:0002909 11682477 t lperfetto We further show that the increase in erm transcriptional activity after pka phosphorylation is closely correlated with a drastic reduction in the dna binding of the transcription factor. These results indicate that the phosphorylation of erm by pka is involved in erm-mediated transcription and suggest that the activation of erm is probably related to conformational changes. SIGNOR-111239 0.2 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ITK protein Q08881 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262236 0.8 PHF12 protein Q96QT6 UNIPROT Sin3B_complex complex SIGNOR-C409 SIGNOR form complex binding 9606 BTO:0000007 21041482 t miannu We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. Sin3B, Pf1, Mrg15, and HDAC1 associate within a stable complex that binds H3K4me3/H3K36me3-enriched nucleosomes. We identify mammalian Pf1, a PHD finger protein, as a homologue of Rco1, and show that all four components, Sin3B, HDAC1, Mrg15, and Pf1, can form a stable complex, which is recruited downstream of the transcriptional start site through complex interactions with histones. these results indicate that the Pf1/Sin3B-containing complex is recruited at discrete sites within actively transcribed loci, likely through its interaction with H3K4me3/H3K36me3-enriched chromatin. SIGNOR-266969 0.793 PTPRJ protein Q12913 UNIPROT SRC protein P12931 UNIPROT up-regulates activity dephosphorylation Tyr530 FTSTEPQyQPGENL 10116 26556953 t lperfetto Expression of Dep1 in transformed rat thyroid PCMPSV cells increased Src activity via Y527 dephosphorylation (corresponding to Y530 in human Src) without affecting the level of phosphorylated Y416 (Y419 in human Src).|Reciprocally, Dep1 can be phosphorylated by Src and Fyn on Y1311 and Y1320, leading to the dephosphorylation of Y530 Src by Dep1 . SIGNOR-276977 0.628 HOXD9 protein P28356 UNIPROT MEIS1 protein O00470 UNIPROT up-regulates activity binding 9606 10523646 t miannu We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9 SIGNOR-220721 0.517 HIPK2 protein Q9H2X6 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Thr880 QTIVIPDtPSPTVSV 9606 BTO:0002181 24145406 t miannu  Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. SIGNOR-276601 0.2 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation Ser1878 SPKYSPTsPTYSPTT 9606 22012619 t miannu Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna SIGNOR-176805 0.778 IL6 protein P05231 UNIPROT IL6R protein P08887 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 8676083 t fspada We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of il-6 and soluble il-6r (sil-6r), a complex that is known to interact with and activate a signal transducing receptor component, gp130 SIGNOR-42866 0.917 LTC4S protein Q16873 UNIPROT leukotriene C4(2-) smallmolecule CHEBI:57973 ChEBI up-regulates quantity chemical modification 9606 27365393 t miannu Leukotriene C4 synthase (LTC4S) catalyzes the formation of the proinflammatory lipid mediator leukotriene C4 (LTC4). SIGNOR-277257 0.8 FFAR4 protein Q5NUL3 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257420 0.445 RUNX2 protein Q13950 UNIPROT BGLAP protein P02818 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 11331591 f gcesareni Tgf-beta inhibited the expression of the cbfa1 and osteocalcin genes, whose expression is controlled by cbfa1 in osteoblast-like cell lines. This inhibition was mediated by smad3, which interacts physically with cbfa1 and represses its transcriptional activity at the cbfa1-binding ose2 promoter sequence SIGNOR-107160 0.589 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 10579915 t lperfetto Mtorc1 promotes protein synthesis by phosphorylating the eukaryotic initiation factor 4e (eif4e)- binding protein 1 (4e-bp1) and the p70 ribosomal s6 kinase 1 (s6k1). In vitro activation of p70alfa by mtor-catalyzed phosphorylation involving p70alfa thr-412. Mtor-catalyzed p70alfa phosphorylation in vitro is accompanied by a substantial restoration in p70alfa kinase activity toward its physiologic substrate, the 40 s ribosomal protein s6. In response toinsulinand nutrients, mtorc1, consisting of mtor, raptor (regulatory-associated protein of mtor), and mlst8, is activated and phosphorylates eukaryotic initiation factor 4e-binding protein (4ebp) and p70 s6 kinase to promote protein synthesis and cell size. SIGNOR-217060 0.752 CCNF protein P41002 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 27653696 t miannu We show that cyclin F, a cell-cycle-regulated substrate receptor (F-box protein) for the SCF, is targeted for degradation by APC/C. Furthermore, we establish that Cdh1 is itself a substrate of SCF(cyclin F). Cyclin F loss impairs Cdh1 degradation and delays S-phase entry, and this delay is reversed by simultaneous removal of Cdh1. SIGNOR-266363 0.525 PP1 proteinfamily SIGNOR-PF54 SIGNOR AKT1 protein P31749 UNIPROT down-regulates activity dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0002419 14633703 t lperfetto Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells SIGNOR-264658 0.2 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates activity deacetylation 9606 BTO:0000007 16613856 t lperfetto HDAC4 and HDAC5 deacetylate Runx2, allowing the protein to undergo Smurf-mediated degradation SIGNOR-227550 0.465 GABPB2 protein Q8TAK5 UNIPROT HCFC1 protein P51610 UNIPROT down-regulates activity binding 9606 BTO:0000567 10675337 t miannu The C1 factor interacts with the GABP_ transactivation domain.The domain of the C1 factor required for C1–GABP interaction can inhibit GABP_dependent transcriptional activation SIGNOR-221318 0.2 Platelet_alpha_granule_formation phenotype SIGNOR-PH136 SIGNOR VWF protein P04275 UNIPROT up-regulates 9606 NBK559062 f lperfetto Exposed VWF bound to collagen from vascular injury and endothelial damage adheres to the GPIb receptor on platelets to initiate signaling pathways for platelet activation, the next step in primary hemostasis. VW|VWF released by Weibel-Palade bodies or alpha-granules can enter circulation or accumulate in the subendothelial matrix binding to collagen through its A3 domain. Once exposed under high shear stress conditions in the arterial circulation, VWF can bind to platelets via its A1 domain. SIGNOR-261863 0.7 metaproterenol chemical CHEBI:6792 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Of the agonists studied here, there was a general trend that those with highest intrinsic efficacy were so across all three receptor subtypes (i.e. at the top of Tables 3–5, e.g. fenoterol, terbutaline, metaproterenol and adrenaline) SIGNOR-257875 0.8 PPP2R1A protein P30153 UNIPROT PPP2CB protein P62714 UNIPROT up-regulates binding 9606 16039140 t miannu Pr65/a acts as a scaffold protein for binding pp2ac and regulatory b subunits in a heterotrimeric holoenzyme SIGNOR-138886 0.888 HDAC2 protein Q92769 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR down-regulates 9606 28793257 f Among histone-modifying enzymes, HDAC2 is a crit- ical negative regulator of structural and functional plasticity in the mammalian nervous system (Guan et al., 2009; Hanson et al., 2013). HDAC2 localizes to the promoters of numerous synap- tic-plasticity-associated genes, where it deacetylates histone substrates (Gra ̈ ff et al., 2012; Guan et al., 2009). Consistently, loss of HDAC2 or HDAC inhibitor treatments promotes synaptic gene expression, long-term synaptic plasticity, and memory pro- cesses, while HDAC2 overexpression has opposing effects SIGNOR-268624 0.7 GNAS protein P63092 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates activity binding 9606 8245028 t MIANNU The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits. SIGNOR-265066 0.328 PTPRG protein P23470 UNIPROT STAT2 protein P52630 UNIPROT up-regulates activity dephosphorylation Tyr690 NLQERRKyLKHRLIV -1 25624455 t miannu PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity. SIGNOR-254728 0.2 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates phosphorylation 9606 14967450 t gcesareni Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1. SIGNOR-121944 0.847 BMP2 protein P12643 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates activity binding 9534 SIGNOR-C29 7791754 t lperfetto Under our assay conditions, bmp-2 binds better to bmpr-ii in combination with actr-i or bmpr-ib than in combination with bmpr-ia SIGNOR-144101 0.796 PIAS3 protein Q9Y6X2 UNIPROT SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR form complex binding 9606 26194464 t mrosina In summary, the TGF-b/IL-6/TCR-ERK-Smad2L (Ser255) axis is the positive regulator, whereas unphosphorylated Smad3C-PIAS3 complex is the negative regulator of STAT3-induced transcriptional processes for TH17 differentiation SIGNOR-255035 0.587 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SERPINA3 protein P01011 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002600 11027208 f miannu We characterize a molecular mechanism responsible for both IL-1 and TNF-induced expression of ACT gene in astrocytes. We identify the 5' distal IL-1/TNF-responsive enhancer of the ACT gene located 13 kb upstream of the transcription start site. This 413-bp-long enhancer contains three elements, two of which bind nuclear factor kB (NF-kB) and one that binds activating protein 1 (AP-1). All of these elements contribute to the full responsiveness of the ACT gene to both cytokines, as determined by deletion and mutational analysis. The 5' NF-kB high-affinity binding site and AP-1 element contribute most to the enhancement of gene transcription in response to TNF and IL-1. SIGNOR-254805 0.2 Lewy_body_formation phenotype SIGNOR-PH56 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 20479780 f lperfetto The genetic causes of PD seem to participate in con­ verging pathways to pathogenesis, but it is unclear whether all or only some of these pathways need to be activated for lewy body deposition and neuronal death to occur. SIGNOR-249703 0.7 WAVE complex complex SIGNOR-C271 SIGNOR ARP2/3 complex SIGNOR-C146 SIGNOR up-regulates activity binding 9606 BTO:0000132 27871158 t lperfetto Cdc42 can induce Arp2/3-mediated filopodia formation through the activation of WASp (Wiskott-Aldrich syndrome proteins) and neuronal N-WASp (Rohatgi et al., 1999). Similarly, Rac1-enhanced lamellipodia formation is related to Arp2/3 activation by the WAVE (WASP-family verprolin-homologous) complex SIGNOR-261876 0.535 FYN protein P06241 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Tyr529 TITKTVEyLHAQGVV 9606 18156174 t llicata Epidermal growth factor stimulates rsk2 activation through activation of the mek/erk pathway and src-dependent tyrosine phosphorylation of rsk2 at tyr-529. By mass spectroscopy-based studies, we identified src tyrosine kinase family members src and fyn as upstream kinases of rsk2 tyr-529. SIGNOR-160048 0.329 NFYA protein P23511 UNIPROT GCH1 protein P30793 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 15496512 f miannu Coactivator RNF4 is involved in the GCH gene expression. Through serial deletion and mutagenesis studies of the GCH promoter, we defined the RNF4-responsive element on GCH proximal promoter as a CCAAT box. RNF4 did not possess specific DNA binding activity toward this CCAAT box, which suggests that RNF4 may be a coactivator of the CCAAT boxbinding protein nuclear factor Y (NF-Y). RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. SIGNOR-252232 0.2 TERF2 protein Q15554 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR down-regulates 10116 27117401 f miannu During neuronal differentiation, use of an alternative splice site on the rat telomere repeat-binding factor 2 (TRF2) mRNA generates a short TRF2 protein isoform (TRF2-S) capable of derepressing neuronal genes. SIGNOR-266805 0.7 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT up-regulates quantity by stabilization phosphorylation Ser118 EPDNRRFsSYSQMEN -1 23444369 t miannu Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry. SIGNOR-273486 0.269 CDK5 protein Q00535 UNIPROT CDK5R1 protein Q15078 UNIPROT down-regulates phosphorylation Thr138 PAVTSAGtPKRVIVQ 9606 18326489 t lperfetto P35 phosphorylation by cdk5 interferes with the microtubule-binding and polymerizing activities of p35. Using a mutational approach, we found that only phosphorylation at thr-138, one of the two residues primarily phosphorylated in vivo, inhibits the polymerizing activity SIGNOR-177967 0.942 MEF2D protein Q14814 UNIPROT MYF6 protein P23409 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000165;BTO:0000222 7739551 t lperfetto Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. SIGNOR-238715 0.562 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT up-regulates activity phosphorylation Ser402 LSGSKTNsPKNSVHK 9606 BTO:0000007 16862148 t lperfetto ROCK phosphorylates FilGAP, and this phosphorylation stimulates its RacGAP activity and is a requirement for FilGAP-mediated bleb formation. | As shown in Fig. 5b, ROCK stimulated the incorporation of phosphate into FilGAP. We identified seven potential phosphorylation sites in FilGAP that was isolated by preparative SDS€“PAGE and subjected to trypsin digestion and mass spectrometry: Ser 391, Ser 402, Ser 413, Ser 415, Ser 437, Thr 452, and a cluster of serine and threonine residues (SSTTT) at position 573€“577 (see Supplementary Information, Table S2). SIGNOR-249304 0.44 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr94 ATADLDItEINKLTA 9606 19530738 t lperfetto First, we confirmed that wild-type borealin is phosphorylated at the previously described sites t88, t94, t169, and t230 when present in complex with survivin borealin might be a substrate for mps1. In the case of wild-type borealin, the fast exchange between the monomeric and dimeric forms may allow mps1 to phosphorylate the monomer. In turn, mps1 may regulate borealin function by unfolding the c-terminal domain and/or shifting the population to the monomeric form. SIGNOR-186155 0.468 ILK protein Q13418 UNIPROT ILK protein Q13418 UNIPROT up-regulates activity phosphorylation Ser343 SMADVKFsFQCPGRM 9606 11313365 t lperfetto Although ilk has been shown to autophosphorylate serine 343 (s343) is in the hydrophobic motif fsf within the activation loop of the kinase domain and has previously been suggested to be the target of autophosphorylation (9). Mutation of serine 343 to alanine (s343a) resulted in the inability of ilk to stimulate phosphorylation of pkb/akt in cos cells (9). SIGNOR-106838 0.2 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser552 VVRTPPKsPSSAKSR 9606 BTO:0000590 10090741 t lperfetto We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. SIGNOR-249316 0.585 ARID5B protein Q14865 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 29326336 f miannu ARID5B transcriptionally activates the oncogene MYC in T-ALL cells SIGNOR-256156 0.277 IDH complex SIGNOR-C396 SIGNOR NADH smallmolecule CHEBI:16908 ChEBI up-regulates quantity chemical modification 9606 28139779 t miannu Human NAD-dependent isocitrate dehydrogenase existing as the Œ±2Œ≤Œ≥ heterotetramer, catalyzes the decarboxylation of isocitrate into Œ±-ketoglutarate in the Krebs cycle, and is allosterically regulated by citrate, ADP and ATP. SIGNOR-266260 0.8 CASP3 protein P42574 UNIPROT GSN protein P06396 UNIPROT down-regulates cleavage 9606 BTO:0000130 9323209 t amattioni Caspase-3 mediates cleavage of gelsolin, generating a fragment that severs actin filaments in an unregulated fashion. The cleavage of gelsolin causes cells to round up, detach and undergo nuclear fragmentation. SIGNOR-51652 0.63 NPTX1 protein Q15818 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates activity binding 10090 BTO:0000938 15115814 t inferred from family member lperfetto We found that NP1 colocalizes and physically associates with the fast excitatory GluR1 AMPA receptors and that hypoxia induces a time-dependent increase in the NP1-GluR1 interactions. Thus hypoxia recruits NP1 protein to GluR1 subunits concurrent with the hypoxic excitotoxic cascade.|Rather we propose that through interactions with GluR1 clusters, NP1 modulates the function of AMPA receptors in a manner whereby increased NP1-GluR1 interactions sensitize neurons to hypoxia-induced excitotoxic death. SIGNOR-270235 0.34 MAPK9 protein P45984 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 BTO:0000938 12040039 t gcesareni Stress in primary cultured cns neurons induces phosphorylation of c-jun serines 63 and 73 and increased c-jun protein. Jnk2/3 activity selectively targets c-jun. SIGNOR-88212 0.883 sertindole chemical CHEBI:9122 ChEBI HTR1E protein P28566 UNIPROT down-regulates activity chemical inhibition 9534 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258543 0.8 MT-CO2 protein P00403 UNIPROT Mitochondrial respiratory chain complex IV complex SIGNOR-C280 SIGNOR form complex binding 30030361 t lperfetto Complex IV (EC 1.9.31) or cytochrome c oxidase (COX) catalyses the oxidation of cytochrome c and the reduction of oxygen to water, coupled to proton translocation [108]. Mammalian cIV contains 13 or 14 subunits SIGNOR-267748 0.761 NSD1 protein Q96L73 UNIPROT PRB4 protein P10163 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0003233 29156722 t miannu We here demonstrate that NSD1 could bind to the promoter regions of PRB4 and activate promoter activity by reducing the binding of H3K27me2 and increasing the binding of H3K36me2 on PRB4 promoter. SIGNOR-268459 0.348 HTR6 protein P50406 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256801 0.488 PARL protein Q9H300 UNIPROT PINK1 protein Q9BXM7 UNIPROT down-regulates quantity by destabilization cleavage 9606 BTO:0000007 22354088 t miannu Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. SIGNOR-261364 0.626 NR3C1/STAT5A complex SIGNOR-C84 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 9606 12540601 f fspada We have shown that stat5a is associated with the glucocorticoid receptor during adipogenesis in a highly regulated manner. SIGNOR-97562 0.7 LAT protein O43561 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 BTO:0000661 10811803 t Our results showed that three distal tyrosines, Tyr(171), Tyr(191), and Tyr(226), are responsible for Grb2-binding; SIGNOR-251521 0.8 SYBU protein Q9NX95 UNIPROT STX1A protein Q16623 UNIPROT up-regulates activity relocalization 9606 BTO:0000938 15459722 t miannu Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. SIGNOR-264812 0.428 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser144 DSPALEVsDSESDEA 9606 10618498 t lperfetto Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability SIGNOR-73883 0.436 ATM protein Q13315 UNIPROT DBF4 protein Q9UBU7 UNIPROT down-regulates phosphorylation Thr449 DDIRQNFtQLPLHKN 9606 22123827 t lperfetto Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication. SIGNOR-177801 0.382 PKA proteinfamily SIGNOR-PF17 SIGNOR Postsynaptic density assembly phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 BTO:0000938 BTO:0004249 23125836 f miannu PKA is activated by Group I mGluRs in ACC neurons. The cAMP signaling pathway contributes to the activity-dependent synaptic plasticity in the anterior cingulate cortex SIGNOR-264960 0.7 SRC protein P12931 UNIPROT LPIN1 protein Q14693 UNIPROT up-regulates activity phosphorylation Tyr413 DPEVAALyFPKNGDP 9606 BTO:0002181 33203880 t miannu Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. SIGNOR-277293 0.2 PDPK1 protein O15530 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT up-regulates phosphorylation Thr228 HEGAVTHtFCGTIEY 9606 9445476 t gcesareni A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. one of the most studied signalling events controlled by ptdins(3,4,5)p3, comprises the activation of a group of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. SIGNOR-55371 0.6 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT up-regulates activity dephosphorylation Ser1714 SPTSPSYsPTSPSYS 9606 BTO:0000567 22137580 t In addition, we show that RPAP2 is a CTD Ser5 phosphatase. Taken together, our results indicate that during transcription of snRNA genes, Ser7 phosphorylation facilitates recruitment of RPAP2, which in turn both recruits Integrator and dephosphorylates Ser5.|The Pol II CTD is first phosphorylated on Ser5 and then on Ser7 by CDK7. RPAP2 associates with the Pol II CTD after Ser7 phosphorylation and tethers a subcomplex of Integrator to snRNA genes. RPAP2 dephosphorylates Ser5P of the CTD, facilitating transcription and the subsequent recruitment of the Int11 catalytic subunit of Integrator SIGNOR-248753 0.731 PPP2CA protein P67775 UNIPROT HDAC7 protein Q8WUI4 UNIPROT up-regulates activity dephosphorylation Ser486 RPLSRAQsSPAAPAS 9606 18339811 t Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions. SIGNOR-248649 0.32 MAPK3 protein P27361 UNIPROT PAX5 protein Q02548 UNIPROT down-regulates activity phosphorylation Ser189; Ser283 SGILGITsPSADTNK;DMKANLAsPTPADIG 9606 BTO:0003079 22593617 t Gianni In this study, we demonstrated that PAX5 was phosphorylated by ERK1/2 in vitro and in vivo at serines 189 and 283. This phosphorylation attenuated the transcriptional repression of BLIMP1 by PAX5. SIGNOR-269086 0.249 S1PR3 protein Q99500 UNIPROT GNA14 protein O95837 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257437 0.368 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity phosphorylation of foxos by akt, ikk, erk, ck1, cdk2, and dyrk1a universally leads to foxo's inhibition. SIGNOR-252907 0.516 MAP3K3 protein Q99759 UNIPROT MAP3K3 protein Q99759 UNIPROT up-regulates phosphorylation Ser526 MSGTGMRsVTGTPYW 9606 BTO:0000007 16407301 t lperfetto Phosphorylation of serine 526 is required for mekk3 activity, and association with 14-3-3 blocks dephosphorylationautophosphorylation of mekk3 at ser526 SIGNOR-143647 0.2 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t lperfetto These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3 .we show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity SIGNOR-236067 0.742 IKBKE protein Q14164 UNIPROT TRAF3IP2 protein O43734 UNIPROT up-regulates activity phosphorylation Ser328 KVILNYPsPWDHEER 9606 21822257 t miannu IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function. SIGNOR-262883 0.421 PPP2CB protein P62714 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248600 0.2 BMP2 protein P12643 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates activity binding -1 18937504 t ggiuliani Here we report the high-resolution NMR structure of BMPR-IA ECD in solution, revealing that a large part of the ligand-binding epitope is unfolded and flexible before formation of the complex. The binding beta4beta5 loop of BMPR-IA passes through a structural rearrangement upon BMP-2 binding. SIGNOR-255771 0.927 PEA15 protein Q15121 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates 9606 11702783 f gcesareni Here, we report that pea-15, a protein variably expressed in multiple cell types, blocks erk-dependent transcription and proliferation by binding erks and preventing their localization in the nucleus._ Pea-15 can redirect the biological outcome of map kinase signaling by regulating the subcellular localization of erk map kinase. SIGNOR-111499 0.864 PPP2CA protein P67775 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates activity dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 18586681 t Both sites were dephosphorylated with the same kinetics; the anti-Ser(P)198 antibody was subsequently used as it exhibited lower background staining. Direct comparison of PP2Cα with purified PP1 and PP2A lead us to conclude that at the same molar ratio PP2Cα was the most efficient in dephosphorylating PAK1 (Fig. 1D). In this case we monitored two autophosphorylation sites in the Pak1 N-terminal regulatory region (Ser57 and Ser198/203) using phosphospecific antibodies: both sites showed the same kinetics of inactivation. SIGNOR-248643 0.362 BCR protein P11274 UNIPROT YWHAZ protein P63104 UNIPROT unknown phosphorylation Thr232 LTLWTSDtQGDEAEA -1 16045749 t llicata We show here that BCR interacts with at least five isoforms of 14-3-3 in vivo and phosphorylates 14-3-3tau on Ser233 and to a lesser extent 14-3-3zeta on Thr233 SIGNOR-250595 0.334 DRD1 protein P21728 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257269 0.271 AGT protein P01019 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates 9606 BTO:0001130 16597412 f gcesareni Endothelin-1 (et-1) and angiotensin ii (angii), two potent vasoactive peptides involved in the regulation of cardiovascular homeostasis, also induce mitogenic and pro-angiogenic responses in vitro and in vivo. Both peptides are produced by cleavage of inactive precursors by metalloproteases (endothelin-converting enzyme and angiotensin-converting enzyme, respectively) and activate two subtypes of membrane receptors (eta-r and etb-r for et-1, at1r and at2r for angii) that all belong to the superfamily of g-protein coupled receptors. SIGNOR-145680 0.821 BMP7 protein P18075 UNIPROT MMP13 protein P45452 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0003858 12734180 f miannu In the present study we investigated the inhibitory effects of IGF-1 and OP-1 on MMP-13 expression in human chondrocytes. We found that the suppressive effect of IGF-1 and OP-1 on the MMP-13 promoter activity was dose-dependent at the transcriptional level with a corresponding decrease in the level of MMP-13 protein. SIGNOR-254801 0.355 SALL4 protein Q9UJQ4 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000356 23954296 f miannu Our shRNA-mediated SALL4 knockdown system and SALL4 overexpression system revealed that SALL4 suppresses the expression of adhesion gene CDH1, and positively regulates the CDH1 suppressor ZEB1. SIGNOR-255123 0.254 POMC protein P01189 UNIPROT MC2R protein Q01718 UNIPROT up-regulates activity binding 10029 BTO:0000047 20371771 t lperfetto Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). SIGNOR-268615 0.779 INSR protein P06213 UNIPROT DOK5 protein Q9P104 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0000671 12730241 f lperfetto Irs5/dok4 and irs6/dok5 represent two new signaling proteins with potential roles in insulin and igf-1 action SIGNOR-101038 0.379 PCGF1 protein Q9BSM1 UNIPROT Noncanonical PRC1 complex SIGNOR-C151 SIGNOR form complex binding 10090 25533466 t miannu inhibition of adipogenesis does not require the JmjC demethylase domain of FBXL10, but it does require the F-box and leucine-rich repeat domains, which we show recruit a noncanonical polycomb repressive complex 1 (PRC1) containing RING1B, SKP1, PCGF1, and BCOR. SIGNOR-255279 0.708 SMARCE1 protein Q969G3 UNIPROT Muscle cell-specific SWI/SNF ARID1A variant complex SIGNOR-C481 SIGNOR form complex binding 9606 BTO:0000887 11073988 t miannu The SWI/SNF family of chromatin-remodeling complexes facilitates gene activation by assisting transcription machinery to gain access to targets in chromatin. Our data suggest that BAF250 confers specificity to the human BAF complex and may recruit the complex to its targets through either protein-DNA or protein-protein interactions. SIGNOR-270691 0.835 FOXP1 protein Q9H334 UNIPROT KLK3 protein P07288 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 18640093 f Notably, we demonstrate that FOXP1 directly interacts with AR and negatively regulates AR signaling ligand-dependently, as exemplified by the transcriptional repression of PSA gene regulated by androgen-dependent FOXP1 recruitment on its enhancer region. SIGNOR-253660 0.277 VWF protein P04275 UNIPROT F8 protein P00451 UNIPROT up-regulates activity binding 9606 23020315 t miannu Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF SIGNOR-251967 0.785 ARAF protein P10398 UNIPROT SLC9A3R2 protein Q15599 UNIPROT up-regulates activity phosphorylation Ser303 QESGLHLsPTAAEAK 9606 BTO:0002269 26310448 t miannu We also identify A-Raf as a kinase necessary for E3KARP phosphorylation at the G2/M stage of the cell cycle. Phosphorylation of Ser-303 regulates the localization, function, and dynamics of E3KARP SIGNOR-273503 0.381 tamsulosin chemical CHEBI:9398 ChEBI ADRA1A protein P35348 UNIPROT down-regulates activity chemical inhibition 10029 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258474 0.8 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2A protein Q9UQM7 UNIPROT up-regulates activity chemical activation 15621017 t It has been reported that Aβ can result in an increase in intracellular Ca2+, which in turn can activates CaMK. SIGNOR-255491 0.8 RPS15A protein P62244 UNIPROT 40S cytosolic small ribosomal subunit complex SIGNOR-C286 SIGNOR form complex binding -1 25901680 t lperfetto Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 Å, reaching 2.9 Å resolution in the most stable regions. |The human ribosome (80S) has a molecular weight of 4.3 MDa: the large subunit (60S) consists of 28S, 5S and 5.8S rRNAs and 47 proteins, while the small subunit (40S) possesses a single 18S rRNA chain and 33 pro- teins. SIGNOR-262436 0.851 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI up-regulates quantity relocalization 9606 18790874 t brain lperfetto GABAA receptors (GABAA-Rs) are the major inhibitory receptors in the central nervous system (CNS). |Mammalian GABAA-Rs are all anion-selective channels. Increased chloride permeability generally reduces neuronal excitability (inhibition) SIGNOR-263810 0.8 PAX7 protein P23759 UNIPROT Quiescence phenotype SIGNOR-PH25 SIGNOR up-regulates BTO:0001103 15501225 f svumbaca Our work presented here provides a possible mechanism involving Pax-7 that allow satellite cells to exit the cell cycle, down-regulate MyoD, and prevent myogenin induction, phenotypes characteristic of the quiescent satellite cell. SIGNOR-255366 0.7 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK1 protein P06493 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258071 0.8 MCM10 protein Q7L590 UNIPROT RECQL4 protein O94761 UNIPROT down-regulates binding 9606 19696745 t miannu Mcm10 inhibits recq4 helicase activity. SIGNOR-187701 0.519 MLLT3 protein P42568 UNIPROT SCNN1A protein P37088 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0005545 20159978 f Regulation miannu AF9/MLLT3 contributes to the regulation of the gene encoding the epithelial sodium channel alpha, ENaCalpha, in renal tubular cells. Specifically, increases in AF9 protein lead to a reduction in ENaCalpha expression and changes in AF9 activity appear to be an important component of aldosterone signaling in the kidney. SIGNOR-251944 0.274 LCK protein P06239 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr191 SRLLHSDyMNMTPRR 9606 BTO:0000782;BTO:0001271 8992971 t lperfetto We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor SIGNOR-45524 0.749 BIRC2 protein Q13490 UNIPROT RIPK4 protein P57078 UNIPROT up-regulates activity polyubiquitination lys145 9606 BTO:0000007 21931591 t miannu CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.Lysine residues K51 and K145 of RIP4 are critical for cIAP1-mediated ubiquitination and NF-kB activation. SIGNOR-272708 0.359 sirolimus chemical CHEBI:9168 ChEBI LILRB1 protein Q8NHL6 UNIPROT down-regulates quantity by repression 9606 18652845 f miannu Although RAPA downregulated ILT2, ILT3 and ILT4 expression in DC, the inhibition of T cell proliferation by RAPA-treated DC is predominantly due to the reduction of CD40, CD80 and CD86 expression rather than the propensity to generate FoxP3 expressing regulatory cells. SIGNOR-255476 0.8 CDKN1A protein P38936 UNIPROT CCNB1 protein P14635 UNIPROT down-regulates binding 9606 19158493 t gcesareni P21-mediated degradation of cyclin b1 in response to dna damage is necessary for the maintenance of g2 cell cycle arrest. SIGNOR-183498 0.826 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT up-regulates phosphorylation 9606 25056917 t miannu P38_ increases gata_2 activity at endogenous target genes by inducing gata_2 multi_site phosphorylation. SIGNOR-205242 0.272 KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 15526160 t miannu C-Kit stimulates rapid and transient tyrosine phosphorylation of JAK2. JAK2 was found to be constitutively associated with c-Kit, with increased association after ligand stimulation of c-Kit SIGNOR-254954 0.603 progesterone smallmolecule CHEBI:17026 ChEBI 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity precursor of 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268649 0.8 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR KIF4A protein O95239 UNIPROT up-regulates activity phosphorylation Thr1161 FFNPVCAtPNSKILK -1 29771379 t miannu Kif4A T1161 was phosphorylated by Cdk1/Cyclin B1 in vitro. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization. SIGNOR-265995 0.459 SEMA3B protein Q13214 UNIPROT NRP2 protein O60462 UNIPROT up-regulates activity binding 9606 BTO:0001176;BTO:0002036 25335892 t miannu Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction. SIGNOR-261816 0.602 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI SAICAR(4-) smallmolecule CHEBI:58443 ChEBI up-regulates quantity precursor of 9606 33179964 t miannu The next two reactions (steps 6 and 7) involve carb oxylation of AIR to 4-carboxy-5-aminoimidazole ribonu cleotide (CAIR) and ligation of the carboxy group of CAIR with an amide group derived from Asp in an ATP dependent reaction forming 4-(N-succinylcarboxamide)- 5-aminoimidazole ribonucleotide (SAICAR). These reac tions are catalyzed by the bifunctional enzyme phosphoribosylaminoimidazole carboxylase/phosphori bosylaminoimidazole succinocarboxamide synthetase (PAICS). SIGNOR-267320 0.8 DRAM2 protein Q6UX65 UNIPROT RHOA protein P61586 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 30755245 f irozzo Here, we show that DRAM2 may act as an oncogenic regulator in non-small cell lung cancer (NSCLC). Furthermore, DRAM2 overexpression increased the expression of proteins RAC1, RHOA, RHOC, ROCK1, and decreased RHOB expression, all of which are cell migration factors. SIGNOR-259142 0.2 MRPL21 protein Q7Z2W9 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262372 0.704 MAPK14 protein Q16539 UNIPROT MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t gcesareni Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity SIGNOR-48349 0.42 TJP2 protein Q9UDY2 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates binding 9606 21808241 t milica In addition, yap and taz interact with another tight junction protein zo-2, which was reported to increase nuclear localization of yap and tight-junction localization of taz. SIGNOR-175931 0.494 HOXA10 protein P31260 UNIPROT MYLK protein Q15746 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0002196 15886193 t Luana Results from these experiments demonstrated that in 10T1/2 cells Hoxa10-1 increased the activity of the telokin promoter 3-fold without affecting the activity of the other promoters analyzed (Fig. 2A). Similar results were also observed in A10 SMC (data not shown). In contrast, Hoxb8 significantly repressed the activity of the telokin, smooth muscle α-actin, and SM22α promoters by 70, 50, and 70%, respectively SIGNOR-261643 0.2 PTPN1 protein P18031 UNIPROT STAT6 protein P42226 UNIPROT down-regulates activity dephosphorylation 9606 22156494 t miannu Phosphorylated STAT6 may also serve as a cytoplasmic substrate for PTP1B since overexpression of PTP1B leads to STAT6 dephosphorylation and the suppression of STAT6 transcriptional activity, whereas PTP1B deficiency increases IL-4-induced STAT6 signaling in B-cells. SIGNOR-277122 0.331 Dinaciclib chemical CID:46926350 PUBCHEM CDK9 protein P50750 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-191331 0.8 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates quantity by destabilization dephosphorylation 9606 10644691 t In addition, PP2C expression relieves Axin-mediated repression of LEF-1-dependent transcription. PP2C utilizes Axin as a substrate both in vitro and in vivo and decreases its half-life. These results indicate that PP2C is a positive regulator of Wnt signal transduction and mediates its effects through the dephosphorylation of Axin. SIGNOR-248488 0.442 GNG2 protein P59768 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 BTO:0000938 16537363 t gcesareni Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt. SIGNOR-145122 0.464 ATM protein Q13315 UNIPROT UBQLN4 protein Q9NRR5 UNIPROT up-regulates activity phosphorylation Ser318 GNSDSSSsQPLRTEN 9606 BTO:0001938 30612738 t lperfetto These results suggest that UBQLN4 phosphorylation on S318 is functionally important for its role in the DSB response.>Particularly HRR is dependent on ATM activity (Dietlein et al., 2014). Here, we showed that UBQLN4 is an ATM substrate and that DSB sealing is markedly impaired in UBQLN4-depleted cells. HRR depends on a 5′-3′ DSB end resection, which is initiated by the MRE11 nuclease SIGNOR-265076 0.2 CHGA protein P10645 UNIPROT Secretory_granule_organization phenotype SIGNOR-PH87 SIGNOR up-regulates 10090 12456801 f CgA was initially identified as the major soluble matrix protein of secretory vesicles formed in neuroendocrine cells. Its functions include modulation of secretory granule stability, prohormone processing, and regulation of peptide sorting into secretory pathways SIGNOR-254274 0.7 NCOR2 protein Q9Y618 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 12897056 t gcesareni The spen protein, sharp (smrt/hdac1-associated repressor protein), was identified as a component of transcriptional repression complexes in both nuclear receptor and notch/rbp-jkappa signaling pathways. SIGNOR-104489 0.2 BMPR1A protein P36894 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates activity phosphorylation 9606 19620713 t lperfetto Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression. SIGNOR-255263 0.725 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR form complex binding BTO:0001103 7566092 t svumbaca Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-Jk and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter. SIGNOR-255363 0.95 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT up-regulates quantity by stabilization phosphorylation Tyr290 RQSVLVPyEPPQVGT 9606 19783996 t Manara In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. SIGNOR-260933 0.532 MAPK3 protein P27361 UNIPROT ETV6 protein P41212 UNIPROT down-regulates phosphorylation Ser257 ESHPKPSsPRQESTR 10090 BTO:0000944 15060146 t miannu Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation. SIGNOR-260085 0.321 HES6 protein Q96HZ4 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000938 19891787 f gcesareni Expression of hes-6 resulted in induction of e2f-1, a crucial target gene for the transcriptional repressor hes-1 SIGNOR-189101 0.2 NODAL protein Q96S42 UNIPROT ACVR1B protein P36896 UNIPROT up-regulates activity binding 9606 19874624 t Regulation miannu Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors. SIGNOR-251939 0.633 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser673 RVQSKIGsLDNITHV -1 12435421 t miannu Ser214, Ser262, Ser356, and Ser409 of tau441‚ were phosphorylated by PKA. tau in PHF is abnormally hyperphosphorylated and lacks its normal activity to bind to microtubules and to stimulate their assembly SIGNOR-250007 0.438 DRAP1 protein Q14919 UNIPROT BTAF1 protein O14981 UNIPROT up-regulates activity binding 9986 15509807 t miannu We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP. SIGNOR-263918 0.514 GLIS1 protein Q8NBF1 UNIPROT WNT5A protein P41221 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32047936 t miannu GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A SIGNOR-269040 0.249 OGG1 protein O15527 UNIPROT Base-excision_repair phenotype SIGNOR-PH222 SIGNOR up-regulates 23545420 f lperfetto The BER pathway is initiated by one of at least 11 distinct DNA glycosylases, depending on the type of lesion (Table 1). SIGNOR-275715 0.7 SNAI2 protein O43623 UNIPROT CDH1 protein P12830 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 15311212 f miannu known E-cadherin transcriptional repressors, such as SLUG (SNAI2), SIP1 (ZEB2), TWIST1, SNAIL (SNAI1) and ZEB1 (TCF8), but not E12/E47 (TCF3), had a lack of upregulation in cells expressing mutated E-cadherin compared to WT. SIGNOR-255155 0.673 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 20185585 t gcesareni The vegfr/pdgfr inhibitor sunitinib (selleck) was used at 35 mg/kg in citrate-buffered water and administered daily by oral gavage for 7 days. SIGNOR-163947 0.8 PRKCD protein Q05655 UNIPROT CYTH1 protein Q15438 UNIPROT unknown phosphorylation Thr395 RKKKVSStKRH 9606 BTO:0001948 11438522 t lperfetto We show here that a serine/threonine motif within the short polybasic stretch of cytohesin-1 is phosphorylated by purified protein kinase C delta in vitro. Furthermore, the respective residues are also found to be phosphorylated after phorbol ester stimulation in vivo. Biochemical and functional analyses show that phosphorylated cytohesin-1 is able to tightly associate with the actin cytoskeleton, and we further demonstrate that phosphorylation of the protein is required for maximal leukocyte function antigen-1-mediated adhesion of Jurkat cells to intercellular adhesion molecule 1.  SIGNOR-249099 0.326 EP300 protein Q09472 UNIPROT PCK1 protein P35558 UNIPROT down-regulates quantity by destabilization acetylation Lys594 KEVEDIEkYLEDQVN 9606 BTO:0000007 21726808 t lperfetto Acetylation Regulates Gluconeogenesis by Promoting PEPCK1 Degradation via Recruiting the UBR5 Ubiquitin Ligase|P300 Acetylates and Destabilizes PEPCK1|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1 SIGNOR-267604 0.533 ATM protein Q13315 UNIPROT FANCD2 protein Q9BXW9 UNIPROT up-regulates phosphorylation Ser1401 LQGEEIKsQNSQEST 9606 12086603 t lperfetto These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint SIGNOR-90109 0.785 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT up-regulates activity phosphorylation Ser1252 QPTLPSSsPVPIPVS 9606 BTO:0000567 37584777 t phosphorylation site remapping based on mass spec table lperfetto CDK1 phosphorylates AMBRA1 at T1209 and S1223. |CDK1-mediated phosphorylation primes PLK1 phosphorylation on AMBRA1|In this work, we show that AMBRA1 is sequentially phosphorylated at mitosis by CDK1 and PLK1 on multiple sites. In particular, CDK1 is responsible for the early phosphorylations on T1209 and S1223, and it promotes additional late phosphorylation events by PLK1 on AMBRA1. Altogether, these phosphorylation events are critical for proper spindle function and orientation. Indeed, phosphorylated AMBRA1 can interact with NUMA1 and is responsible for NUMA1 proper localization at the cell cortex. Moreover, we observe that loss of AMBRA1 leads to PLK1 protein stabilization and to an increase in phospho-NUMA1 levels which, in turn, contributes to spindle orientation defects. SIGNOR-272969 0.258 PIM2 protein Q9P1W9 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates quantity by stabilization phosphorylation Thr145 QGRKRRQtSMTDFYH 9606 20307683 t lperfetto Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo SIGNOR-164646 0.409 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT down-regulates activity phosphorylation Ser362 QGRSGCSsQSISPMR -1 28130417 t lperfetto Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3. SIGNOR-264870 0.266 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 22163316 t lperfetto We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase. SIGNOR-216892 0.318 MAPK7 protein Q13164 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser78 ANPSPPPsPSQQINL 9606 11254654 t lperfetto Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78. SIGNOR-105728 0.393 FOXO proteinfamily SIGNOR-PF27 SIGNOR MYOD1 protein P15172 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000222 18854138 f gcesareni Our cell-based assays and in vitro studies reveal a tight codependent partnership between foxo3 and pax3/7 to coordinately recruit rna polymerase ii and form a preinitiation complex (pic) to activate myod transcription in myoblasts. SIGNOR-252937 0.2 PARP1 protein P09874 UNIPROT POLA1 protein P09884 UNIPROT up-regulates activity binding 9606 BTO:0000567 9518481 t Federica We provide evidence that in proliferating cells: (i) PARP is physically associated with the catalytic subunit of the DNA polymerase α–primase tetramer, an association confirmed by confocal microscopy, demonstrating that both enzymes are co-localized at the nuclear periphery of HeLa cells.|(iii) PARP-deficient cells derived from PARP knock-out mice exhibited reduced DNA polymerase activity, SIGNOR-261270 0.346 ECSIT protein Q9BQ95 UNIPROT MAVS protein Q7Z434 UNIPROT up-regulates activity binding 9606 22588174 t Giorgia ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation SIGNOR-260371 0.435 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates activity phosphorylation Thr46 GGTLFSTtPGGTRII 9823 BTO:0001840 SIGNOR-C3 23486913 t lperfetto These results indicate that arg, leu, and gln act coordinately to stimulate proliferation of ptr cells through activation of the mtor-rps6k-rps6-eif4ebp1 signal transduction pathway. Specifically as part of mtorc1, mtor directly phosphorylates the ribosomal protein s6 kinases (s6k1 and s6k2) and the eukaryotic initiation factor 4e (eif4e)-binding proteins (4e-bp1 and 4e-bp2), both of which control specific steps in the initiation of cap-dependent translation SIGNOR-219266 0.925 GSK3A protein P49840 UNIPROT NBR1 protein Q14596 UNIPROT down-regulates activity phosphorylation Thr586 HNTPVDVtPCMSPLP -1 24879152 t lperfetto The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation. SIGNOR-261794 0.325 SNTA1 protein Q13424 UNIPROT DGC complex SIGNOR-C217 SIGNOR form complex binding 9606 15117830 t apalma The DGC is composed of dystrophin (blue), an elongated cytoskeletal protein that links to cytoplasmic γ-actin and the transmembrane components of the DGC. Dystrophin binds to the tail of β-dystroglycan (orange). Dystroglycan is composed of 2 subunits, α and β, each produced from the same gene. Dystroglycan binds to the extracellular matrix protein laminin-α2. The sarcoglycan complex (blue-green) is composed of multiple subunits. Mutations in the genes encoding α-, β-, γ-, and δ-sarcoglycan lead to a similar phenotype as dystrophin mutations and include cardiomyopathy and muscular dystrophy in humans and mice. Additional subcomplexes in the DGC in skeletal muscle include α and β dystrobrevin, the syntrophins, nNOS, and caveolin 3 (pink). SIGNOR-255991 0.523 MK-2206 chemical CHEBI:67271 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates chemical inhibition 9606 BTO:0001286 21841310 t gcesareni Treatment with the pi3k inhibitor ly294002 or the akt inhibitor mk2206 diminished s473 phosphorylation. SIGNOR-176043 0.8 adenosine 5'-monophosphate smallmolecule CHEBI:16027 ChEBI IMP smallmolecule CHEBI:17202 ChEBI up-regulates quantity precursor of 9606 BTO:0001103 1631143 t miannu AMP deaminase (AMPD; EC 3.5.4.6) is encoded by a multigene family in mammals. The AMPD1 gene is expressed at high levels in skeletal muscle, where this enzyme is thought to play an important role in energy metabolism. AMP deaminase (AMPD; EC 3.5.4.6), an enzyme that catalyzes deamination of AMP to IMP, and the purine nucleotide cycle, of which AMPD is one component, play a central role in purine nucleotide interconversion in eukaryotic cells. SIGNOR-269774 0.8 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates chemical activation 9606 4344326 t Bell's palsy gcesareni SIGNOR-251704 0.8 EGR1 protein P18146 UNIPROT PDGFC protein Q9NRA1 UNIPROT up-regulates quantity by expression transcriptional regulation 10116 BTO:0001685 15247255 f The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad.|These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.|Egr-1 and Sp1 specifically bind the PDGF-C promoter SIGNOR-254268 0.253 TNF protein P01375 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates 9606 10485710 f gcesareni Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k). SIGNOR-70619 0.256 MLL3 complex complex SIGNOR-C446 SIGNOR H3C1 protein P68431 UNIPROT down-regulates activity methylation Lys5 kQTARKST 9606 34156443 t miannu MLL3/KMT2C and MLL4/KMT2D are two paralogous histone modifiers that belong to the SET1/MLL (also named COMPASS) family of lysine methyltransferases and play critical roles in enhancer-regulated gene activation. MLL3 and MLL4 form identical multi-protein complexes for modifying mono-methylation of histone H3 lysine 4 (H3K4) at enhancers, which together with the p300/CBP-mediated H3K27 acetylation can generate an active enhancer landscape for long-range target gene activation. SIGNOR-268810 0.2 BCR-ABL fusion protein SIGNOR-FP6 SIGNOR LASP1 protein Q14847 UNIPROT unknown phosphorylation Tyr171 IPTSAPVyQQPQQQP 9606 BTO:0000664 24913448 t phosphorylation blocks localization at focal adhesion sites and induces binding to CRLK lperfetto LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia|We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients SIGNOR-271703 0.2 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT down-regulates quantity by destabilization cleavage Glu30 GLFDFMLeDEASGIG -1 9148753 t miannu Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues. SIGNOR-256349 0.687 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser282 NSLQRVPsYDSFDSE 9606 BTO:0000782 12475968 t lperfetto Treatment of ets1 by t-cell nuclear extract or phosphorylation of these four serines by calmodulin-dependent kinase ii (camk ii) has recently been reported to decrease ets1 dna binding by reinforcing autoinhibition SIGNOR-96338 0.311 GABRA4 protein P48169 UNIPROT GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR form complex binding 9606 BTO:0000227 18790874 t brain, See table 3 for identified complexes lperfetto The assembly of GABAA-R as heteropentamers produces complex subtype heterogeneity in structure, which is the major determinant of their pharmacological profile.|Evidence is greatly in favor of a pentameric receptor and most GABAA-R subtypes are formed from two copies of a single alpha, two copies of a single beta, and one copy of another subunit, such as gamma, delta, or epsilon. SIGNOR-263759 0.605 rizatriptan chemical CHEBI:48273 ChEBI HTR1D protein P28221 UNIPROT up-regulates activity chemical activation 9606 10193663 t Luana This study has demonstrated that the 5-HT receptor binding profile of eletriptan is qualitatively similar to the binding profile of sumatriptan, zolmitriptan, naratriptan and rizatriptan. As expected these compounds demonstrated high affinity for the human 5-HT1B and 5-HT1D receptors which is consistent with their known vasoconstrictor properties in isolated vascular tissues  SIGNOR-258342 0.8 AATF protein Q9NY61 UNIPROT BAX protein Q07812 UNIPROT down-regulates quantity transcriptional regulation 9606 22909821 t We identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. SIGNOR-259916 0.2 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT up-regulates activity phosphorylation Ser1005 EHDSDESsDDDSDSE 9606 BTO:0000661 10066810 t llicata Mutational analysis of CK2 consensus sites showed that the target for CK2 was in an acidic insert of 19 amino acids in the D2 domain, and Ser to Ala mutations at amino acids 965, 968, 969, and 973 abrogated CK2 phosphorylation of CD45. CK2 phosphorylation increased CD45 activity 3-fold toward phosphorylated myelin basic protein, and this increase was reversible by PP2A treatment.  SIGNOR-251030 0.441 CSNK2A1 protein P68400 UNIPROT ATXN3 protein P54252 UNIPROT up-regulates activity phosphorylation Ser335 SDLGDAMsEEDMLQA 9606 BTO:0000007 19542537 t miannu Here we show that protein casein kinase 2 (CK2)-dependent phosphorylation controls the nuclear localization, aggregation and stability of ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3). The main phosphorylation of ATXN3 in vivo thus occurred at serine residues within the three conserved UIMs. SIGNOR-276226 0.2 ATG101 protein Q9BSB4 UNIPROT ATG13 protein O75143 UNIPROT up-regulates binding 9606 19597335 t gcesareni Furthermore, atg101 is important for the stability and basal phosphorylation of atg13 and ulk1 SIGNOR-186989 0.958 AKT proteinfamily SIGNOR-PF24 SIGNOR CDCA7 protein Q9BWT1 UNIPROT down-regulates phosphorylation Thr163 SRRPRRRtFPGVASR 9606 23166294 t llicata The prosurvival kinase akt phosphorylates cdca7 at threonine 163, promoting binding to 14-3-3, dissociation from myc, and sequestration to the cytoplasm. we have mapped the domains of interaction and have discovered that akt phosphorylates cdca7 near this contact region, leading to loss of its association with myc, binding to 14-3-3 proteins, and exclusion from the nucleus. SIGNOR-199776 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PTPN1 protein P18031 UNIPROT up-regulates activity phosphorylation Ser386 LRGAQAAsPAKGEPS 9606 BTO:0000567 23348582 t phosphorylation site remapping based on mass spec table lperfetto Cdk1-cyclin B1 directly phosphorylates PTP1B at serine 386 in a kinase assay. Recombinant Plk1 phosphorylates PTP1B on serine 286 and 393 in vitro, however, it requires a priming phosphorylation by Cdk1 at serine 386 highlighting a novel co-operation between Cdk1 and Plk1 in the regulation of PTP1B.|Finally, phosphorylation on serine 286 enhanced PTP1B phosphatase activity. SIGNOR-272971 0.511 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 ChEBI HDAC2 protein Q92769 UNIPROT down-regulates activity chemical inhibition -1 17868033 t Luana Our findings suggest that hydroxamic acid-derived compounds such as TSA, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat act as potent pan-HDAC isoform inhibitors. A notable observation was the similarity between belinostat and vorinostat in the biochemical isoform assays; both compounds exhibit similar EC50 values in all but the HDAC8 assay. SIGNOR-257931 0.8 PRKCA protein P17252 UNIPROT SHOC2 protein Q9UQ13 UNIPROT down-regulates quantity by destabilization phosphorylation Thr71 VAFSVDNtIKRPNPA 29383184 t lperfetto PKCalpha/delta phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. SIGNOR-275568 0.2 BTRC protein Q9Y297 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates ubiquitination 9606 14988407 t gcesareni Here we show that beta-trcp1, a f-box protein in the scf e3 ligase complex, interacts with smad4 and induces the degradation of smad4 SIGNOR-123057 0.392 GNB1 protein P62873 UNIPROT PLCB2 protein Q00722 UNIPROT up-regulates binding 9606 1465133 t gcesareni Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc. SIGNOR-19447 0.543 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr45 PGGTLFStTPGGTRI 9606 11777913 t gcesareni Phosphorylation of 4e-bp1 is mediated by the p38/msk1 pathway in response to uvb irradiation. In the present study we demonstrated that uvb induced 4e-bp1 phosphorylation at multiple sites, thr-36, thr-45, ser-64, and thr-69, leading to dissociation of 4e-bp1 from eif-4e. Uvb-induced phosphorylation of 4e-bp1 was blocked by p38 kinase inhibitors, pd169316 and sb202190, and msk1 inhibitor, h89, but not by mitogen-activated protein kinase kinase inhibitors, pd98059 or u0126. SIGNOR-113563 0.653 PRKCD protein Q05655 UNIPROT EEF1A1 protein P68104 UNIPROT unknown phosphorylation Thr432 AVRDMRQtVAVGVIK 7890750 t lperfetto PKC delta phosphorylates eEF-1 alpha at Thr-431 SIGNOR-248902 0.337 EPX protein P11678 UNIPROT RNASE2 protein P10153 UNIPROT up-regulates activity post translational modification 9606 BTO:0000399 18694936 t miannu Human eosinophils are bone marrow-derived, non-dividing granulocytes of the innate immune system, which store the highly cationic proteins eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and eosinophil cationic protein (ECP) in secondary granules. we demonstrated that Tyr nitration of the eosinophil granule proteins is exclusively mediated by EPO, in the presence of functional NADPH oxidase and minute amounts of NOx. EPO appears to nitrate itself via an autocatalytic mechanism. SIGNOR-261704 0.486 ZMIZ1 protein Q9ULJ6 UNIPROT MYC protein P01106 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 26522984 t miannu The N-terminal domain (NTD) of Zmiz1 is important for driving Myc transcription and proliferation […] Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites. SIGNOR-263939 0.368 CAMK2A protein Q9UQM7 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2426 ASGDRPPsVSSVHSE 9606 22888005 t lperfetto We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation. SIGNOR-191773 0.2 ARHGAP31 protein Q2M1Z3 UNIPROT CDC42 protein P60953 UNIPROT down-regulates activity gtpase-activating protein 9606 BTO:0000007 32203420 t Luana We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2). SIGNOR-260490 0.665 SLC25A12 protein O75746 UNIPROT glutamic acid smallmolecule CHEBI:18237 ChEBI down-regulates quantity relocalization 9606 12084073 t miannu Aralar1 and citrin are members of the subfamily of calcium-binding mitochondrial carriers and correspond to two isoforms of the mitochondrial aspartate/glutamate carrier (AGC). These proteins are activated by Ca2+ acting on the external side of the inner mitochondrial membrane. SIGNOR-265154 0.8 WNT3 protein P56703 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131820 0.623 ceritinib chemical CHEBI:78432 ChEBI ALK protein Q9UM73 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0002058 24670165 t miannu Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies. SIGNOR-259263 0.8 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT up-regulates activity phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 BTO:0000007 SIGNOR-C3 SIGNOR-C3 19864431 t lperfetto Our data that insulin-stimulated raptor ser863 phosphorylation requires kinase-active mtorc1 and displays rapamycin sensitivity in intact cells, together with the data of wang et al. (67) that mtor phosphorylates raptor ser863 in vitro, strongly suggest that mtor itself mediates raptor ser863 phosphorylation. / strikingly, raptor ser863 phosphorylation is absolutely required for raptor ser859 and ser855 phosphorylation. These data suggest that mtorc1 activation leads to raptor multisite phosphorylation and that raptor ser863 phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation SIGNOR-188924 0.989 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity phosphorylation Ser19 SHGSSACsQPHGSVT 9606 BTO:0000007 10973490 t lperfetto Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to ir SIGNOR-81391 0.832 Shikonin chemical CHEBI:81068 ChEBI PKM protein P14618 UNIPROT down-regulates activity chemical inhibition 9606 21516121 t lperfetto Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2. |Shikonin and alkannin are potent inhibitors of recombinant human PKM2|Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x(L) and A549) that primarily express PKM2. SIGNOR-262008 0.8 TWIST1 protein Q15672 UNIPROT RAP1A protein P62834 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255533 0.2 MAP2K4 protein P45985 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 BTO:0000149;BTO:0001129 22730327 t gcesareni Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1) SIGNOR-197998 0.721 NR3C1 protein P04150 UNIPROT TDO2 protein P48775 UNIPROT down-regulates quantity by repression transcriptional regulation 16272140 t lperfetto Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development. SIGNOR-268995 0.342 H2AC4 protein P04908 UNIPROT Nucleosome_H3.1t variant complex SIGNOR-C325 SIGNOR form complex binding -1 20498094 t miannu A histone H3 variant, H3T, is highly expressed in the testis, suggesting that it may play an important role in the chromatin reorganization required for meiosis and/or spermatogenesis. In the present study, we found that the nucleosome containing human H3T is significantly unstable both in vitro and in vivo, as compared to the conventional nucleosome containing H3.1. SIGNOR-263724 0.2 UTS2R protein Q9UKP6 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256779 0.251 ABCA7 protein Q8IZY2 UNIPROT APOA1 protein P02647 UNIPROT up-regulates activity binding 9606 BTO:0000007 12917409 t miannu ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux. HEK293 cells overexpressing ABCA7 showed specific binding and cross-linking of lipid-poor apoA-I. ABCA7 expression increased cellular phosphatidylcholine and sphingomyelin efflux to apoA-I in a manner similar to ABCA1 but had no effect on cholesterol efflux. SIGNOR-265178 0.458 ERBB4 protein Q15303 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 16729043 t gcesareni Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength. SIGNOR-146876 0.826 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI EGFR protein P00533 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189942 0.8 SRC protein P12931 UNIPROT RHOA protein P61586 UNIPROT down-regulates activity phosphorylation Tyr34 KDQFPEVyVPTVFEN 9606 BTO:0000567 23027962 t lperfetto When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity SIGNOR-271702 0.661 KATNAL2 protein Q8IYT4 UNIPROT Acrosome_assembly phenotype SIGNOR-PH156 SIGNOR up-regulates 9606 28347630 f miannu The majority of elongated spermatids also displayed a detached acrosome (Fig 5B), indicating that KATNAL2, or KATNAL2-regulated structures, have a role in the deposition of ‘adhesive components’ into the acroplaxome. The acroplaxome is an electron dense structure that overlies the anterior pole of the sperm nucleus and is thought to play a pivotal role in acrosome formation and attachment. These data strongly suggest that KATNAL2 is required for multiple aspects of male haploid germ cell development, and depending on the cellular context, KATNAL2 may act in either a KATNB1-dependent (manchette function) and KATNB1-independent manner (acrosome and axoneme development). SIGNOR-267179 0.7 PJA2 protein O43164 UNIPROT PRKAR2B protein P31323 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 21423175 t miannu Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits SIGNOR-271858 0.2 SOAT1 protein P35610 UNIPROT cholesteryl ester smallmolecule CHEBI:17002 ChEBI down-regulates quantity chemical modification 9606 31848472 t miannu Excess cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT; also known as SOAT) to cholesteryl esters SIGNOR-265160 0.8 (2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide chemical CHEBI:94760 ChEBI AR protein P10275 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-189623 0.8 PIP3 smallmolecule CHEBI:16618 ChEBI mTORC2 complex SIGNOR-C2 SIGNOR up-regulates activity chemical activation 9606 26293922 t gcesareni PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation SIGNOR-252430 0.8 risperidone chemical CHEBI:8871 ChEBI HTR2A protein P28223 UNIPROT down-regulates activity chemical inhibition 10090 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258529 0.8 CSNK1A1 protein P48729 UNIPROT PHLPP1 protein O60346 UNIPROT down-regulates quantity by destabilization phosphorylation Thr1363 HVQSVLLtPQDEFFI 9606 BTO:0002181 19797085 t miannu We show that the beta-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3beta (GSK-3beta), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3beta activity.  SIGNOR-276262 0.311 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT up-regulates activity phosphorylation Tyr753 ERDINSLyDVSRMYV 9606 BTO:0000776 11507089 t lperfetto These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as btk-dependent phosphorylation sites in vitro, coordinately contribute to bcr-induced activation of plcgamma2. SIGNOR-109754 0.773 MAP2 protein P11137 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates quantity by stabilization binding 9606 BTO:0000938 10704996 t lperfetto MAP2 interacts with MTs through its tubulin-binding domain which mainly associates with the acidic region of the C-terminal region of tubulin|no neurite growth is observed when MAP2 expression is suppressed in neuronal cell cultures after treatment with specific antisense oligonucleotides SIGNOR-264837 0.7 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates quantity by destabilization phosphorylation Ser927 DSDSVCDsGVETSFR 9606 BTO:0000459 SIGNOR-C13 10469655 t lperfetto Ikkbeta phosphorylates p105 resulting in its degradation, which releases tpl2 resulting in activation of the pro-proliferative map kinase- pathway. SIGNOR-70469 0.85 GSK3B protein P49841 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates quantity by stabilization phosphorylation Ser903 KTTSQAHsLPLSPAS 10090 BTO:0000452 12871932 t GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α. SIGNOR-251251 0.393 CAK complex complex SIGNOR-C456 SIGNOR TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 9315650 t llicata The cdk7-cych-p36 complex of transcription factor iih phosphorylates p53, enhancing its sequence-specific dna binding activity in vitro.  serines 371, 376, 378, and 392 may be the potential sites for this kinase. SIGNOR-269325 0.442 iloprost chemical CHEBI:63916 ChEBI PTGIR protein P43119 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257574 0.8 DAPK1 protein P53355 UNIPROT DAPK1 protein P53355 UNIPROT down-regulates activity phosphorylation Ser308 ARKKWKQsVRLISLC 9606 BTO:0000007 11579085 t lperfetto The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism.These results are consistent with a molecular model in which phosphorylation on ser(308) stabilizes a locked conformation of the cam-regulatory domain within the catalytic cleft and simultaneously also interferes with cam binding. SIGNOR-110807 0.2 RNF111 protein Q6ZNA4 UNIPROT SKIL protein P12757 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 23530057 t miannu Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4. SIGNOR-272885 0.717 MSTN protein O14793 UNIPROT ACVR2B protein Q13705 UNIPROT up-regulates activity binding 10090 11459935 t gcesareni The purified C-terminal myostatin dimer was capable of binding the activin type II receptors, Act RIIB and, to a lesser extent, Act RIIA SIGNOR-235153 0.655 MSL acetyltransferase complex SIGNOR-C344 SIGNOR H2BC18 protein Q5QNW6 UNIPROT down-regulates activity monoubiquitination Lys35 KKRKRSRkESYSVYV 9606 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271987 0.2 RFX3 protein P48380 UNIPROT Cilium_assembly phenotype SIGNOR-PH64 SIGNOR up-regulates 10090 32725242 f miannu RFX2 and RFX3 are key regulators of ependymal cell ciliogenesis in vitro and in vivo. We show here that RFX2 and RFX3 have both redundant and specific functions in the biogenesis of motile cilia on mouse ependymal cells, whereas RFX1 does not seem to play a key regulatory role in this process. SIGNOR-266927 0.7 ID1 protein P41134 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates activity binding 10090 BTO:0000222 8380166 t 2 miannu Id1 and Id2 interacted strongly with MyoD and Myf-5.Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo. SIGNOR-240265 0.486 R2SP co-chaperone complex SIGNOR-C517 SIGNOR Chaperone-mediated protein folding phenotype SIGNOR-PH120 SIGNOR up-regulates 9606 29844425 f miannu Systematic interaction analyses show that one RPAP3-like protein, SPAG1, binds PIH1D2 and RUVBL1/2 to form an R2TP-like complex termed R2SP.  This co-chaperone is enriched in testis and among 68 of the potential clients identified, some are expressed in testis and others are ubiquitous. One substrate is liprin-α2, which organizes large signaling complexes. SIGNOR-270941 0.7 PIK3R1 protein P27986 UNIPROT PIK3CB protein P42338 UNIPROT up-regulates activity binding 9534 BTO:0004055 14665640 t lperfetto Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival SIGNOR-242640 0.848 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser645 NLSTNADsQSSSDFE 9606 16600297 t lperfetto Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin SIGNOR-145841 0.692 pimozide chemical CHEBI:8212 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9760039 t miannu Marked differences were observed between the actions of ‘antagonists’ (Table 2; Fig. 2D ). methiothepin and butaclamol, as well asspiperone, exhibited negative efficacy by concentration-dependently inhibiting S GTPgS binding below basal levels, indicating that they act as inverse agonists in this system.WAY 100,135, yUH 301 and the 5-HTreceptor1A and b-adrenergic receptor antagonist ,ytertatolol, acted as ‘neutral’ antagonists, exhibiting antagonist activity without any detectable agonist or inverse agonist effects. SIGNOR-258841 0.8 TAB1 protein Q15750 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates activity binding 9606 8638164 t lperfetto The yeast two-hybrid system has now revealed two human proteins, termed tab1 and tab2 (for tak1 binding protein), that interact with tak1. Overproduction of tab1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by tgf-beta, and increased the kinase activity of tak1. Tab1 activates the kinase activity of tak1 by directly binding to its catalytic domain. Tab1 overexpression increase the kinase activity of tak1 in mammalian cells. SIGNOR-41941 0.928 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT down-regulates quantity by destabilization cleavage Ala20 VVGTAWTaDSGEGDF -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. |Fibrinogen was subjected to MMP-cleavage, and the resulting fragments were isolated. The amino acid sequences were determined by automated Edman degradation.|MMP-12 20ADSGEGD a-chain| 540FVSETESRG a-chain|433LVTSKGDK a-chain SIGNOR-263622 0.2 RFWD3 protein Q6PCD5 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates activity binding 9606 BTO:0002552 20173098 t miannu RFWD3 is a positive regulator of p53 abundance and regulates the G1 checkpoint in response to IR. We found that an E3 ubiquitin ligase RFWD3 (RNF201/FLJ10520) forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and is required to stabilize p53 in the late response to DNA damage.  SIGNOR-271945 0.369 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI BRAF protein P15056 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258097 0.8 PAMPs stimulus SIGNOR-ST11 SIGNOR AP-3/clathrin vescicle complex SIGNOR-C250 SIGNOR up-regulates 9606 25720354 f scontino APCs have several cell surface receptors that facilitate antigen entry into antigen-processing compartments through clathrin-mediated endocytosis. SIGNOR-267859 0.7 MYOD1 protein P15172 UNIPROT MYOD/E2-2 complex SIGNOR-C129 SIGNOR form complex binding 9606 16847330 t 2 miannu The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. SIGNOR-241100 0.694 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT up-regulates activity phosphorylation Ser91 ASFHAYDsHTNTYYL 9606 BTO:0000007 21321328 t miannu We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. SIGNOR-263130 0.589 SCAND1 protein P57086 UNIPROT MZF1 protein P28698 UNIPROT up-regulates activity binding -1 10777584 t miannu Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function SIGNOR-221561 0.369 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser236 AKRRRLSsLRASTSK 9606 17360704 t gcesareni We demonstrate that while ribosomal s6 kinase 1 (s6k1) phosphorylates rps6 at all sites, rsk exclusively phosphorylates rps6 at ser(235/236) in vitro and in vivo using an mtor-independent mechanism. SIGNOR-252812 0.2 NCBP1 protein Q09161 UNIPROT Cap-binding complex complex SIGNOR-C440 SIGNOR form complex binding 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268359 0.969 LAMTOR5 protein O43504 UNIPROT LAMTOR complex SIGNOR-C26 SIGNOR form complex binding 9606 20381137 t lperfetto Mammals express four rag proteinsRaga, ragb, ragc, and ragdthat form heterodimers consisting of raga or ragb with ragc or ragd. Raga and ragb, like ragc and ragd, are highly similar to each other and are functionally redundant SIGNOR-164781 0.896 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 18177723 f miannu Altogether, these data demonstrate that IL-6 loss results in deficient STAT3 signaling in activated satellite cells, leading to their reduced proliferation and myogenic progression, and highlight the major role played by the IL-6/STAT3 axis in controlling these processes during compensatory hypertrophy. SIGNOR-255632 0.7 PRKAA1 protein Q13131 UNIPROT MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 11724780 t gcesareni Ampk has also been suggested to phosphorylate the glucose-sensitive transcription factor chrebpthe dna binding activity, as assayed in a gel-shift assay of the truncated chrebp, was gradually inactivated with time by treatment with ampk SIGNOR-112289 0.437 KCNN4 protein O15554 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI up-regulates quantity relocalization 10116 BTO:0000078 25274816 t miannu KCa3.1 activation is expected to maintain a negative membrane potential, which will increase Ca2+ influx through nonvoltage gated Ca2+-release-activated Ca2+ (CRAC) channels that are prevalent in rat microglia SIGNOR-276856 0.8 clomipramine chemical CHEBI:47780 ChEBI SLC6A4 protein P31645 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000007 9537821 t miannu Among the antidepressants that we tested, paroxetine, which is a serotonin selective re-uptake inhibitor based on animal data, was the most potent for the human serotonin transporter with a KD=0.13±0.01 nM. Some tricyclic antidepressants (clomipramine, imipramine and amitriptyline), as well as some other antidepressants (sertraline, fluoxetine, citalopram and fluvoxamine) and some of their metabolites (norfluoxetine, desmethylsertraline and desmethylcitalopram) were also very potent at the human serotonin transporter. SIGNOR-258876 0.8 CENPQ protein Q7L2Z9 UNIPROT CCAN complex complex SIGNOR-C365 SIGNOR form complex binding 9606 BTO:0000567 18007590 t lperfetto CENP-A NAC/CAD components have been subdivided into either NAC proteins (nucleosome-associated complex; CENP-C, CENP-H, CENP-50CENP−U, CENP-M, CENP-T and Chl4RCENP−N) or CAD proteins (CENP-A Distal; CENP-I, Mcm21RCENP−O, Fta1RCENP−L, Sim4RCENP−K, CENP-P, CENP-Q, CENP-R and CENP-S). SIGNOR-265207 0.782 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT up-regulates activity phosphorylation Tyr280 PKPSNPIyNEPDEPI 9606 BTO:0000782 18541536 t miannu Here we mapped Lck phosphorylation and interaction sites on TSAd and evaluated their functional importance. The three C-terminal TSAd tyrosines Tyr(280), Tyr(290), and Tyr(305) were phosphorylated by Lck and functioned as docking sites for the Lck Src homology 2 (SH2) domain. Lck binds to TSAd prolines and phosphorylates and interacts with the three C-terminal TSAd tyrosines. We propose that through multivalent interactions with Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition. SIGNOR-262888 0.59 PIP3 smallmolecule CHEBI:16618 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates activity relocalization 9606 23119004 t lperfetto Binding of IGF to IGF-1R activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology ph) domain, including AKT and PDK1. SIGNOR-236509 0.8 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates relocalization 9606 14517246 t gcesareni Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin. SIGNOR-103360 0.703 SRC protein P12931 UNIPROT CDH5 protein P33151 UNIPROT up-regulates phosphorylation Tyr685 LDARPSLyAQVQKPP 9606 BTO:0000975 16909109 t llicata In vitro src assay, the ve-cadherin cytoplasmic domain is directly phosphorylated by purified src as well as the tyrosine residue 685 (tyr)685-containing peptide finally, we found that in a vegf-induced wound-healing assay, cadherin adhesive activity was impaired by src kinase inhibitors.RPSLY(685)aqvq. SIGNOR-148818 0.578 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m). SIGNOR-105500 0.362 GOT1 protein P17174 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI down-regulates quantity chemical modification 9606 26003525 t miannu Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and √鬱-ketoglutarate into oxaloacetate and L-glutamate and plays a key role in carbon and nitrogen metabolism in all organisms. In human tissues, GOTs are pyridoxal 5'-phosphate-dependent (PLP) enzymes which exist in cytoplasm and mitochondrial forms, GOT1 and GOT2, respectively. GOT1 expression correlates with the growth of several tumors because cancer cells can utilize the amino acid glutamine to fuel anabolic processes, and therefore, GOT1 represents a new therapeutic target in cancer. SIGNOR-268064 0.8 PRKCA protein P17252 UNIPROT RORA protein P35398 UNIPROT unknown phosphorylation Ser35 ETPLNQEsARKSEPP 9606 20122401 t llicata Wnt5a/pkcalpha-dependent phosphorylation on serine residue 35 of roralpha is crucial to link roralpha to wnt/beta-catenin signaling, which exerts inhibitory function of the expression of wnt/beta-catenin target genes. SIGNOR-163702 0.253 MAP3K4 protein Q9Y6R4 UNIPROT MAP2K3 protein P46734 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000298 9305639 t lperfetto These results, therefore, suggest that mtk1 directly phosphorylates and activates mkk3, mkk6 and sek1. SIGNOR-50891 0.631 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 12356758 t lperfetto Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase SIGNOR-93989 0.265 glycine smallmolecule CHEBI:15428 ChEBI (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI up-regulates quantity precursor of 9606 16051266 t lperfetto The glycine cleavage system is a mitochondrial multienzyme system composed of four proteins termed P, H, T and L-protein, and catalyzes the reversible oxidation of glycine yielding carbon dioxide, ammonia, 5,10-methylenetetrahydrofolate (5,10-CH2-H4folate), and reduced pyridine nucleotide. SIGNOR-268237 0.8 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates binding 9606 12000790 t lperfetto We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms. SIGNOR-227973 0.526 MECOM protein Q03112 UNIPROT RUNX1 protein Q01196 UNIPROT down-regulates activity binding 10090 17575132 t irozzo The results that we present here support this model and show that EVI1 interacts with and inhibits RUNX1. As for GATA1, EVI1 seems to repress RUNX1 function by interacting specifically with its DNA-binding domain Runt, leading to destabilization and dissolution of the DNA-RUNX1 complex. SIGNOR-255716 0.515 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDK9 protein P50750 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11689688 t miannu Here we report that CDK9 is ubiquitinated and degraded by the proteasome whereas cyclin T1 is stable. SCF(SKP2) was recruited to CDK9/cyclin T1 via cyclin T1 in an interaction requiring its PEST domain. CDK9 ubiquitination was modulated by cyclin T1 and p45(SKP2).  SIGNOR-272666 0.353 NCBP1 protein Q09161 UNIPROT messenger RNA smallmolecule CHEBI:33699 ChEBI up-regulates activity relocalization 9606 26382858 t lperfetto The cap-binding complex (CBC), consisting of the nuclear cap-binding protein (NCBP) 2 and its adaptor NCBP1, is believed to bind all capped RNA and to be necessary for its processing and intracellular localization. SIGNOR-268363 0.8 LEPR protein P48357 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity binding 9606 BTO:0001282 18718905 t miannu Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. SIGNOR-263491 0.769 PTPN9 protein P43378 UNIPROT GHR protein P10912 UNIPROT down-regulates activity dephosphorylation 10029 BTO:0000246 12907755 t Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR SIGNOR-248505 0.317 RNA Polymerase III complex SIGNOR-C389 SIGNOR tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI up-regulates quantity chemical modification 9606 27911719 t lperfetto RNAPIII is specialized for transcription of short, abundant nonprotein-coding RNA transcripts. In addition to all tRNAs, RNAPIII transcribes the 5S rRNA and other essential RNAs, including the U6 small nuclear RNA (snRNA), the snR52 small nucleolar RNA and the RNA components of the signal recognition particle (SRP1) and RNase P (RPR1) SIGNOR-269499 0.8 CTNND2 protein Q9UQB3 UNIPROT CDH3 protein P22223 UNIPROT up-regulates quantity by stabilization binding 9606 BTO:0001109 14610055 t miannu To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member. SIGNOR-252130 0.296 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR UBTF protein P17480 UNIPROT up-regulates phosphorylation Ser389 INKKQATsPASKKPA 9606 11698641 t lperfetto Phosphorylation of ubf at serine 388 is required for interaction with rna polymerase i and activation of rdna transcription. After g(1) progression ubf is phosphorylated at serine 388 by cdk2/cyclin e and cdk2/cyclin a. Conversion of serine 388 to glycine abolishes ubf activity SIGNOR-216678 0.376 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR MOB1B protein Q7L9L4 UNIPROT up-regulates phosphorylation 9606 21808241 t The regulation of MOB1 and LATS1/2 by MST1/2 may be organ and disease-specific. gcesareni Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction. SIGNOR-270221 0.2 TLRs proteinfamily SIGNOR-PF20 SIGNOR MYD88 protein Q99836 UNIPROT up-regulates activity binding 10090 22664090 t miannu To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group SIGNOR-260151 0.2 MN1 protein Q10571 UNIPROT EP300 protein Q09472 UNIPROT up-regulates activity binding -1 12569362 t irozzo Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300. SIGNOR-256020 0.346 PRKG1 protein Q13976 UNIPROT CREB1 protein P16220 UNIPROT unknown phosphorylation Ser119 EILSRRPsYRKILND -1 11175347 t lperfetto G-kinase phosphorylated GST-CREB, albeit less efficiently than A-kinase, but GST was not phosphorylated by either kinase (Figure 5a). GST-CREB purified from bacteria was similarly phosphorylated by G-kinase, whereas GST-CREB containing a serine 133 to alanine mutation was not (Figure 5b). These results demonstrate that G-kinase can directly phosphorylate CREB on serine 133. SIGNOR-249076 0.643 chelerythrine chemical CHEBI:78373 ChEBI MAPK8 protein P45983 UNIPROT up-regulates chemical activation 9606 Other t CellSignaling gcesareni SIGNOR-190964 0.8 PTPN2 protein P17706 UNIPROT STAT1 protein P42224 UNIPROT down-regulates dephosphorylation Tyr701 DGPKGTGyIKTELIS 9606 12138178 t miannu Stat1 becomes tyrosine phosphorylated and translocates into the nucleus, where it binds to dna to activate transcription. The activity of stat1 is dependent on tyrosine phosphorylation, and its inactivation in the nucleus is accomplished by a previously unknown protein tyrosine phosphatase (ptp). We have now purified a stat1 ptp activity from hela cell nuclear extract and identified it as tc45, the nuclear isoform of the t-cell ptp (tc-ptp). Tc45 can dephosphorylate stat1 both in vitro and in vivo. SIGNOR-90814 0.728 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates activity phosphorylation Thr198 PGLRRRQt 9606 12042314 t lperfetto Because Thr198-phosphorylated p27Kip1 was localized only in the cytoplasm, Akt might promote 14-3-3 binding to p27Kip1 by phosphorylation at Thr198, allowing its cytoplasmic localization and degradation. SIGNOR-244194 0.2 CSNK2A1 protein P68400 UNIPROT PIP4K2A protein P48426 UNIPROT up-regulates phosphorylation Ser304 DGEEEGEsDGTHPVG 9606 BTO:0000567 10508590 t lperfetto Here, we demonstrate the partial purification of a protein kinase that phosphorylates the type iialpha pip kinase at a single site unique to that isoform - ser304. This kinase was identified as protein kinase ck2 (formerly casein kinase 2). Mutation of ser304 to aspartate to mimic its phosphorylation had no effect on pip kinase activity, but promoted both redistribution of the green fluorescent protein (gfp)-tagged enzyme in hela cells from the cytosol to the plasma membrane, and membrane ruffling. SIGNOR-71014 0.426 CREB5 protein Q02930 UNIPROT LGALS3BP protein Q08380 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0002812 21132541 f miannu Our result verified CREB5 biological regulation module in the upstream of frontal cortex of HIVE-control patients (MAPKAPK3 activation; DGKG, LY96, TNFRSF11B inhibition) and downstream (ATP6V0E1, CFB, DGKG, MX1, TGFBR3 activation; LGALS3BP, RASGRP3, RDX, STAT1 inhibition), SIGNOR-253805 0.2 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Ser175 FGLARAFsLAKNSQP 9606 21533037 t gcesareni Protein phosphatase-1 activates cdk9 by dephosphorylating ser175 SIGNOR-173450 0.2 MAPK9 protein P45984 UNIPROT NFATC3 protein Q12968 UNIPROT down-regulates phosphorylation Ser163 SYRESSLsPSPASSI 9606 BTO:0000782 9374467 t lperfetto Ser163 and ser165 represent the major sites of in vitro phosphorylation of nfat4 by jnk. / the negative regulation of nfat4 nuclear accumulation caused by jnk provides a mechanism for cell type?specific Responses to extracellular stimulation SIGNOR-53364 0.703 MMP9 protein P14780 UNIPROT A2M protein P01023 UNIPROT down-regulates quantity by destabilization cleavage Arg719 VMGRGHArLVHVEEP -1 9344465 t lperfetto The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP. SIGNOR-261740 0.479 CASP3 protein P42574 UNIPROT NFKBIA protein P25963 UNIPROT up-regulates quantity by stabilization cleavage -1 9367996 t lperfetto The cell-death protease cpp32 (caspase-3) in vitro specifically cleaved chicken and human ikappab-alpha at a conserved asp-ser sequence.Therefore, cleavage of I_B-_ by a CPP32-like protease could create what is sometimes called a super-repressor form of I_B-_ (20). That is, cleavage by CPP32 would block the ability of I_B-_ to undergo signal-induced degradation by removing the sites of signal-induced ubiquitination and by likely disrupting the ability of I_B-_ to become phosphorylated at critical Ser residues. SIGNOR-51936 0.429 CDK1 protein P06493 UNIPROT PLK1 protein P53350 UNIPROT up-regulates activity binding 9606 26259146 t miannu Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition. SIGNOR-273589 0.6 EXT1 protein Q16394 UNIPROT WNT8A protein Q9H1J5 UNIPROT up-regulates activity 9606 24860992 f miannu Decreased Ext1 was shown to reduce the level of Wnt8 and BMP4 signaling and disrupt ventral-specific gene expression. Ext1 function is required for maintenance of normal levels of BMP and wnt, as well as their target genes. In addition, expression of xbra and the establishment of ventral mesoderm depend upon normal levels of Ext1. These findings suggest that ext1-dependent synthesis of HSPG is critical for wnt and BMP signaling, mesodermal identity, and ventral pattern. SIGNOR-264019 0.2 PRKACA protein P17612 UNIPROT CSNK1A1L protein Q8N752 UNIPROT up-regulates phosphorylation 9606 16481469 t lperfetto Mutation of either the three pka sites or pka-primed cki sites prevents phosphorylation of ci by cki in vitro and blocks ci cleavage in embryos SIGNOR-144557 0.381 TWIST2 protein Q8WVJ9 UNIPROT CTPS1 protein P17812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004828 19051271 f miannu we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion SIGNOR-255500 0.2 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1861 TPTSPKYsPTSPKYS 9606 24385927 t lperfetto Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself SIGNOR-203560 0.773 CENPE protein Q02224 UNIPROT BUB1B protein O60566 UNIPROT up-regulates activity binding 10090 BTO:0000452 12925705 t lperfetto Without CENP-E, diminished levels of BubR1 are recruited to kinetochores and BubR1 kinase activity remains at basal levels. CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro. Thus, CENP-E is required for enhancing recruitment of its binding partner BubR1 to each unattached kinetochore and for stimulating BubR1 kinase activity, implicating it as an essential amplifier of a basal mitotic checkpoint signal. SIGNOR-252043 0.842 SMURF2 protein Q9HAU4 UNIPROT SMAD2/SMURF2 complex SIGNOR-C11 SIGNOR form complex binding 9606 11389444 t gcesareni We show that in the presence of tgf-beta, smad2 interacts through its proline-rich ppxy motif with the tryptophan-rich ww domains of smurf2, a recently identified e3 ubiquitin ligases. SIGNOR-108496 0.773 CALM1 protein P0DP23 UNIPROT PPP3CA protein Q08209 UNIPROT up-regulates binding 9606 11796223 t gcesareni Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain. SIGNOR-114098 0.752 NOG protein Q13253 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates activity binding 9606 BTO:0001593 BTO:0000140 SIGNOR-C29 22298955 t Create trimers (2 typeII and 1 typeI) with serine/threonine kinase function lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors.Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors (pmid 12478285) SIGNOR-195612 0.578 chlorpromazine chemical CHEBI:3647 ChEBI DRD3 protein P35462 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 1975644 t miannu Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. Table1. pharmacology of D2 and D3 receptors expressed in CHO cells. SIGNOR-258371 0.8 STAT5A protein P42229 UNIPROT PIM1 protein P11309 UNIPROT up-regulates quantity by expression transcriptional regulation 16146838 t lperfetto The results of 2 microarray experiments demonstrated that the aberrant activation of STAT proteins by Flt3-ITDs resulted in the up-regulation of several STAT5-responsive genes, such as Pim-1, Pim-2, and members of the SOCS (suppressor of cytokine signaling) protein family. These results are particularly interesting because recent data point to an important role of Pim kinases in the antiapoptosis of hematopoietic cells. SIGNOR-249621 0.382 LYN protein P07948 UNIPROT WAS protein P42768 UNIPROT up-regulates activity phosphorylation Tyr291 AETSKLIyDFIEDQG 9606 BTO:0000801 17890224 t done miannu We demonstrated that WASP is phosphorylated on tyrosine 291 in macrophages, and the WASP phosphorylation is important for the phagocytic cup formation. In addition, we showed that WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation.  SIGNOR-273959 0.383 YIF1B protein Q5BJH7 UNIPROT HTR1A protein P08908 UNIPROT up-regulates activity relocalization 10116 BTO:0000938 18685031 t nucleus lperfetto Together, our results provide strong evidence that Yif1B is a member of the ER/Golgi trafficking machinery, which plays a key role in specific targeting of 5-HT(1A)R to the neuronal dendrites. This finding opens up new pathways for the study of 5-HT(1A)R regulation by partner proteins and for the development of novel antidepressant drugs.|We confirmed 5-HT(1A)R-Yif1B interaction by glutathione S-transferase pull-down experiments using rat brain extracts and transfected cell lines. SIGNOR-268299 0.406 TSLP protein Q969D9 UNIPROT CRLF2 protein Q9HC73 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 11418668 t gcesareni Human tslp is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human tslp receptor and the il-7r alpha-chain. SIGNOR-108920 0.923 TBP protein P20226 UNIPROT TFIID complex SIGNOR-C343 SIGNOR form complex binding 9606 27096372 t miannu The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1-13), which specifically interact with a variety of core promoter DNA sequences. SIGNOR-263933 0.891 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 7736585 t gcesareni D-type cyclins (cyclin d1, d2, or d3) and their associated cyclin-dependent kinases (cdk4, cdk6) connect signals from cytokines to the cell cycle machinery, and they propel cells through the g1 restriction point and into the s phase when activated by cyclin d1, cdk4 is able to phosphorylate prb, SIGNOR-32295 0.964 SMARCA4 protein P51532 UNIPROT Embryonic stem cell-specific SWI/SNF complex SIGNOR-C484 SIGNOR form complex binding 10090 BTO:0001086 19279220 t miannu An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency SIGNOR-270726 0.759 PLK3 protein Q9H4B4 UNIPROT SNCB protein Q16143 UNIPROT down-regulates activity phosphorylation Ser118 LMEPEGEsYEDPPQE 9606 19889641 t lperfetto Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. SIGNOR-189057 0.386 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser670 CGKRFTRsDELQRHK 9606 BTO:0000887;BTO:0001260 18258854 t llicata Here we have used a variety of approaches to identify 3 amino acids (thr668, ser670, and thr681) in the zinc finger domain of sp1 that are modified by pkc-zeta angiotensin ii, which activates pkc-? Phosphorylation (at thr410) via the angiotensin ii type 1 receptor, stimulates sp1 phosphorylation and increases sp1 binding to the platelet-derived growth factor-d promoter. SIGNOR-160766 0.492 IL22RA1 protein Q8N6P7 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 12087100 t gcesareni Il-22 activates jak1 and tyk2 SIGNOR-90165 0.531 Gbeta proteinfamily SIGNOR-PF4 SIGNOR RPS3 protein P23396 UNIPROT unknown phosphorylation 9606 15950189 t inferred from 70% family members llicata Erk phosphorylates threonine 42 residue of ribosomal protein s3. SIGNOR-270019 0.2 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MCM4 protein P33991 UNIPROT down-regulates phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 12714602 t lperfetto We reported that the dna helicase activity of the human and mouse mcm4-6-7 complex, a sub-complex of the mcm2-7 heterohexamer, is inhibited by the phosphorylation by cdk2-cyclin a we identified six sites, including ser-32, ser-53, and thr-109, in the amino-terminal region of mouse mcm4 that are required for the phosphorylation with cdk2-cyclin a. SIGNOR-217352 0.692 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4B protein P23588 UNIPROT up-regulates activity stabilization 9606 17581632 t lperfetto EIF3 plays many functions in initiation complex formation. It interacts with eIF1, eIF5, eIF4B and eIF4G, and the direct interaction between eIF3 and eIF4G may serve as a bridge between the 40S ribosomal subunit and eIF4F-bound mRNA (Hershey and Merrick, 2000). eIF3 stabilizes the binding of the eIF2-GTP-Met-tRNAiMet ternary complex to the 40S subunit SIGNOR-269158 0.63 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT down-regulates quantity by destabilization polyubiquitination Lys74 DTGRILSkLHTVQPK -1 19240029 t miannu S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP. SIGNOR-272742 0.471 DDX41 protein Q9UJV9 UNIPROT STING1 protein Q86WV6 UNIPROT up-regulates activity binding 10090 BTO:0002572 25704810 t miannu The kinase and SH3/SH2 interaction domains of BTK bind, respectively, the DEAD-box domain of DDX41 and transmembrane region of STING. BTK phosphorylates DDX41, and its kinase activities are critical for STING-mediated IFN-β production. We show that Tyr364 and Tyr414 of DDX41 are critical for its recognition of AT-rich DNA and binding to STING, and tandem mass spectrometry identifies Tyr414 as the BTK phosphorylation site. SIGNOR-266403 0.2 pictrelisib chemical CHEBI:65326 ChEBI PIK3CA protein P42336 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258113 0.8 mTORC1 complex SIGNOR-C3 SIGNOR RPS6KB1 protein P23443 UNIPROT up-regulates activity phosphorylation Thr390 DSKFTRQtPVDSPDD 9606 11914378 t Thr229 phosphorylation requires prior phosphorylation of the Ser/Thr-Pro sites in the autoinhibitory domain and Thr389 in the linker domain,[…] Moreover, in vitro mTOR directly phosphorylates Ser371, and this event modulates Thr389phosphorylation by mTOR, compatible with earlier in vivo findings. SIGNOR-255840 0.752 MMP3 protein P08254 UNIPROT ECM_disassembly phenotype SIGNOR-PH80 SIGNOR up-regulates 17318226 f lperfetto Historically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. SIGNOR-272373 0.7 JAK1 protein P23458 UNIPROT IFNGR1 protein P15260 UNIPROT up-regulates phosphorylation Tyr457 KAPTSFGyDKPHVLV 9606 7615558 t lperfetto Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor. SIGNOR-29866 0.696 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR AMP smallmolecule CHEBI:456215 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270424 0.8 belinostat chemical CHEBI:61076 ChEBI HDAC9 protein Q9UKV0 UNIPROT down-regulates activity chemical inhibition -1 20139990 t Luana Collaboratively, we synthesized and assembled a panel of structurally-diverse small-molecule HDACi 1, 2, 7-20 that comprise most of the relevant literature-reported tool compounds and pharmaceutically developed clinical candidates (Supplementary Fig 3). We next conducted a high-throughput, precise profiling of HDACi potency against all Class I and II enzymes, in a miniaturized dose-ranging format (Supplementary Table 1). SIGNOR-257952 0.8 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT up-regulates phosphorylation Thr1969 DKASLTRtLQHRIAL 9606 BTO:0000938 19824698 t lperfetto We identified ser1403, thr1404, thr1410, thr1491 located within the roc domain, as well as thr1967 and thr1969 in the kinase domain, as the autophosphorylation sites. Substitution of thr1967, an autophosphorylation site located within the kinase domain, to ala caused a significant decrease in the kinase activity SIGNOR-188421 0.2 MAX protein P61244 UNIPROT MXD4 protein Q14582 UNIPROT up-regulates activity binding 9606 7954804 t 2 miannu the role MAX plays in transcription is thought to be primarily as a cofactor for DNA binding. In this capacity, however, it appears to be essential for most, if not all, the known biological activities of MYC. MAX also functions as a cofactor for DNA binding for a group of bHLHZip proteins related to MYC, including MNT, MXD1-4 (formerly Mad1, Mxi1, Mad3 and Mad4), and MGA. Like MYC, these proteins do not homodimerize and appear to be incapable of binding DNA on their own, but when bound to MAX, they recognize E-box sequences. SIGNOR-240224 0.491 HK2 protein P52789 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates activity 10090 16892090 f HK II via its mitochondrial location also suppresses the death of cancer cells, thus increasing their possibility for metastasis and the ultimate death of the human host SIGNOR-259979 0.7 PPP2CB protein P62714 UNIPROT CHEK2 protein O96017 UNIPROT up-regulates activity dephosphorylation Thr68 SSLETVStQELYSIP 9606 16596250 t Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation. SIGNOR-248582 0.312 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1474 GSSNGHVyEKLSSIE 11483655 t lperfetto We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src and Fyn and compared this to phosphorylation by tyrosine kinases associated with the postsynaptic density (PSD)|Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases SIGNOR-249338 0.763 PPP1CA protein P62136 UNIPROT CASP9 protein P55211 UNIPROT up-regulates dephosphorylation Thr125 PEVLRPEtPRPVDIG 9606 22311969 t gcesareni Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis. SIGNOR-195992 0.2 PRKACA protein P17612 UNIPROT PRKAR2B protein P31323 UNIPROT up-regulates activity phosphorylation Ser114 NRFTRRAsVCAEAYN 9606 15187164 t gcesareni Serine 114 phosphorylation is required for both nuclear localization and down-regulation of il-2 production by riibeta. SIGNOR-125545 0.878 CAD protein P27708 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI up-regulates quantity chemical modification 9606 28552578 t miannu CAD is a 243 kDa polypeptide formed by the fusion of four enzymatic domains that initiate the de novo biosynthesis of pyrimidine nucleotides . The first two domains, glutaminase (GLN) and carbamoyl phosphate synthetase (CPS-II), initiate the pathway, catalyzing the formation of carbamoyl phosphate (CP) from bicarbonate, glutamine, and two ATP molecules. Next, the labile CP is partially channeled to the C-terminal aspartate transcarbamoylase (ATC) domain where it reacts with aspartate to form carbamoyl aspartate. Then, carbamoyl aspartate is condensated to dihydroorotate, the cyclic precursor of the pyrimidine ring, by the dihydroorotase (DHO), a Zn metalloenzyme fused between CPS and ATC domains. SIGNOR-267421 0.8 PPP2CA protein P67775 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates activity dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 15367694 t Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes SIGNOR-248652 0.729 C5AR2 protein Q9P296 UNIPROT ITGAM protein P11215 UNIPROT up-regulates quantity by expression 1847994 f lperfetto The C5a receptor mediates the pro-inflammatory and chemotactic actions of the complement anaphylatoxin C5a. In addition to stimulating chemotaxis, granule enzyme release and superoxide anion production, this receptor stimulates upregulation of expression and activity of the adhesion molecule MAC-1, and of CR1, and a decrease in cell-surface glycoprotein 100MEL-14 on neutrophils. SIGNOR-263463 0.298 SH3KBP1 protein Q96B97 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 24167568 t gcesareni The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix. SIGNOR-203139 0.741 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR PFKP protein Q01813 UNIPROT down-regulates activity phosphorylation Ser679 MQQGGAPsPFDRNFG 9606 BTO:0000782 28607489 t lperfetto Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3–CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2.|Phosphomimicking mutants of PFKP (S679E) or PKM2 (S37E) displayed decreased catalytic activity SIGNOR-273033 0.2 GPR132 protein Q9UNW8 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257074 0.2 PLK3 protein Q9H4B4 UNIPROT HIF1A protein Q16665 UNIPROT down-regulates phosphorylation Ser576 DDDFQLRsFDQLSPL 9606 BTO:0000567 18519666 t lperfetto Polo-like kinase 3 functions as a tumor suppressor and is a negative regulator of hypoxia-inducible factor-1 alpha under hypoxic conditionsplk3 can potentially inhibit hif-1_ by physical interaction and direct phosphorylation SIGNOR-178739 0.352 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR up-regulates activity phosphorylation Thr359 DTEFTSRtPKDSPGI 9534 BTO:0001538 9430688 t lperfetto Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733. SIGNOR-252755 0.723 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 7545671 t gcesareni Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase SIGNOR-28800 0.585 MAPK3 protein P27361 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 t The effect has been demonstrated using O43561-2 gcesareni Lat, an adapter protein essential for t-cell signaling, is phosphorylated at its thr 155 by erk in response to t-cell receptor stimulation. Thr 155 phosphorylation reduces the ability of lat to recruit plcgamma1 and slp76, leading to attenuation of subsequent downstream events such as [ca2+]i mobilization and activation of the erk pathway. SIGNOR-125770 0.308 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Ser193 AEVDPDMsWSSSLAT 9606 BTO:0001938 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102486 0.549 CEP43 protein O95684 UNIPROT FGFR1OP/CEP350 complex SIGNOR-C52 SIGNOR form complex binding 9606 16314388 t miannu Here we show that cap350 and fop (fgfr1 oncogene partner) form a centrosomal complex required for mt anchoring. SIGNOR-142358 0.2 FGF11 protein Q92914 UNIPROT SCN11A protein Q9UI33 UNIPROT down-regulates activity binding 9606 BTO:0000938 20679355 t miannu Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels. SIGNOR-253438 0.2 KDM5D protein Q9BY66 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity demethylation Lys5 kQTARKST 9606 30246379 t miannu KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing. SIGNOR-264308 0.2 HOXB13 protein Q92826 UNIPROT AR protein P10275 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001321 15604291 f miannu These results suggest that HOXB13 functions as an AR repressor to modulate the complex AR signaling and subsequent growth regulation of prostate cancer cells. SIGNOR-254475 0.503 FGF2 protein P09038 UNIPROT ANKH protein Q9HCJ1 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0004473 19049325 f miannu FGF2 increases PC-1 and Ank expression while inhibiting Tnap expression in primary pre-osteoblast cells. Additionally, we show that the induction of PC-1 by FGF2 is cell type specific and mediated by the transcription factor, Runx2. SIGNOR-252193 0.2 MAPK1 protein P28482 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser8 MESEMLQsPLLGLGE 9606 SIGNOR-C3 21071439 t llicata We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1. SIGNOR-169518 0.527 ROBO proteinfamily SIGNOR-PF14 SIGNOR CCND3 protein P30281 UNIPROT down-regulates phosphorylation Thr283 QGPSQTStPTDVTAI 9606 BTO:0000782 15326477 t lperfetto P38sapk2 phosphorylates cyclin d3 at thr-283 and targets it for proteasomal degradation SIGNOR-128402 0.2 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1934 SPTYSPTsPKGSTYS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120160 0.314 GFs stimulus SIGNOR-ST12 SIGNOR AKT3 protein Q9Y243 UNIPROT up-regulates activity 9606 23300340 f lperfetto Akt normally resides in the cytosol under serum-starved conditions, but translocates to the plasma membrane where it is subsequently phosphorylated and activated in response to growth factor treatment. Phosphorylation of Akt at Thr308 by phosphoinositide-dependent kinase-1 (PDK1) and at Ser473 by mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is required for full Akt activation SIGNOR-245408 0.7 P2RY1 protein P47900 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257394 0.2 BMPR1A protein P36894 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates activity phosphorylation 9606 19620713 t ggiuliani To ascertain whether overexpression of BMPr1A can initiate adipocyte lineage commitment in the absence of its BMP ligand, constitutively active (CA)-BMPr1A and CA-BMPr1B were expressed in C3H10T1/2 stem cells using a mouse stem cell virus (MSCV) retroviral system. […]Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway. SIGNOR-255772 0.7 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT up-regulates activity phosphorylation Ser392 FKTEGPDsD 9606 BTO:0000568 10747897 t llicata Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities. SIGNOR-250967 0.66 PRKCG protein P05129 UNIPROT PEBP1 protein P30086 UNIPROT up-regulates activity phosphorylation Ser153 RGKFKVAsFRKKYEL 10116 BTO:0003036 12551925 t lperfetto Here we report that one mechanism involves dissociation of Raf kinase inhibitory protein (RKIP) from Raf-1. Classic and atypical but not novel PKC isoforms phosphorylate RKIP at serine 153 (Ser-153). RKIP Ser-153 phosphorylation by PKC either in vitro or in response to 12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor causes release of RKIP from Raf-1, whereas mutant RKIP (S153V or S153E) remains bound. I SIGNOR-249190 0.386 PTPN1 protein P18031 UNIPROT EPHA3 protein P29320 UNIPROT down-regulates activity dephosphorylation Tyr779 EDDPEAAyTTRGGKI 9606 21135139 t Nevertheless, the finding that phosphorylation of the activation loop tyrosine (EphA3-Y779), a recently identified PTP1B substrate (Mertins et al., 2008), is essential for ligand-induced endocytosis (Janes et al., 2009) SIGNOR-248426 0.424 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR GORASP1 protein Q9BQQ3 UNIPROT down-regulates activity phosphorylation Ser373 FEVSFLDsPGAQAQA 10116 15678101 t Giulio The pS376 antibody gave the strongest staining when Golgi apparatus fragmentation is initiated during prophase and in metaphase when it has become converted into a haze of small vesicles and some larger tubulovesicular remnants (Figure 4A). Therefore, GRASP65, like GM130, is phosphorylated in mitotic entry on Cdk1–cyclin B sites during the period when the Golgi apparatus is fragmented. SIGNOR-260606 0.565 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr96 EENADDSyEPPPVEQ 9606 12456653 t llicata The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex. SIGNOR-96052 0.802 HNF4A protein P41235 UNIPROT AFP protein P02771 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000972 9792724 f miannu AFP promoter-chloramphenicol acetyltransferase transient transfection assays demonstrated that the level of HNF1 had a direct impact on basal transcription as well as RA-mediated down-regulation of the AFP gene, and that co-transfection of HNF1 and HNF4, but not transfection of either factor alone, reversed the RA-mediated inhibition. Taken together these data point to an interaction among the RA, HNF1, and HNF4 signals, which is reflected in decreased expression of AFP. SIGNOR-254446 0.411 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI up-regulates quantity chemical modification 9606 BTO:0001363;BTO:0000048;BTO:0000050 17192295 t lperfetto THE MICROSOMAL ENZYME P450c17 catalyzes two reactions: the 17α-hydroxylation of progesterone and pregnenolone and the subsequent cleavage of the C17–20 carbon bond to produce dehydroepiandrosterone (DHEA) and androstenedione. Whereas only 17α-hydroxylase activity is necessary for the production of corticosteroids, both activities of P450c17 are required to synthesize sex hormones. SIGNOR-268653 0.8 NRXN3 protein Q9HDB5 UNIPROT DAG1 protein Q14118 UNIPROT up-regulates activity binding 9606 BTO:0000142 22626542 t miannu The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM. SIGNOR-265462 0.2 SMURF2 protein Q9HAU4 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11016919 t miannu The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway. Consistent with these results, Smurf2 potently reduced the transcriptional activity of Smad2.  SIGNOR-272935 0.773 CASP3 protein P42574 UNIPROT CASP9 protein P55211 UNIPROT up-regulates activity cleavage Asp330 LRTFDQLdAISSLPT 9606 BTO:0001412 15657060 t lperfetto In turn, casp3 directs feedback cleavage of casp9 at asp-330 to generate p37 and p10 subunits. SIGNOR-133264 0.628 PCM1 protein Q15154 UNIPROT CEP250 protein Q9BV73 UNIPROT up-regulates relocalization 9606 15659651 t miannu Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1 SIGNOR-133334 0.539 RB1 protein P06400 UNIPROT TRIP11 protein Q15643 UNIPROT down-regulates binding 9606 9256431 t miannu The wild-type rb is able to interact with the rb-binding domain of trip230 / rb represses trip230-mediated activation of tr-regulated transcription. SIGNOR-50266 0.327 SMO protein Q99835 UNIPROT GATA2 protein P23769 UNIPROT up-regulates activity 10090 BTO:0000011 16399502 f fferrentino In mammalian models [...] Hh signaling also inhibits mammalian adipogenesis. Hh signals elicit this function early in adipogenesis, upstream of PPARγ, potentially diverting preadipocytes as well as multipotent mesenchymal prescursors away from adipogenesis and toward osteogenesis. Hh may elicit these effects by inducing the expression of antiadipogenic transcription factors such as Gata2. SIGNOR-251656 0.2 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates activity dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 BTO:0000567 11030334 t NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity SIGNOR-248685 0.619 NPFF protein O15130 UNIPROT NPFFR1 protein Q9GZQ6 UNIPROT up-regulates binding 9606 11024015 t gcesareni Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems SIGNOR-82916 0.742 SYP protein P08247 UNIPROT VAMP2 protein P63027 UNIPROT up-regulates quantity binding 9606 26903854 t miannu Recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval. These cargoes are synaptophysin (for sybII) and SV2A (for synaptotagmin-1). SV2A Acts as an iTRAP to Direct Synaptotagmin-1 Retrieval to SVs. SIGNOR-264117 0.612 GRK1 protein Q15835 UNIPROT RHO protein P08100 UNIPROT up-regulates activity phosphorylation Ser334 PLGDDEAsATVSKTE -1 8617805 t That light-dependent phosphorylation of Rho is mediated primarily by RK. Addition of an inhibitory antibody against rhodopsin kinase (RK) lowered phosphorylation at Ser334, Ser338, and Ser343, without changing the ratio between phosphorylation sites. upon illumination, Ser334c, Ser338, and Ser343 are phosphorylated. SIGNOR-251189 0.922 AMPK complex SIGNOR-C15 SIGNOR MAPT protein P10636 UNIPROT down-regulates activity phosphorylation Ser396 DDKKAKTsTRSSAKT -1 21204788 t done miannu AMPK phosphorylation inhibits tau binding of microtubules. In order to study further the phosphorylation of tau by AMPK, we compared phosphorylation of tau by MARK4 or AMPK using a panel of phospho-tau antibodies (Figure 2A). Five phosphorylation sites common to both kinases were identified (Thr231, Ser262, Ser356, Ser396 and Ser422). In addition, AMPK, but not MARK4, was capable of phosphorylating Ser214 (Figure 2A). SIGNOR-273930 0.257 EEF1A1P5 protein Q5VTE0 UNIPROT Glu-tRNA(Glu) smallmolecule CHEBI:29157 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269549 0.8 ELAVL4 protein P26378 UNIPROT ADAM10 protein O14672 UNIPROT up-regulates quantity post transcriptional regulation 9606 19221430 t miannu Neuronal ELAV (nELAV) proteins are RNA-binding proteins which play a physiological role in controlling gene expression in memory formation, and their alteration may contribute to cognitive impairment associated with neurodegenerative pathologies such as Alzheimer's disease (AD). The experiments show for the first time that ADAM10mRNA represents a nELAV target and that these RNA-binding proteins can play a role in the post-transcriptional regulation of ADAM10 expression. nELAV proteins specifically bind the ADAM10 mRNA and this binding is disrupted following Aβ exposure SIGNOR-266865 0.2 oxymetazoline chemical CHEBI:7862 ChEBI ADRA1B protein P35368 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 7651358 t miannu Membrane preparations from CHO cells stably transfected with the cloned human a1-AR genes showed saturable binding of [‘251]HEAT; Bm,,ı values were 1.3 ± 0.2, 5.5 ± 0.1, and 1.1 ± 0.1 pmol/mg of protein, with Kd values of 110 ± 21, 60 ± 1, and 300 ± 26 ıM (three experiments each), for the ala-, alb-, and ald-ARS, respectively. The potencies of a1-AR agonists and antagonists at the cloned human a1-ARs are shown in Table 1. SIGNOR-258461 0.8 GLI3 protein P10071 UNIPROT CCND1 protein P24385 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000150;BTO:0000551 19860666 f gcesareni Gli activators bind to gaccaccca motif to regulate transcription of gli1, ptch1, ptch2, hhip1, mycn, ccnd1, ccnd2, bcl2, cflar, foxf1, foxl1, prdm1 (blimp1), jag2, grem1, and follistatin. SIGNOR-188878 0.58 NSFL1C protein Q9UNZ2 UNIPROT CTSL protein P07711 UNIPROT down-regulates activity binding -1 15498563 t lperfetto The SEP domain of p47 acts as a reversible competitive inhibitor of cathepsin L. SIGNOR-265043 0.2 pipamperone chemical CHEBI:78549 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10116 BTO:0000601 8935801 t miannu Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). The binding affinities of the compounds for various neurotransmitter receptors were measured using membrane preparations of animal brain regions and of recombinant cells expressing cloned, mostly human receptors. Receptors, tissues and cells are indicated in Table I; results are shown in Table 4A-B. SIGNOR-258575 0.8 EFNB1 protein P98172 UNIPROT EPHB4 protein P54760 UNIPROT up-regulates binding 9606 9330863 t tpavlidou Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor SIGNOR-52580 0.749 DUSP3 protein P51452 UNIPROT STAT3 protein P40763 UNIPROT down-regulates activity dephosphorylation 9606 32475380 t miannu DUSP3 interacted with the C-terminal domain of STAT3 and dephosphorylated p-Y705 of STAT3.|In summary, DUSP3 downregulated the transcriptional activity of STAT3 via dephosphorylation at Y705 and also suppressed the migratory activity of cancer cells. SIGNOR-277070 0.2 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Thr564 LEEADNQtLDSYRNE -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276215 0.2 AKT proteinfamily SIGNOR-PF24 SIGNOR IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 BTO:0001454 19609947 t lperfetto Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta SIGNOR-244281 0.649 AR protein P10275 UNIPROT BTG1 protein P62324 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 16281084 f After AR antagonist flutamide treatment, three hundred and twenty-six genes (3.93%) expressed differentially, 97 down-regulated and 219 up-regulated. Among them, eight up-regulated genes might be cell cycle-related, namely CDC10, NRAS, BTG1, Wee1, CLK3, DKFZP564A122, CDKN1A and BTG2. The CDKN1A and BTG1 gene mRNA expression was confirmed to be higher in the experimental group by RT-PCR, while p53 mRNA expression had no significant changes. SIGNOR-253673 0.2 PPP1CC protein P36873 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity. SIGNOR-248504 0.2 NPEPPS protein P55786 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI down-regulates quantity chemical modification 9606 11062501 t The proteasome generates exact major histocompatibility complex (MHC) class I ligands as well as NH2-terminal-extended precursor peptides| We performed in vitro peptide digests using recombinant PSA | PSA behaved exclusively as an aminopeptidase |BH and PSA act as complementary and redundant systems responsible for the final trimming of the correct NH2 terminus. SIGNOR-272467 0.8 FGF1 protein P05230 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates activity binding 9606 BTO:0001487 18940940 t fspada Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity. SIGNOR-236936 0.913 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB3 protein P05106 UNIPROT up-regulates activity binding 9606 29544897 t miannu Kindlins bind with β-integrin cytoplasmic tails and execute broad biological functions including directed cell migration, proliferation, differentiation and survival. SIGNOR-259002 0.2 GPR174 protein Q9BXC1 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257029 0.2 NEO1 protein Q92859 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 17204444 f miannu Neogenin, a close relative of the axon guidance receptor Deleted in Colorectal Cancer (DCC), has been shown to be a receptor for members of the Netrin and Repulsive Guidance Molecule (RGM) families. While Netrin-1-Neogenin interactions result in a chemoattractive axon guidance response, the interaction between Neogenin and RGMa induces a chemorepulsive response. SIGNOR-268395 0.7 Wnt proteinfamily SIGNOR-PF40 SIGNOR LRP6 protein O75581 UNIPROT up-regulates activity binding 9606 15578921 t Gianni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131577 0.2 CD300LB protein A8K4G0 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9534 BTO:0004055 20959446 t lperfetto The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2. SIGNOR-264833 0.472 CDK1 protein P06493 UNIPROT E2F1 protein Q01094 UNIPROT up-regulates phosphorylation Ser332 TDSATIVsPPPSSPP 9606 8087847 t lperfetto Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro. SIGNOR-36022 0.692 TFAP2C protein Q92754 UNIPROT ECM1 protein Q16610 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0002828 17187826 f miannu Comparative cDNA microarray hybridization identified a set of genes induced by overexpression of AP2alpha and AP2gamma in HMECs. The up-regulation of cellular retinoic acid-binding protein 2 (CRABPII), EST-1, and ECM1 was induced by overexpression of AP2alpha, AP2gamma, or a chimeric AP2 factor in which the activation domain of AP2alpha was replaced by the activation domain of herpesvirus VP16. SIGNOR-255396 0.289 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 16829981 t gcesareni Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow. SIGNOR-147841 0.582 CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR BORA protein Q6PGQ7 UNIPROT up-regulates activity phosphorylation 9606 29870721 t lperfetto The active cyclin A/cdk1 complex phosphorylates Bora and promotes Plx1 activation SIGNOR-267573 0.441 alvimopan chemical CHEBI:135686 ChEBI OPRK1 protein P41145 UNIPROT down-regulates activity chemical inhibition -1 18313920 t Luana A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, l opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective l opioid receptor antagonist, which interacts selectively with l peripheral receptors. SIGNOR-257774 0.8 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT up-regulates quantity transcriptional regulation 10116 11069927 f In the liver, glucocorticoids induce a 10-15-fold increase in the rate of transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene, which encodes a key gluconeogenic enzyme SIGNOR-253056 0.365 CS protein O75390 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 ChEBI down-regulates quantity chemical modification 9606 3013232 t miannu Citrate synthase catalyzes an important step within the cycle, the Claisen condensation of acetyl-Coenzyme A with oxaloacetate to form citrate; and it is the only enzyme in the cycle that can catalyze the formation of a carbon-carbon bond. SIGNOR-266238 0.8 PRKG1 protein Q13976 UNIPROT GKAP1 protein Q5VSY0 UNIPROT unknown phosphorylation Ser106 SNPVQKDsREENWQE 9534 10671526 t lperfetto Although both cGK-Ialpha and -Ibeta, but not cAMP-dependent protein kinase, phosphorylated GKAP42 in vitro, GKAP42 was a good substrate only for cGK-Ialpha in intact cells, suggesting that the association with kinase protein is required for the phosphorylation in vivo. SIGNOR-249037 0.637 KCNQ1 protein P51787 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI up-regulates quantity relocalization 9606 19298256 t miannu KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which widely regulates neuronal excitability, although other subunits may contribute to M-like currents in some locations. SIGNOR-265981 0.8 ALK protein Q9UM73 UNIPROT PIK3R3 protein Q92569 UNIPROT up-regulates activity phosphorylation 9606 BTO:0000762 27322022 t lperfetto Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K. SIGNOR-253217 0.369 GABA-A (a1-b1-g2) receptor complex SIGNOR-C330 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268600 0.248 AKT1 protein P31749 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates quantity by stabilization phosphorylation Ser166 SSRRRAIsETEENSD 9606 11504915 t lperfetto Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186. SIGNOR-116270 0.807 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser96 TSLSDEDsGKGSQPP 9606 15448698 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-129422 0.568 XL-647 chemical CID:10458325 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 22722787 t gcesareni Xl647 is an oral small-molecule inhibitor of multiple receptor tyrosine kinases, including endothelial growth factor receptor (egfr), vascular endothelial growth factor receptor 2, her2 and ephrin type-b receptor 4 (ephb4). SIGNOR-197962 0.8 NDN protein Q99608 UNIPROT BMI1 protein P35226 UNIPROT down-regulates 9606 BTO:0000007 24392140 f lperfetto In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, SIGNOR-253384 0.254 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser467 DTSYVIEsDEDLEME 9606 BTO:0000007 24429382 t llicata Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair. SIGNOR-203741 0.654 AKT1 protein P31749 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11035810 t gcesareni In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. SIGNOR-252589 0.626 LRFN3 protein Q9BTN0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu This study finds that all SALMs (SALMs 1–5) possess the abilityto promote neurite outgrowth and branching, as demonstrated byoverexpression and knockdown experiments. SIGNOR-264101 0.7 axitinib chemical CHEBI:66910 ChEBI PDGFRA protein P16234 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258074 0.8 PURB protein Q96QR8 UNIPROT MYH6 protein P13533 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 12933792 f miannu In functional assays, PURalpha and PURbeta repressed alpha-myosin heavy chain (alpha-MHC) gene expression in the presence of upstream regulatory sequences of the gene. SIGNOR-253901 0.37 GRIN2B protein Q13224 UNIPROT NMDA receptor_2B complex SIGNOR-C348 SIGNOR form complex binding 9606 BTO:0000938 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. The NMDA receptor subtypes are encoded by three gene families that process mRNA transcripts to yield six distinct subunits (NR1, NR2A-2D, NR3A). Receptors are thought to be tetrameric complexes of two NR1 and two NR2 subunits SIGNOR-264123 0.721 NOG protein Q13253 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates activity binding 9031 BTO:0000140 12478285 t lperfetto Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors. SIGNOR-219221 0.602 GATA2 protein P23769 UNIPROT KLF1 protein Q13351 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 8195185 f irozzo Regulation of the Erythroid Kruppel-like Factor (EKLF) Gene Promoter by the Erythroid Transcription Factor GATA-l.Accordingly,we have also demonstrated that GATA-2, like GATA-1, is able to activate the EKLF promoter in NIH3T3. SIGNOR-256052 0.438 (1R,4S,5S,6S)-4-amino-2,2-dioxo-2$l^{6}-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid chemical CHEBI:94640 ChEBI GRM2 protein Q14416 UNIPROT up-regulates chemical activation 9606 Other t Selleck gcesareni SIGNOR-193728 0.8 WWP2 protein O00308 UNIPROT WWP1 protein Q9H0M0 UNIPROT up-regulates activity binding 9606 BTO:0000007 25071155 t miannu WWP1 in complex with WWP2 specifically regulates ΔNp73.  In our study, we identified WWP2, an E3 ligase, as a novel p73-associated protein that ubiquitinates and degrades p73. In contrast, WWP2 heterodimerizes with another E3 ligase, WWP1, which specifically ubiquitinates and degrades ΔNp73.  SIGNOR-272231 0.2 PAK1 protein Q13153 UNIPROT NF2 protein P35240 UNIPROT down-regulates phosphorylation Ser518 DTDMKRLsMEIEKEK 9606 18071304 t lperfetto Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth, SIGNOR-159764 0.636 PRKCG protein P05129 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway. SIGNOR-115726 0.327 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser244 LRASTSKsESSQK 9606 21233202 t lperfetto In response to mitogenic stimuli, rps6 undergoes ordered c-terminal phosphorylation by p70 s6 kinases and p90 ribosomal s6 kinases on four conserved ser residues (ser-235, ser-236, ser-240, and ser-244) whose modification potentiates rps6 cap binding activity SIGNOR-252764 0.2 SNX9 protein Q9Y5X1 UNIPROT DNM2 protein P50570 UNIPROT up-regulates binding 9606 BTO:0000567 15703209 t miannu Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes. SIGNOR-133976 0.807 MNAT1 protein P51948 UNIPROT CAK complex complex SIGNOR-C456 SIGNOR form complex binding 9606 30860024 t lperfetto CdK activating kinase (CAK) complex, which harbors the kinase activity of CDK7 as well as the Cyclin H and MAT1 subunits SIGNOR-269320 0.947 GABA-A (a6-b1-g2) receptor complex SIGNOR-C334 SIGNOR CRHR1 protein P34998 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268607 0.263 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 9606 14662762 t lperfetto Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination. SIGNOR-120140 0.314 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 7834749 t Nuclear p53 amattioni Bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis SIGNOR-33922 0.747 N-[3-[[5-bromo-4-[2-(1H-imidazol-5-yl)ethylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91357 ChEBI PDPK1 protein O15530 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190804 0.8 dopamine smallmolecule CHEBI:18243 ChEBI DRD2 protein P14416 UNIPROT up-regulates activity chemical activation 9606 BTO:0002524 31160049 t Ligand-GPCR dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257478 0.8 ITGAM protein P11215 UNIPROT AM/b2 integrin complex SIGNOR-C170 SIGNOR form complex binding 16988024 t lperfetto Integrins are one of the major families of cell adhesion receptors (Humphries, 2000; Hynes, 2002). All integrins are non-covalently-linked, heterodimeric molecules containing an α and a β subunit. Both subunits are type I transmembrane proteins, containing large extracellular domains and mostly short cytoplasmic domains (Springer and Wang, 2004; Arnaout et al., 2005). Mammalian genomes contain 18 α subunit and 8 β subunit genes, and to date 24 different α,β combinations have been identified at the protein level. Although some subunits only appear in a single heterodimer, twelve integrins contain the β1 subunit, and five contain αV. SIGNOR-253191 0.748 BIRC2 protein Q13490 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates quantity by destabilization ubiquitination 9606 BTO:0000007 12525502 t miannu  Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac. SIGNOR-271392 0.893 PRKAA1 protein Q13131 UNIPROT HIPK2 protein Q9H2X6 UNIPROT up-regulates activity phosphorylation Ser121 LMRRSTVsLLDTYQK -1 23871434 t miannu These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J). SIGNOR-276467 0.2 GYS1 protein P13807 UNIPROT Glycogen_synthesis phenotype SIGNOR-PH39 SIGNOR up-regulates 9534 BTO:0004055 14593110 f lperfetto Glycogen synthase, a key enzyme in the regulation of glycogen synthesis by insulin, is controlled by multisite phosphorylation. SIGNOR-235751 0.7 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr129 ITEIADLtQKIFDLR 9606 BTO:0000671 18986304 t llicata Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143). SIGNOR-182049 0.2 PBK protein Q96KB5 UNIPROT Histone H3 proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 9606 16982762 t gcesareni Pbk/topk could phosphorylate histone h3 at ser10 in vitro and in vivo, and mediated its growth-promoting effect through histone h3 modification. SIGNOR-265364 0.2 GABARAPL2 protein P60520 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates activity binding 9606 BTO:0000567 17580304 t lperfetto P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha SIGNOR-156307 0.862 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates activity phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t JAK2 is autophosphorylated on tyrosines 221 and 1007. tyrosines 221 and 570 in JAK2 may serve as regulatory sites in JAK2, with phosphorylation of tyrosine 221 increasing kinase activity and phosphorylation of tyrosine 570 decreasing kinase activity SIGNOR-251356 0.2 IRAK1 protein P51617 UNIPROT PELI3 protein Q8N2H9 UNIPROT up-regulates phosphorylation 9606 12874243 t gcesareni Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity. SIGNOR-103983 0.721 SMC6 protein Q96SB8 UNIPROT SMC5/6 complex SIGNOR-C374 SIGNOR form complex binding -1 27427983 t miannu The SMC5/6 complex, consisting of SMC5, SMC6, and non-SMC elements NSMCE1–6, has key roles in the maintenance of chromosome integrity during mitotic proliferation, meiosis, and DNA repair and is critical for genome stability. In particular, the SMC5/6 complex is involved in resolving intermediates during recombination (5, 6) and other complex DNA structures, such as stalled replication forks SIGNOR-265482 0.898 PPP2CA protein P67775 UNIPROT DDHD1 protein Q8NEL9 UNIPROT up-regulates activity dephosphorylation Ser711 NPAKEPTsVSENEGI -1 11328814 t miannu Here we incubated a recombinant preparation of the phospholipase in vitro with several enzymes including protein kinase CK2 (CK2), extracellular signal-regulated kinase 2 (ERK2), and protein phosphatase 2A (PP2A) to identify effects that might be of regulatory importance in vivo.Major findings were that 1) CK2 phosphorylated the phospholipase on serines 93, 105, and 716; 2) ERK2 phosphorylated the enzyme on serine 730; 3) there was cross-antagonism between the reactions that phosphorylated serines 716 and 730; 4) PP2A selectively hydrolyzed phosphate groups that were esterified to serines 716 and 730. The results of two independent experiments with each type of assay indicated that the incubation caused a 50% loss of phospholipase activity (TableV). These results differed from those of corresponding incubation experiments with PA-PLA1α plus ERK2 and MgATP (see “Experimental Procedures”), which provided no evidence for complex formation or phosphorylation-dependent loss of phospholipase activity SIGNOR-262975 0.2 PPM1A protein P35813 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates activity dephosphorylation Ser608 ENTEDQYsLVEDDED 10090 BTO:0000944 15016818 t Protein phosphatase-2C alpha as a positive regulator of insulin sensitivity through direct activation of phosphatidylinositol 3-kinase in 3T3-L1 adipocytes|PP2Cα dephosphorylates the p85 subunit of PI3K, and dephosphorylation of the p85 subunit of PI3K at Ser608 increases its activity SIGNOR-248489 0.327 PPP2CA protein P67775 UNIPROT CILK1 protein Q9UPZ9 UNIPROT down-regulates dephosphorylation Thr157 IRSKPPYtDYVSTRW 9606 BTO:0002181 15988018 t lperfetto In addition, mass spectrometry showed that pp2a treatment completely abolished the dually phosphorylated form, leaving only the singly phosphorylated form (data not shown). We conclude that a portion of ick in unstimulated and asynchronized hek293t cells is dually phosphorylated on the tdy motif. SIGNOR-138428 0.2 LYRM4 protein Q9HD34 UNIPROT Mitochondrial Fe-S Cluster Assembly Complex complex SIGNOR-C276 SIGNOR form complex binding -1 27519411 t lperfetto As the architecture of the human machinery remains undefined, we co-expressed in Escherichia coli the following four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. SIGNOR-262126 0.696 CLOCK protein O15516 UNIPROT MAGEL2 protein Q9UJ55 UNIPROT down-regulates activity binding 9606 BTO:0000007 22208286 t miannu Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. SIGNOR-253516 0.2 Multiaminoacyl-tRNA synthetase complex SIGNOR-C472 SIGNOR Pro-tRNA(Pro) smallmolecule CHEBI:29154 ChEBI up-regulates quantity chemical modification 9606 28271488 t miannu Aminoacyl-tRNA synthetases (AARSs) are essential enzymes that specifically aminoacylate one tRNA molecule by the cognate amino acid. In mammals, nine synthetases, those specific for amino acids Arg, Asp, Gln, Glu, Ile, Leu, Lys, Met and Pro, associate into a multi-aminoacyl-tRNA synthetase complex, an association which is believed to play a key role in the cellular organization of translation, but also in the regulation of the translational and nontranslational functions of these enzymes. SIGNOR-270430 0.8 Factor FVIIa:TF complex SIGNOR-C319 SIGNOR F5 protein P12259 UNIPROT down-regulates activity cleavage Arg1046 HHAPLSPrTFHPLRS -1 10026263 t lperfetto Factor VIIa/tissue factor generates a form of factor V with unchanged specific activity, resistance to activation by thrombin, and increased sensitivity to activated protein C| In this study, we found that TF/VIIa was able to cleave multiple peptide bonds in the coagulation cofactor, factor V. SDS-PAGE analysis and sequencing indicated the factor V was cleaved at Arg679, Arg709, Arg1018, and Arg1192 SIGNOR-263645 0.498 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates quantity by destabilization phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 19833968 t miannu We demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Phosphorylation of S71 or S280 by AMPK destabilizes CRY1 SIGNOR-268046 0.355 alpha-D-glucose 6-phosphate(2-) smallmolecule CHEBI:58225 ChEBI 6-O-phosphono-D-glucono-1,5-lactone smallmolecule CHEBI:16938 ChEBI up-regulates quantity precursor of 9606 24769394 t miannu G6PD catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate and concomitantly reduces NADP+ to NADPH, which is the rate-limiting and primary control step of the NADPH-generating portion in the PPP. Thus, G6PD acts as a guardian of cellular redox potential during oxidative stress SIGNOR-267049 0.8 MAPK3 protein P27361 UNIPROT MITF protein O75030 UNIPROT down-regulates quantity by destabilization phosphorylation Ser180 PGSSAPNsPMAMLTL 10841026 t lperfetto More interestingly, ERK-dependent phosphorylation of MITF at Ser 73 is essential for MITF ubiquitinilation and degradation (87). Putting together all these findings, it can be proposed that MAPK activation inhibits melanogenesis due to an increased MITF degradation which is dependent on the MAPK-induced MITF phosphorylation and ubiquitinilation. In summary, although the phosphorylation of MITF at Ser73 increases its intrinsic transcriptional activity, this phosphorylation also targets MITF to the proteasome for its degradation. Consequently, the decrease in MITF levels leads to a down-regulation of melanogenic enzymes expression and to an inhibition of melanogenesis. SIGNOR-249620 0.531 PRKAG1 protein P54619 UNIPROT AMPK complex SIGNOR-C15 SIGNOR form complex binding 9606 BTO:0000443 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000759 16054041 t lperfetto Gamma non-catalytic subunit mediates binding to amp, adp and atp, leading to activate or inhibit ampk: amp-binding results in allosteric activation of alpha catalytic subunit (prkaa1 or prkaa2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. SIGNOR-139170 0.759 STK25 protein O00506 UNIPROT CCM2 protein Q9BSQ5 UNIPROT up-regulates phosphorylation Ser384 GRGIITDsFGRHRRA 9606 BTO:0001757 22782892 t miannu CCM2 can be phosphorylated by STK25, and the kinase activity of STK25 is required for death signaling. SIGNOR-263144 0.51 FER protein P16591 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates activity phosphorylation Tyr142 AVVNLINyQDDAELA -1 12640114 t Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases.  Transfection of these kinases to epithelial cells disrupted the association between both catenins. SIGNOR-251131 0.711 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MFN1 protein Q8IWA4 UNIPROT up-regulates activity phosphorylation Thr562 LPRSLASTPTAPTTP 10090 BTO:0002572 25801171 t Barakat Finally, in Mfn1 -/- cells re-expressing the MFN1 T562A mutant, phosphorylation was undetectable even in the presence of EGF. Taken together, these data indicate that ERK phosphorylates MFN1 at T562. SIGNOR-274134 0.2 PRKCD protein Q05655 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser159 KKKKKRFsFKKSFKL -1 8422248 t lperfetto These results indicate that in vitro, PKC phosphorylates MARCKS only at three sites, but not at Ser160 as that reported previously, and there was no preferential phosphorylation of MARCKS by either PKC isozyme I, II or III. SIGNOR-248924 0.476 CCKBR protein P32239 UNIPROT GNAQ protein P50148 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257305 0.439 DUSP1 protein P28562 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 10617468 t gcesareni The mitogen-activated protein (map) kinase cascade is inactivated at the level of map kinase by members of the map kinase phosphatase (mkp) family, including mkp-1. SIGNOR-73617 0.781 oxymetazoline chemical CHEBI:7862 ChEBI ADRA2A protein P08913 UNIPROT up-regulates activity chemical activation 9606 BTO:0000007 9605427 t miannu AR agonists stimulated binding of [35S]GTPgS to HEK 293 cell membranes containing the human a2a, a2b, or a2c ARs (Fig. 6). EPI and NE were full agonists; clonidine and oxymetazoline were partial agonists, while antagonists (e.g. rauwolscine, 5 mM) did not stimulate [35S]GTPgS incorporation (Table 3). Although a few agonists showed a great deal of selectivity for a single receptor subtype, the rank order of agonist potency for selected compounds at the human receptors (Table 3) was: a2a: Dexmedetomidine . guanabenz . UK-14304 .clonidine . ST-91 . NE a2b: Dexmedetomidine . clonidine . guanabenz . NE .ST-91 . UK-14304 a2c: Dexmedetomidine . NE . UK-14304 . ST-91 $ clonidine .. guanabenz SIGNOR-258917 0.8 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190152 0.8 SMARCA4 protein P51532 UNIPROT ZEB1 protein P37275 UNIPROT up-regulates binding 9606 20418909 t miannu Zeb1 represses e-cadherin transcription / we reported that brg1 binds to the ntr of zeb1 acting as its co-repressor in the regulation of the e-cadherin promoter. SIGNOR-165017 0.41 IFNLR1 protein Q8IU57 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 15120645 t gcesareni Despite signaling through distinct receptor complexes, type i ifns and ifn-_s activate similar signaling events and biological activities, consistent with their common ability to mediate an antiviral state in cells (fig. 6). In both cases, receptor engagement leads via the activation of the jak kinases jak1 and tyk2 SIGNOR-124483 0.549 MAPK1 protein P28482 UNIPROT XPO5 protein Q9HAV4 UNIPROT down-regulates activity phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 BTO:0000007 27846390 t lperfetto Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.  SIGNOR-262981 0.304 NAB2 protein Q15742 UNIPROT EGR2 protein P11161 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000414 20506119 f miannu Our results suggest that in many cells of neuroectodermal and epithelial origin EGR1, EGR2, and EGR3 activate NAB2 transcription which is in turn repressed by NAB2, thus establishing a negative feedback loop. SIGNOR-253888 0.587 BTF3 protein P20290 UNIPROT MADCAM1 protein Q13477 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0000584 17312387 f In contrast, BTF3 silencing resulted in down-regulation of several cancer-associated genes, including EPHB2, ABL2, HPSE2 and ATM, and up-regulation of KRAG, RRAS2, NFkappa-B, MRVI1, MADCAM1 and others. In conclusion, BTF3 is overexpressed in PDAC, where it acts as a transcriptional regulator rather than a direct modulator of apoptosis. SIGNOR-253945 0.2 MAOB protein P27338 UNIPROT (R)-adrenaline smallmolecule CHEBI:28918 ChEBI up-regulates quantity chemical modification 9606 BTO:0000142 20493079 t Luana The selective monoamine oxidase inhibitors clorgyline and (−)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (−)-noradrenaline and (+),(−)-adrenaline in homogenates from seven different regions of human brain. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. SIGNOR-269746 0.8 CBP/p300 complex SIGNOR-C6 SIGNOR H3-3A protein P84243 UNIPROT down-regulates activity acetylation Lys28 LATKAARkSAPSTGG 9606 21131905 t Acetlyation of H3 causes transcriptional activation, thus has an inhibitory role on H3 lperfetto These results highlight the substrate and site specificities of hats in cells, demonstrate the distinct roles of gcn5/pcaf- and cbp/p300-mediated histone acetylations in gene activation, and suggest an important role of cbp/p300-mediated h3k18/27ac in nr-dependent transcription. SIGNOR-217214 0.2 serotonin smallmolecule CHEBI:28790 ChEBI HTR1A protein P08908 UNIPROT up-regulates activity chemical activation 9606 BTO:0000938 25601315 t miannu Serotonin or 5-hydroxytryptamine (5-HT) remains one of the most widely studied chemical messengers. Serotonin produces a myriad of physiological effects in humans, mediated through 14 distinct receptor subtypes, of which 13 are G protein coupled receptors (GPCRs), and one ligand-gated cation channel SIGNOR-264285 0.8 SRP19 protein P09132 UNIPROT SRP68 protein Q9UHB9 UNIPROT up-regulates activity binding -1 30649418 t miannu Mammalian SRP comprises the highly base-paired SRP RNA (also referred to as 7SL RNA) of ∼300 nt and six proteins (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) (Figure ​(Figure1A).1A). The hierarchy of protein addition always starts with the scaffolding protein SRP19 (together with SRP9/14 for the entire SRP) followed by SRP68/72 and finally by SRP54. SIGNOR-261167 0.949 GPR35 protein Q9HC97 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-256860 0.2 PRKCA protein P17252 UNIPROT PLD2 protein O14939 UNIPROT up-regulates phosphorylation Ser243 RWLVVKDsFLLYMCL 9606 15979581 t miannu The phosphorylation sites in phospholipase d2 (pld2) induced by activation of protein kinase calpha (pkcalpha) in cos 7 cells were analyzed by mass spectrometry. Ser134, 146, and 243, and thr72, 99/100, and 252 were identified. These sites were mutated to ala and the double mutation of ser243 and thr252 eliminated the phosphorylation. / the s243/t252a mutant showed a partial decrease in pld2 activity SIGNOR-138351 0.684 GLI1/GLI2 complex SIGNOR-C450 SIGNOR BCL2 protein P10415 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000304 32766732 t GLI2 and GLI1 heterodimerize via the Zn-finger domain SimoneGraziosi GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells.|Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. | RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells SIGNOR-269211 0.39 EGF protein P01133 UNIPROT HBB protein P68871 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 9168989 f Regulation miannu We describe the roles of Stat5 and of these tyrosine residues in the EPOR in the erythroid differentiation of murine hematopoietic cell line SKT6 which produces hemoglobin in response to EPO. Chimeric receptors carrying the extracellular domain of the EGF receptor and the intracellular domain of the EPOR were introduced into SKT6 cells. Like EPO, EGF equally activated Stat5 and induced hemoglobin. SIGNOR-251782 0.261 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr57 RAGETRFtDTRKDEQ 9606 8386634 t gcesareni The eef-2 kinase could phosphorylate a synthetic peptide based on residues 49-60 of eef-2 (ragetrftdtrk), albeit only at a very low rate, and with a very high km, compared to eef-2 itself. SIGNOR-38552 0.784 MRPL41 protein Q8IXM3 UNIPROT 39S mitochondrial large ribosomal subunit complex SIGNOR-C285 SIGNOR form complex binding -1 25838379 t lperfetto We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by single-particle electron cryo-microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three rRNA molecules SIGNOR-262355 0.703 PLK1 protein P53350 UNIPROT SRI protein P30626 UNIPROT unknown phosphorylation Thr155 YSTNGKItFDDYIAC 9606 24427308 t lperfetto Sorcin interacts physically with plk1, is phosphorylated by plk1 and induces plk1 autophosphorylation, thereby regulating kinase activity. SIGNOR-203732 0.381 GABA-A (a4-b1-g2) receptor complex SIGNOR-C333 SIGNOR CRHR2 protein Q13324 UNIPROT down-regulates 9606 BTO:0000614 33536967 f lperfetto OT inhibits corticotropin-releasing factor (CRF) mRNA expression at the hypothalamus, resulting in antistress and anti-anxiety effects| It has been demonstrated that the inhibitory effect of OT on CRF mRNA expression is not a direct one on CRF neurons. GABAergic neurons are present in the surroundings of the PVN (peri-PVN). These GABA-projecting neurons into the PVN inhibits CRF expression via GABAA receptors SIGNOR-268592 0.2 CDK2 protein P24941 UNIPROT FOXK2 protein Q01167 UNIPROT up-regulates phosphorylation Ser428 FAQSAPGsPLSSQPV 9606 20810654 t gcesareni We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis. SIGNOR-167834 0.373 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR EGR1 protein P18146 UNIPROT up-regulates binding 9606 10671503 t lperfetto The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo SIGNOR-216328 0.403 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2A protein P49459 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271361 0.666 ELOVL1 protein Q9BW60 UNIPROT 3-hydroxyoctadecanoyl-CoA smallmolecule CHEBI:50583 ChEBI up-regulates quantity chemical modification 9606 31616255 t miannu The ELOVL family of enzymes in mammals is comprised of seven members that all reside in the endoplasmic reticulum (ER) and are thought to form a multimeric complex. Together, the ELOVL family is responsible for the elongation of saturated and unsaturated fatty acids.Fatty acid elongation occurs by cycling through a four step process (condensation, reduction, dehydration, and reduction), with two carbon atoms added through each cycle. SIGNOR-267896 0.8 UBE4B protein O95155 UNIPROT FEZ1 protein Q99689 UNIPROT up-regulates activity polyubiquitination 10116 BTO:0001009 15466860 t K27 miannu  E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis. SIGNOR-271510 0.397 SIAH2 protein O43255 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates 9606 17003045 f gcesareni The ring finger ubiquitin ligase siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the phd3, which controls the stability of hif-1alpha SIGNOR-149893 0.367 PRKAA1 protein Q13131 UNIPROT NRF1 protein Q16656 UNIPROT up-regulates 9606 15509864 f gcesareni In muscle, it causes increased dna binding by the transcription factors nrf1 (bergeron et al., 2001) and mef2 (zheng et al., 2001), which may be involved in regulation of mitochondrial genes and glut4, respectively. SIGNOR-130076 0.2 TOMM40 protein O96008 UNIPROT TOM40 complex complex SIGNOR-C421 SIGNOR form complex binding 9606 BTO:0000567 18331822 t lperfetto The fungal preprotein translocase of the mitochondrial outer membrane (TOM complex) comprises import receptors Tom70, Tom20, and Tom22, import channel Tom40, and small Tom proteins Tom5, Tom6, and Tom7, which regulate TOM complex assembly. These components are conserved in mammals; unlike the other components, however, Tom5 and Tom6 remain unidentified in mammals. We immuno-isolated the TOM complex from HeLa cells expressing hTom22-FLAG and identified the human counterparts of Tom5 and Tom6, together with the other components including Tom7. These small Tom proteins are associated with Tom40 in the TOM complex. SIGNOR-267681 0.741 9-(1-Methyl-4-pyrazolyl)-1-[1-(1-oxoprop-2-enyl)-2,3-dihydroindol-6-yl]-2-benzo[h][1,6]naphthyridinone chemical CID:71748056 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 24556163 t miannu This analysis revealed that QL47 also potently inhibits BMX with an IC50 of 6.7 nM but impressively displays more than 100-fold selectivity against EGFR, HER2, JAK3, BLK, TEC, and ITK that possess an equivalently placed cysteine SIGNOR-262233 0.8 TFEB protein P19484 UNIPROT NAGLU protein P54802 UNIPROT up-regulates quantity by expression transcriptional regulation 19556463 f Figure 1 lperfetto Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes.|Expression analysis of lysosomal genes after TFEB overexpression and silencing. Blue bars show the fold change of the mRNA levels of lysosomal genes in TFEB- versus pcDNA3-transfected cells. SIGNOR-276543 0.328 CUL1 protein Q13616 UNIPROT ARIH1 protein Q9Y4X5 UNIPROT up-regulates activity binding 9606 BTO:0000007 24076655 t miannu Here, we provide evidence that Ariadne RBR E3 ubiquitin ligases such as TRIAD1 and HHARI can bind and be activated by CRL complexes. Whereas TRIAD1 specifically associates with CUL5–RBX2, HHARI is more promiscuous towards cullin types and associates with RBX1-associated cullins 1, 2, 3, and 4A. Interestingly, both TRIAD1 and HHARI show a strong preference for binding the neddylated form of the cullin. Our data suggest a novel function of NEDD8 in directing specific CRLs to Ariadne RBR ligases, which in turn exert influence on the levels of their cognate neddylated cullin. SIGNOR-268844 0.36 LEF1 protein Q9UJU2 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 17081971 f amattioni The interaction of beta-catenin with the N terminus of tcf/lef transiently converts it into an activator, translating the Wnt signal into the transient transcription of Tcf target genes. The Wnt pathway has distinct transcriptional outputs, which are determined by the identity of the responding cell, and range from cell proliferation and survival to the terminal differentiation of postmitotic cells. SIGNOR-229770 0.7 SMC2 protein O95347 UNIPROT Condensin II complex SIGNOR-C342 SIGNOR form complex binding 9606 32445620 t miannu The majority of higher eukaryotes, including humans, have two condensins, condensin I (CI) and II (CII) Although sharing the same SMC subunits (SMC2 and SMC4), condensin I and II have distinct non-SMC regulatory subunits, including the kleisin subunit (CAP-H and CAP-H2, respectively) and a pair of HEAT repeat subunits (CAP-D2/G and CAP-D3/G2, respectively; Figure 1B). the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction. SIGNOR-263908 0.815 ZIC1 protein Q15915 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 BTO:0002181 11238441 f fspada Moreover, gli proteins were translocated to cell nuclei by coexpressed zic proteins, and both proteins regulated each others transcriptional activity.In Nih3t3 and 293t cells, both gli1 and gli3 proteins were located predominantly in the cytoplasm (fig. 2, c, d, h, k, l, and p). Coexpression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels (fig. 2, e and m). SIGNOR-105494 0.382 GABA-B receptor complex SIGNOR-C336 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates activity binding 9606 30541966 t miannu GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. SIGNOR-264965 0.416 DOCK7 protein Q96N67 UNIPROT CDC42 protein P60953 UNIPROT up-regulates activity guanine nucleotide exchange factor 10090 BTO:0000132 29187380 t lperfetto As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover. SIGNOR-261886 0.732 RAG1 protein P15918 UNIPROT MTOR protein P42345 UNIPROT up-regulates relocalization 9606 22790199 t gcesareni Rag gtpases, together with a multi-protein complex called ragulator, mediate amino acid-mediated mtor recruitment to the lysosome surface where mtor becomes activated. SIGNOR-198242 0.258 RRAGC protein Q9HB90 UNIPROT RAGAC complex SIGNOR-C113 SIGNOR form complex binding 9606 20381137 t gcesareni Mammals express four Rag proteins€”RagA, RagB, RagC, and RagD€”that form heterodimers consisting of RagA or RagB with RagC or RagD. RagA and RagB, like RagC and RagD, are highly similar to each other and are functionally redundant SIGNOR-228161 0.774 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT up-regulates activity phosphorylation Tyr724 ANCTHDLyMIMRECW 9606 BTO:0000007 11294897 t lperfetto Ligand stimulation leads to autophosphorylation of fgfr3taken together, these results clearly implicate y724 in the activation of stat proteins by constitutively activated mutants of fgfr3 and suggest that both y724 and y760 are required for maximal stat activation. SIGNOR-106738 0.2 TNK2 protein Q07912 UNIPROT SNX9 protein Q9Y5X1 UNIPROT up-regulates phosphorylation 9606 16316319 t gcesareni We have previously shown that sh3px1, phosphorylated by ack2 (activated cdc42-associated tyrosine kinase 2), regulates the degradation of egf (epidermal growth factor) receptor. SIGNOR-142569 0.513 PRKCD protein Q05655 UNIPROT BLVRA protein P53004 UNIPROT up-regulates activity phosphorylation Ser33 DLRNPHPsSAFLNLI 22584576 t lperfetto LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation. SIGNOR-275527 0.2 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser99 KEEEEGIsQESSEEE -1 2806554 t llicata Sequence analysis of the native peptide (90-107) after treatment, which specifically converts phosphoserine residues to S-ethylcysteine, revealed that 70-80% of serine residues 102 and 103 were phosphorylated in vivo. Both residues were fully phosphorylated in vitro by incubation with casein kinase II. These results suggest that casein kinase II is involved in the regulation of HMG-I function in the cells. | After an 80 min incubation with CK-II, both serines were fully phosphorylated to 1 mol/mol and serine-99 to 0.3 mol/mol. SIGNOR-251006 0.331 EPAS1 protein Q99814 UNIPROT KDM6B protein O15054 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 32938217 t SaraGualdi To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a. SIGNOR-271586 0.2 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNB1 protein P14635 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189969 0.8 Av/b2 integrin complex SIGNOR-C176 SIGNOR Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 25388208 f miannu Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. SIGNOR-269025 0.7 MMP14 protein P50281 UNIPROT FGG protein P02679 UNIPROT down-regulates quantity by destabilization cleavage Leu92 QLIKAIQlTYNPDES -1 10930399 t lperfetto Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-14 27YVATRDN g-chain| 105XDAATLKSR g-chain | 92LTYNPDES g-chain |105LTTNIXEXL a-chain|433LVTSKGDKE a-chain| 117FXSANNRD a-chain SIGNOR-263617 0.2 OXSR1 protein O95747 UNIPROT SLC12A3 protein P55017 UNIPROT up-regulates phosphorylation Thr60 MRTFGYNtIDVVPTY 9606 BTO:0000007 BTO:0000671 18270262 t miannu We demonstrate that the spak and osr1 kinases that are activated by wnk1 phosphorylate human ncc at three conserved residues (thr46, thr55 and thr60) / our results also indicate that phosphorylation of thr60 plays the most crucial role in triggering the activation of ncc in hek293 cells and its mutation also inhibits phosphorylation of the adjacent thr46 and thr55 sites. SIGNOR-160833 0.394 HDAC2 protein Q92769 UNIPROT MBD3/NuRD complex complex SIGNOR-C338 SIGNOR form complex binding 9606 27098840 t miannu The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.In humans, an assembly of proteins called the NuRD complex makes chromatin more compact by removing acetyl groups from nucleosomes. This complex is important for early development and for the stability and repair of our genes. Three proteins make up its core: HDAC1, which removes the acetyl group from the nucleosome; MTA1, which acts as a scaffold to hold the complex together; and RBBP4, which enables the complex to interact with nucleosomes. MBD2 and MBD3 are members of the methyl cytosine-guanosine (CpG)-binding domain (MBD) family of proteins42; 43. Of the five MBD members, only MBD2 and MBD3 associate with NuRD and are required for the complex formation and gene repression. SIGNOR-263850 0.792 CSNK2B protein P67870 UNIPROT MME protein P08473 UNIPROT unknown phosphorylation Ser6 sQMDITDI 9606 BTO:0003288 8943850 t llicata Taken together, these data indicate that CD10/NEP is itself phosphorylated by CKII and that CD10/NEP co-associates with additional tyrosine phosphoproteins including lyn. SIGNOR-251078 0.38 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 9606 9335504 t llicata In contrast to the bmp-stimulated phosphorylation of smad1, which affects carboxy-terminal serines and induces nuclear accumulation of smad1, erk-mediated phosphorylation specifically inhibits the nuclear accumulation of smad1. phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of smad1 SIGNOR-52674 0.597 GSK3B protein P49841 UNIPROT SNAI1 protein O95863 UNIPROT down-regulates phosphorylation Ser107 SQPPSPPsPAPSSFS 9606 20305697 t lperfetto Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt SIGNOR-164621 0.568 GRIK5 protein Q16478 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000938 24564659 f miannu Excitatory synaptic transmission in the mammalian brain is mediated primarily by the amino acid glutamate, activating two different groups of glutamate receptors: ionotropic and metabotropic. SIGNOR-264346 0.7 SMAD4 protein Q13485 UNIPROT SMAD8/SMAD4 complex SIGNOR-C206 SIGNOR form complex binding 9606 20957627 t lperfetto Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus. SIGNOR-255269 0.675 PRKCD protein Q05655 UNIPROT PRKCD protein Q05655 UNIPROT up-regulates phosphorylation Ser299 NQVTQRAsRRSDSAS 9606 17603046 t gcesareni Here, we demonstrate that pkcdelta undergoes in vitro autophosphorylation at three sites within its v3 region (s299, s302, s304), each of which is unique to this pkc isoform and evolutionarily conserved SIGNOR-156523 0.2 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR up-regulates activity binding 9606 21078818 t gcesareni Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt Beta-catenin signaling. SIGNOR-253128 0.805 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT up-regulates phosphorylation Thr224 MSRFSSStEQSSASR 9606 22609948 t lperfetto We demonstrated that dvl2 is phosphorylated at s143 and t224 in a manner that requires both non-canonical wnt5a ligand and casein kinase 1 epsilon (ck1_), and that this event is critical to interact with plk1 in early stages of the cell cycle SIGNOR-197555 0.685 SIRT1 protein Q96EB6 UNIPROT FOXO4 protein P98177 UNIPROT up-regulates deacetylation 9606 15126506 t gcesareni Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes. SIGNOR-124714 0.739 CDK5 protein Q00535 UNIPROT MAPK10 protein P53779 UNIPROT down-regulates activity phosphorylation Thr131 ISLLNVFtPQKTLEE 9606 BTO:0000007 11823425 t llicata Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation. SIGNOR-250668 0.349 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 9812896 t gcesareni Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity SIGNOR-61561 0.516 MAPK14 protein Q16539 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates activity phosphorylation Thr692 QAAYYGQtPGPGGPQ 10090 BTO:0000165 16364914 t lperfetto KSRP, an important factor for AU-rich element (ARE)-directed mRNA decay, undergoes p38-dependent phosphorylation during muscle differentiation. KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery SIGNOR-235856 0.562 AMPK complex SIGNOR-C15 SIGNOR PDHA1 protein P08559 UNIPROT up-regulates activity phosphorylation Ser295 RYHGHSMsDPGVSYR -1 33022274 t miannu In vitro kinase assay revealed that PDHA could be readily phosphorylated by active AMPK complex in a dose-dependent manner (Figure 6C).  SIGNOR-276835 0.256 TGFBI protein Q15582 UNIPROT A3/b1 integrin complex SIGNOR-C161 SIGNOR up-regulates activity binding 10090 BTO:0001175 10906123 t lperfetto In addition, we demonstrated the functional receptor for betaig-h3 is alpha(3)beta(1) integrin. These results, therefore, establish the essential motifs within the 2nd and the 4th domains of betaig-h3, which interact with alpha(3)beta(1) integrin to mediate HCE cell adhesion to betaig-h3 and suggest that other proteins containing Asp-Ile in their fas-1 domains could possibly function as cell adhesion molecules. SIGNOR-253211 0.44 (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol chemical CHEBI:94562 ChEBI KDR protein P35968 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190708 0.8 ABT-737 chemical CID:11228183 PUBCHEM BCL2L2 protein Q92843 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-189174 0.8 arecoline chemical CHEBI:2814 ChEBI CHRM2 protein P08172 UNIPROT up-regulates activity chemical activation 10029 BTO:0000246 9224827 t miannu We investigated whether the allosteric modulators can also increase the affinity of receptors for their agonists. Twelve agonists and five allosteric modulators were tested in experiments on membranes of CHO cells that had been stably transfected with genes for the M1-M4 receptor subtypes. Affinities of agonists for the M1–M4 receptor subtypes were determined according to the ability of the agonist to inhibit [3H]NMS binding in the presence of 0.5 mM GTP; in this way, the low affinity binding of agonists was measured.The computed pKi and nH values are summarized in Table 2. SIGNOR-258639 0.8 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT down-regulates quantity by destabilization phosphorylation Thr57 LSSTPLStPCSSVPS 9606 18042454 t miannu We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity. SIGNOR-159470 0.259 IGF1R protein P08069 UNIPROT IGF1R protein P08069 UNIPROT up-regulates activity phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 7493944 t lperfetto Insulin and insulin-like growth factor (igf-i) receptors are heterotetrameric proteins consisting of two alpha-and two beta-subunits and members of the transmembrane tyrosine kinase receptors. Specific ligand binding to the receptor triggers a cascade of intracellular events, which begins with autophosphorylation of several tyrosine residues of the beta-subunit of the receptor. SIGNOR-26590 0.2 KNL1 protein Q8NG31 UNIPROT BUB1B protein O60566 UNIPROT up-regulates binding 9606 17981135 t gcesareni Association of the amino and middle domain of blinkin with the tpr domains in the amino termini of bubr1 and bub1 is essential for bubr1 and bub1 to execute their distinct mitotic functions SIGNOR-158894 0.2 CSNK2A1 protein P68400 UNIPROT PIAS1 protein O75925 UNIPROT up-regulates phosphorylation Ser468 DLTIDSSsDEEEEEP 9606 19217413 t llicata Ck2 phosphorylates serine residues adjacent to the sim of pias1 these findings show that the phosphosim module mediates binding to free sumo and sumo conjugates in a phosphorylation-dependent mode, with ck2 being the critical kinase involvedin this process. SIGNOR-184047 0.335 AMPK complex SIGNOR-C15 SIGNOR RB1 protein P06400 UNIPROT unknown phosphorylation Ser811 IYISPLKsPYKISEG 9606 19217427 t lperfetto Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site. SIGNOR-216635 0.2 PLK1 protein P53350 UNIPROT TTK protein P33981 UNIPROT up-regulates activity phosphorylation Ser345 PLVSDEKsSELIITD -1 26119734 t miannu Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro SIGNOR-276198 0.386 DIO1 protein P49895 UNIPROT L-thyroxine smallmolecule CHEBI:18332 ChEBI down-regulates quantity chemical modification 9606 1400883 t scontino The type I 5' iodothyronine deiodinase (5' DI) catalyzes the deiodination of T4 to the biologically active hormone T3 and accounts for a significant fraction of its production. SIGNOR-266944 0.8 3',5'-cyclic AMP smallmolecule CHEBI:17489 ChEBI PRKAR2A protein P13861 UNIPROT down-regulates activity chemical inhibition 9606 26687711 t Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets SIGNOR-258761 0.8 Ub:E1 (UBA6 substrate) complex SIGNOR-C496 SIGNOR UBE2NL protein Q5JXB2 UNIPROT up-regulates activity ubiquitination 9606 34199813 t miannu The ubiquitination process is mediated sequentially by three classes of enzymes consisting of a Ub-activating enzyme E1, a Ub-conjugating enzyme E2, and a Ub ligase E3. Ub is first activated by E1 in an adenosine 5‚Ä≤-triphosphate (ATP)-dependent manner t SIGNOR-271370 0.2 PRKCE protein Q02156 UNIPROT ALDH2 protein P05091 UNIPROT up-regulates activity phosphorylation Thr202 KLGPALAtGNVVVMK -1 28056995 t lperfetto Post-translational enhancement of ALDH2 activity can be achieved by serine/threonine phosphorylation by epsilon protein kinase C (epsilonPKC). |e identified S279 as a critical εPKC phosphorylation site in the activation of ALDH2. The critical catalytic site, cysteine 302 (C302) of ALDH2 is susceptible to adduct formation by reactive aldehyde, 4HNE, which readily renders the enzyme inactive. We show that phosphomimetic mutations of T185E, S279E and T412E confer protection of ALDH2 against 4HNE-induced inactivation, indicating that phosphorylation on these three sites by εPKC likely also protects the enzyme against reactive aldehydes. SIGNOR-271865 0.284 NOTCH1 protein P46531 UNIPROT TCFL5 protein Q9UL49 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000782 16990763 f gcesareni Interestingly, in absence of delta signal, both hes-1 and tcfl5 decreased, and further decreased by incubation with dapt. (figure 4). This pharmacological approach therefore provides additional evidence that tcfl5, similar to hes1, is a true notch target gene. SIGNOR-149807 0.2 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 8626512 t lperfetto Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. SIGNOR-216908 0.393 BBS5 protein Q8N3I7 UNIPROT BBsome complex complex SIGNOR-C288 SIGNOR form complex binding 9606 BTO:0004910 19081074 t lperfetto We recently showed that seven highly conserved BBS proteins form a stable complex, the BBSome, that functions in membrane trafficking to and inside the primary cilium.|As a first step in characterizing this protein, we investigated the biochemical properties of its binding to the core BBSome (previously defined as the BBS1, -2, -4, -5, -7, -8, and -9 complex). We subjected the native LAP-BBS4 eluate to velocity sedimentation analysis (Figure 1C). BBIP10 clearly cosedimented with BBS4 at 14S, suggesting that BBIP10 strongly associates with the core BBSome SIGNOR-262559 0.878 PTPN11 protein Q06124 UNIPROT SLC25A4 protein P12235 UNIPROT down-regulates activity dephosphorylation 9606 29255148 t miannu Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation). SIGNOR-277124 0.273 Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT AGTR2 protein P50052 UNIPROT up-regulates activity binding 9606 32201502 t MIANNU Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways SIGNOR-260237 0.2 SATB1 protein Q01826 UNIPROT IGFBP2 protein P18065 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000664 17343824 f miannu We found 59 up-regulated and 75 down-regulated genes in the K562-SATB1 cells that were not observed in the K562 cells. Partial genes that have special biological functions are listed in Table 1. SIGNOR-255129 0.2 OXGR1 protein Q96P68 UNIPROT GNAS protein P63092 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0. SIGNOR-256770 0.2 PAK1 protein Q13153 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 18775988 t gcesareni P21-activated protein kinases (paks) are serine/threonine protein kinases that phosphorylate raf-1 at ser-338 and ser-339. SIGNOR-180812 0.591 CR2 protein P20023 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity binding 9606 BTO:0000776 31732528 t scontino Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. SIGNOR-266642 0.779 NUP54 protein Q7Z3B4 UNIPROT p62_complex complex SIGNOR-C259 SIGNOR form complex binding 10116 BTO:0000154 2050741 t Simone Thus, the p62-p58-p54 complex defines a group of proteins with strong protein-protein interactions that form a unit of pore structure essential for pore function. SIGNOR-261259 0.939 EXOC7 protein Q9UPT5 UNIPROT Exocyst_EXOC6 variant complex SIGNOR-C492 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270790 0.941 NCOA1 protein Q15788 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f inferred from family member miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-270223 0.2 GABBR2 protein O75899 UNIPROT GABA-B receptor complex SIGNOR-C336 SIGNOR form complex binding 9606 BTO:0000007 9872316 t brain lperfetto Heterodimerization is required for the formation of a functional GABA(B) receptor.|These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2. SIGNOR-263743 0.684 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation Thr455 ALGTPVLtPPTEAAS 10090 BTO:0000944 11689711 t gcesareni We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT. SIGNOR-252985 0.2 GATA2 protein P23769 UNIPROT CYBB protein P04839 UNIPROT down-regulates quantity transcriptional regulation 9606 10734088 t These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils. SIGNOR-259948 0.252 CEP135 protein Q66GS9 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR up-regulates activity binding -1 27477386 t miannu Here, we analyzed in detail the microtubule-binding activity of human CEP135 (HsCEP135).  Biochemical, cryo-electron, and fluorescence microscopy analyses revealed that in vitro HsCEP135-N interacts with tubulin, protofilaments, and microtubules and induces the formation of microtubule bundles SIGNOR-269678 0.2 ATR protein Q13535 UNIPROT XPA protein P23025 UNIPROT up-regulates phosphorylation Ser196 RSLEVWGsQEALEEA 9606 23178497 t lperfetto Atr phosphorylates xpa. at serine 196. Atr-mediated xpa phosphorylation enhances xpa stability by inhibiting herc2-mediated ubiquitination and subsequent degradation. SIGNOR-199802 0.5 CTNNB1 protein P35222 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 10090 BTO:0000165 19000719 t Through Armadillo repeat domain gcesareni Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential. SIGNOR-236858 0.77 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR NDE1 protein Q9NXR1 UNIPROT up-regulates quantity by stabilization phosphorylation Thr215 ATGSVPStPIAHRGP 9606 BTO:0000007 16682949 t done miannu Here, we demonstrate that Su48 can associate with Nde1. Moreover, we found that Nde1 is subjected to phosphorylation in vivo. In particular, we identified six putative Cdc2 phosphorylation sites in Nde1 and found that alteration of these sites diminishes phosphorylation by Cdc2 in vitro and affects the stability of Su48-Nde1 interactions and the centrosomal localization of Nde1. SIGNOR-274082 0.533 TIRAP protein P58753 UNIPROT MYD88 protein Q99836 UNIPROT up-regulates activity binding 9606 11544529 t gcesareni Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. SIGNOR-252063 0.625 CSNK2B protein P67870 UNIPROT IKZF1 protein Q13422 UNIPROT down-regulates phosphorylation Thr23 ESPPVSDtPDEGDEP 9606 BTO:0001271 21750978 t miannu We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway SIGNOR-174856 0.2 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates activity phosphorylation 9606 19701891 t miannu The binding of TGF‐β1 to its receptor complex activates the intracellular kinase domain of TGF‐βRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non‐Smad proteins (Smad‐independent pathway) SIGNOR-254361 0.808 CAMK2B protein Q13554 UNIPROT RETREG1 protein Q9H6L5 UNIPROT up-regulates activity phosphorylation Ser151 AQLWRSLsESWEVIN -1 31930741 t miannu Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy.  SIGNOR-273554 0.2 PLK1 protein P53350 UNIPROT G6PD protein P11413 UNIPROT up-regulates activity phosphorylation Thr406 AVYTKMMtKKPGMFF 9606 BTO:0000007 29138396 t lperfetto We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD SIGNOR-267580 0.351 lidocaine chemical CHEBI:6456 ChEBI SCN2A protein Q99250 UNIPROT down-regulates activity chemical inhibition 10116 1658608 t miannu This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. SIGNOR-258354 0.8 EP300 protein Q09472 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11796223 t lperfetto Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription. SIGNOR-232159 0.735 PRKACA protein P17612 UNIPROT PPP1R8 protein Q12972 UNIPROT down-regulates activity phosphorylation Ser199 PKRKRKNsRVTFSED -1 9407077 t miannu NIPP-1 is the RNA-binding subunit of a major species of protein phosphatase-1 in the nucleus. The purified recombinant protein was a potent (Ki = 9.9 +/- 0.3 pM) and specific inhibitor of protein phosphatase-1 and was stoichiometrically phosphorylated by protein kinases A and CK2. At physiological ionic strength, phosphorylation by these protein kinases drastically decreased the inhibitory potency of free NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A SIGNOR-250033 0.491 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr373 SEDDEDCyGNYDNLL 9606 20643654 t lperfetto Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376 (11, 12, 14, 17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376 SIGNOR-166710 0.345 SOX9 protein P48436 UNIPROT CEBPB protein P17676 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 19254573 f fspada Sox9 directly binds to the promoter regions of c/ebpbeta and c/ebpdelta to suppress their promoter activity, preventing adipocyte differentiation SIGNOR-184280 0.329 TARS1 protein P26639 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI up-regulates quantity chemical modification 9606 25824639 t miannu Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. SIGNOR-270504 0.8 GSK3B protein P49841 UNIPROT CRMP1 protein Q14194 UNIPROT up-regulates phosphorylation Thr509 PVYEVPAtPKYATPA 9606 BTO:0000938 16611631 t lperfetto In summary, phosphorylation of thr509 of human crmp1 appears to be regulated by two mechanisms; direct phosphorylation by cdk5, or by priming of ser522 by cdk5 followed by sequential phosphorylation of ser518, thr514, and thr509 by gsk3. SIGNOR-145995 0.456 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 BTO:0000938 21079800 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-169682 0.429 HNF4A protein P41235 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR up-regulates quantity by expression transcriptional regulation 9606 16308421 f inferred from family member gcesareni In the gk gene regulation, foxo1 represses hnf-4-potentiated transcription of the gene, whereas it synergizes with hnf-4 in activating the g6pase gene transcription. SIGNOR-267790 0.259 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates activity phosphorylation Ser416 SSAFLGFsYAPEDDD 10548550 t miannu SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. SIGNOR-250376 0.587 NEDD9 protein Q14511 UNIPROT AURKA protein O14965 UNIPROT up-regulates activity binding 9606 16184168 t miannu HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins. SIGNOR-262653 0.581 CADM2 protein Q8N3J6 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates activity 9606 BTO:0000007 29506532 f Gianni The results indicated that CADM2 […} modulates EMT process and migration ability via focal adhesion kinase (FAK) /AKT signaling pathway in HCC. SIGNOR-268855 0.2 ITGA6 protein P23229 UNIPROT PMP22 protein Q01453 UNIPROT up-regulates activity binding 10090 16436605 t Regulation miannu PMP22 is in a complex with α6β4 integrin and laminin. PMP22 and β4 integrin are in a complex in a variety of cell types. The interaction with the integrins provides PMP22 with the ability to modulate the cell–ECM communications, as well as intracellular events. Signaling between the ECM and the intracellular compartment is essential for SC myelination, as well as cellular differentiation and motility, in general. The identification of PMP22 as a binding partner for an integrin signaling complex provides a major step toward understanding the role of this disease-linked molecule in the nervous system and in non-neural cell types. SIGNOR-251895 0.368 PRKAA2 protein P54646 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser722 PRLRSVSsYGNIRAV 10090 SIGNOR-C3 18439900 t lperfetto These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK SIGNOR-263045 0.686 NFIA protein Q12857 UNIPROT NEUROD1 protein Q13562 UNIPROT up-regulates quantity transcriptional regulation 10090 31838646 t Gianni For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8) SIGNOR-268890 0.286 IKBKB protein O14920 UNIPROT BCL10 protein O95999 UNIPROT up-regulates activity phosphorylation Ser138 NNLSRSNsDESNFSE 9606 BTO:0000007 16818229 t miannu Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling. SIGNOR-276292 0.768 glutamic acid smallmolecule CHEBI:18237 ChEBI NMDA receptor_2B complex SIGNOR-C348 SIGNOR up-regulates activity chemical activation 9606 12871085 t miannu The NMDA receptor, a ligand-gated ion channel composed of the NR1 and NR2 subunits, is located mainly at synapses of CNS neurons. Each receptor has two binding sites for glycine and two binding sites for glutamate SIGNOR-264129 0.8 EXOC8 protein Q8IYI6 UNIPROT Exocyst_EXOC6B variant complex SIGNOR-C491 SIGNOR form complex binding 9606 26240175 t miannu The exocyst is an octameric protein complex that is implicated in the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. SIGNOR-270783 0.914 ATE1 protein O95260 UNIPROT HSPA5 protein P11021 UNIPROT down-regulates quantity by destabilization post transcriptional regulation 9606 BTO:0000567 29295953 t miannu We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. SIGNOR-261345 0.298 Factor VIIIa-IXa complex SIGNOR-C320 SIGNOR F10 protein P00742 UNIPROT up-regulates activity cleavage 10090 BTO:0000131 25769543 t lperfetto The present data point to key roles of FVIII and FIX in FX activation at the site of a platelet thrombus by supporting: (i) thrombin generation, (ii) thrombus growth and platelet phosphatidylserine exposure, and (iii) fibrin formation at the platelet surface. The likely mechanism is that tenase activity via FVIIIa and FIXa, which is confined to the sites of platelet thrombi, generates FXa that directly catalyzes the conversion of prothrombin into thrombin. SIGNOR-263538 0.561 CREB3L1 protein Q96BA8 UNIPROT OXT protein P01178 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000007 35051932 f lperfetto Transcriptional and post-transcriptional regulation of oxytocin and vasopressin gene expression by CREB3L1 and CAPRIN2|By luciferase assays, we demonstrate that CREB3L1 may be a transcription factor regulating Oxt gene expression. By RNA immunoprecipitation assays and northern blot analysis of Oxt mRNA poly(A) tails, we have found that CAPRIN2 binds Oxt mRNA and regulates its poly(A) tail length.|To investigate transcriptional regulation of the OXT gene by CREB3L1, we performed luciferase assays using a proximal Oxt promoter region transfected in HEK293T cells. The expression of full-length CREB3L1 (CREB3L1FL) and a constitutively active CREB3L1 (CREB3L1CA) significantly increased luciferase activity by 5.4- and 3.2-fold, respectively, compared with controls SIGNOR-268555 0.2 carfilzomib chemical CHEBI:65347 ChEBI PSMB2 protein P49721 UNIPROT down-regulates activity chemical inhibition 9606 BTO:0000898 17591945 t miannu Carfilzomib is a tetrapeptide epoxyketone related to epoxomicin (Figure 1A), the latter of which shows high specificity in vitro for the ChT-L proteasome activity. To evaluate the proteasomal inhibitory potential of carfilzomib in MM, extracts from ANBL-6 cells were exposed to increasing concentrations of carfilzomib. Extended exposure to carfilzomib for 5 hours saturated the β5 and β5i active sites in a dose-dependent manner and also led to increased binding to the β1, β1i, β2, and β2i subunits, with maximal binding observed at 50 nM. SIGNOR-259310 0.8 CSNK2A2 protein P19784 UNIPROT TCF7L2 protein Q9NQB0 UNIPROT up-regulates activity phosphorylation Ser60 ETNQNSSsDSEAERR -1 11711551 t llicata We show here that Tcf-4 can be phosphorylated in vitro by protein kinase CK2 stoichiometrically in amino acids Ser-58-Ser-59-Ser-60. Phosphorylation of these residues does not modify the interaction of Tcf-4 with beta-catenin but reduces its association to plakoglobin. | Experiments performed using a Tcf-4 mutant with decreased interaction to plakoglobin demonstrated that binding to this protein negatively affected the transcriptional activity of Tcf-4. SIGNOR-251046 0.383 3,5-diiodo-L-tyrosine smallmolecule CHEBI:15768 ChEBI L-thyroxine smallmolecule CHEBI:18332 ChEBI up-regulates quantity precursor of 9606 28153798 t scontino The synthesis of T3 and T4 is achieved through the transfer of an iodophenoxyl group from a MIT or DIT residue called a ‚Äúdonor‚Äù onto a DIT residue called an ‚Äúacceptor‚Äù. TPO seems to be primarily responsible for catalyzing the oxidations of iodotyrosines. SIGNOR-267038 0.8 MAPK14 protein Q16539 UNIPROT M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 22933625 f apalma The IL-10-mediated shift in macrophage phenotype in injured muscle may be amplified by activation of mitogen-activated protein kinase (MAPK), especially p38 MAPK, through signaling that is antagonized by MAPK phosphatase-1 (MKP-1). SIGNOR-255447 0.7 SHC1 protein P29353 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9823 BTO:0004007 10523831 t lperfetto Phosphorylation of the adapter protein shc by growth factor receptors provides association sites for grb2-sos, thereby activating the ras/map kinase pathway. SIGNOR-235615 0.965 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr130 PAQLLCStPNGLDRG 9606 SIGNOR-C17 10864927 t gcesareni Activation of human cdc25c at the g2/m transition occurs concomitantly with phosphorylation of five serine/threonine-proline sites: thr48, thr67, ser122, thr130, and ser214, presumably by cdc2-cyclin b. SIGNOR-78424 0.855 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT down-regulates activity phosphorylation Thr203 SSLATPPtLSSTVLI 9606 12815053 t lperfetto M phase-specific phosphorylation of brca2 by polo-like kinase 1 correlates with the dissociation of the brca2-p/caf complex.Plk1 interacts with brca2 in vivo, and mutation of ser193, ser205/206, and thr203/207 to ala in br-n1 abolished plk1 phosphorylation, suggesting that brca2 is the substrate of plk1 SIGNOR-102498 0.549 SNAI1 protein O95863 UNIPROT CLDN7 protein O95471 UNIPROT down-regulates quantity by repression transcriptional regulation 9606 BTO:0001570 19277896 f lperfetto We propose that CtBP1 is recruited by SNAI1P at the CLDN7 gene promoter indirectly through another yet to be identified protein. Based on our observations, we propose a model for SNAI1P-mediated down regulation of human CLDN7 gene expression by chromatin remodeling SIGNOR-254104 0.413 P-TEFb complex SIGNOR-C238 SIGNOR POLR2A protein P24928 UNIPROT up-regulates activity phosphorylation 9606 32048991 t miannu Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. To perform this task, Pol II needs to be activated by a complex of proteins called P-TEFb; however, P-TEFb is usually found in an inactive form held by another group of proteins. Yet, it is unclear how P-TEFb is released and allowed to activate Pol II. SIGNOR-261039 0.749 PDGFRA protein P16234 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates 9606 24743741 f To further investigate the signaling pathway through which PDGFRαpromotes the proliferation of PDGFRα+ cells, we used inhibitors of PI3K-Akt and Ras-MAPK pathways, which are known to be downstream signaling pathways of PDGFRα. Thus, both PI3K-Akt and MEK2-MAPK pathways are necessary for PDGFRα-driven proliferation. SIGNOR-254377 0.328 PRKCD protein Q05655 UNIPROT TAGLN protein Q01995 UNIPROT down-regulates activity phosphorylation Ser181 VIGLQMGsNRGASQA -1 11053353 t lperfetto Of the three consensus protein kinase C or casein kinase II phosphorylation sites in SM22, only Ser-181 was readily phosphorylated by protein kinase C in vitro, and such phosphorylation greatly decreased actin binding. SIGNOR-249061 0.33 RPS6KA1 protein Q15418 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Ser9 SGRPRTTsFAESCKP 9606 11584304 t lperfetto S6k then phosphorylates the same serine residue on gsk3 that is targeted by pkb/akt (fig. 1), thereby inhibiting its activity. SIGNOR-110917 0.363 ETV6 protein P41212 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0000960;BTO:0002062 15958056 f irozzo We thus conclude that TEL is also an accelerator for erythroid differentiation upon cytokine stimulation in human hematopoietic cells. We demonstrated in the present study that TEL accelerates erythroid differentiation induced by a physiological cytokine EPO in human leukemia cell line UT-7/GM. SIGNOR-256017 0.7 CSNK2A1 protein P68400 UNIPROT BID protein P55957 UNIPROT up-regulates activity phosphorylation Thr59 EGYDELQtDGNRSSH 9606 BTO:0000567 11583622 t llicata Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid. SIGNOR-250831 0.288 POU5F1 protein Q01860 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 9606 BTO:0001086 25126380 f flangone Sex determining region Y-box 2 (Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells (PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency.  SIGNOR-242067 0.7 STAT3 protein P40763 UNIPROT HSPA1B protein P0DMV9 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 19754877 f miannu Hsp105beta upregulates hsp70 gene expression through signal transducer and activator of transcription-3. Hsp105beta induces Hsp70 expression markedly through the STAT3 pathway in heat-shocked cells. This may represent the mechanism that connects the heat shock protein and STAT families for cell defense against deleterious stress. SIGNOR-255241 0.2 ETS1 protein P14921 UNIPROT ATP2A3 protein Q93084 UNIPROT up-regulates quantity by expression transcriptional regulation 10090 BTO:0000255 12119294 t Luana Ets-1 was able to transactivate the SERCA3 promoter in MoBr 204 as cotransfection of an Ets-1 expression vector increased the activity of the −97/+301-Luc construct by 6-fold. SIGNOR-261601 0.331 PRKCA protein P17252 UNIPROT F11R protein Q9Y624 UNIPROT unknown phosphorylation Thr92 DRVTFLPtGITFKSV -1 7646439 t lperfetto Internal amino acid sequence analysis of the F11 antigen provided information concerning 68 amino acids and suggested two consensus phosphorylation sites for protein kinase C (PKC). The phosphorylation by PKC of the isolated F11 antigen was observed following stimulation by phorbol 12-myristate 13-acetate. SIGNOR-248901 0.325 NSD1 protein Q96L73 UNIPROT RELA protein Q04206 UNIPROT up-regulates methylation Lys218 EIFLLCDkVQKEDIE 9606 SIGNOR-C13 20080798 t miannu Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation. SIGNOR-163454 0.471 CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR SERPINE1 protein P05121 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0001615 22198637 t lperfetto Both CLOCK:ARNTL and CLOCK:ARNTL2 heterodimers powerfully activate the promoter of the PAI-1 gene, officially called SERPINE1 and located on the seventh chromosome (7q21.3-q22), underlying the circadian variation in circulating PAI-1 SIGNOR-253712 0.514 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation Tyr1222 PAFDNLYyWDQDPPE 9606 15156151 t gcesareni Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227 SIGNOR-124860 0.2 ABL1 protein P00519 UNIPROT CD19 protein P15391 UNIPROT up-regulates activity phosphorylation Tyr508 EDMRGILyAAPQLRS 10090 11120811 t gcesareni The results revealed that only tyrosine (Y)490 of CD19 was phosphorylated by c-Abl. SIGNOR-245283 0.543 UBE2I protein P63279 UNIPROT BHLHE40 protein O14503 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 11278694 t miannu  Co-expression of STRA13 and UBC9 led to an increase of the pSTRA13 ubiquitination and subsequent degradation. These data established that UBC9/STRA13 association in cells is of physiological importance, presenting direct proof of UBC9 involvement in the ubiquitin-dependent degradation of pSTRA13. We also checked whether UBC9 is directly involved in pSTRA13 ubiquitination. Taken together, these results strongly suggest that pSTRA13 is targeted for proteolysis by the ubiquitin-dependent proteasome pathway through association with UBC9. SIGNOR-272579 0.329 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 BTO:0000567 9687510 t gcesareni Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha SIGNOR-59443 0.604 ATM protein Q13315 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair. SIGNOR-151441 0.694 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1113 VREAEAAsIKIRTDA -1 11741957 t lperfetto PKC Phosphorylates Serines 1033 and 1045 in Helix H5 SIGNOR-249129 0.395 RELA protein Q04206 UNIPROT EGR1 protein P18146 UNIPROT up-regulates binding 9606 SIGNOR-C13 10671503 t gcesareni The early growth response transcription factor egr-1 can also interact with rela in vitro and regulate nf-kappab transcriptional activity in vivo SIGNOR-75001 0.439 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dl complex SIGNOR-C436 SIGNOR up-regulates activity binding 9606 BTO:0000776 32323266 t scontino The recognition of antigen by the BCR initiates BCR signaling cascade. SIGNOR-268205 0.8 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT up-regulates quantity by stabilization phosphorylation 9606 17157788 t miannu Atm/atr are generally sensors of dna damage, but, together with the checkpoint kinases chk1 and chk2, they also function as response effectors by phosphorylation of key substrates, such as p53, brca1, and nbs1. In particular, p53 phosphorylation leads to protein accumulation and activation, which in turn promotes cell-cycle arrest or apoptosis. SIGNOR-151138 0.841 phenylalanine smallmolecule CHEBI:28044 ChEBI tyrosine smallmolecule CHEBI:18186 ChEBI up-regulates quantity precursor of 9606 NBK536726 t brain lperfetto L-phenylalanine is converted into L-tyrosine in the liver, by the enzyme phenylalanine hydroxylase (PH) in the presence of oxygen, iron, and tetrahydrobiopterin as cofactors SIGNOR-264172 0.8 ASH1L protein Q9NR48 UNIPROT H3C1 protein P68431 UNIPROT up-regulates activity trimethylation Lys37 APATGGVkKPHRYRP -1 21239497 t Gianni We show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases SIGNOR-269055 0.2 MAPK14 protein Q16539 UNIPROT CDX2 protein Q99626 UNIPROT down-regulates quantity by destabilization phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 t miannu ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation SIGNOR-250095 0.421 PSAT1 protein Q9Y617 UNIPROT O-phosphonato-L-serine(2-) smallmolecule CHEBI:57524 ChEBI up-regulates activity chemical modification 3702 30034403 t lperfetto Phosphoserine aminotransferase (PSAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of 3-phosphohydroxypyruvate (3-PHP) to 3-phosphoserine (PSer) in an L-glutamate (Glu)-linked reversible transamination reaction. SIGNOR-268560 0.8 STAT5A protein P42229 UNIPROT NR3C1/STAT5A complex SIGNOR-C84 SIGNOR form complex binding 9606 8878484 t fspada We show here that the glucocorticoid receptor can act as a transcriptional co-activator for stat5 and enhance stat5-dependent transcription. Stat5 forms a complex with the gluco-corticoid receptor which binds to dna independently of the gre. This complex formation between stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a gre-con-taining promoter. SIGNOR-44379 0.54 EVI5 protein O60447 UNIPROT PLK1 protein P53350 UNIPROT down-regulates 9606 16439210 f gcesareni Evi5 antagonizes scf(betatrcp)-dependent emi1 ubiquitination and destruction by binding to a site adjacent to emi1's dsgxxs degron and blocking both degron phosphorylation by polo-like kinases and subsequent betatrcp binding. SIGNOR-143683 0.596 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser688 RLFVENDsPSDGGTP 9606 BTO:0001938 11157749 t llicata We now identify 22 in vivo phosphorylation sites of p130, targeted by diverse kinases, and present evidence for three cyclin-dependent kinase 4(6) [cdk4(6)] specific phosphorylations, which appear critical for controlling the growth-restraining activity of p130. SIGNOR-104687 0.846 RXRA protein P19793 UNIPROT PPARD protein Q03181 UNIPROT up-regulates binding 9606 11237216 t lperfetto Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology SIGNOR-105442 0.57 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Thr8 MSSILPFtPPIVKRL 9606 19114991 t lpetrilli In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity SIGNOR-182983 0.752 AMPA proteinfamily SIGNOR-PF58 SIGNOR Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f inferred from family member Luana AMPAR surface diffusion tunes short-term plasticity. | Accordingly, recent studies have suggested that about half of synaptic AMPARs are organized in nanoclusters that are aligned with presynaptic transmitter release sites, supporting the concept of functional nanocolumns to increase the fidelity of fast excitatory transmission. This peculiar organization might also support the proposal that we made 10 years ago that fast surface diffusion of AMPARs tunes frequency-dependent short-term plasticity (FD-STP) by allowing the fast replacement of desensitized receptors by na√Øve ones. SIGNOR-270304 0.7 TP53 protein P04637 UNIPROT THBS1 protein P07996 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 10029407 f miannu p53 transcriptionally activates expression of the genes encoding epidermal growth factor receptor, matrix metalloproteinase (MMP)-2, cathepsin D, and thrombospondin-1 but represses expression of the genes encoding basic fibroblast growth factor and multidrug resistance-1. SIGNOR-255433 0.449 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 20444238 t gcesareni Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement. SIGNOR-165208 0.429 PPARGC1A protein Q9UBK2 UNIPROT CYP7A1 protein P22680 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000599 16891307 f miannu Overexpression of SRC1 and PGC1alpha by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4alpha-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. SIGNOR-255057 0.441 solifenacin chemical CHEBI:135530 ChEBI CHRM1 protein P11229 UNIPROT down-regulates activity chemical inhibition -1 21524581 t Luana The IC50 values for solifenacin, YM-46303, tiotropium bromide and ipratropium bromide were also determined for reference SIGNOR-258312 0.8 MAPK3 protein P27361 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation 9606 10197981 t gcesareni Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus SIGNOR-66755 0.516 TFEB protein P19484 UNIPROT GOLPH3L protein Q9H4A5 UNIPROT up-regulates quantity by expression transcriptional regulation 32978159 f lperfetto Up-regulated proteins belonged to classes related to protein catabolism, including lysosomal and autophagic proteins (ATP6V1H, CAT, CTSB, CTSC, CTSL, CTSZ, LANCL2, GNS, and PLIN2), endosome/multivesicular body proteins (AP1G1, CHMP1B, CHMP2B, EEA1, RAB7A, and VPS35), Golgi proteins (COPB1 and GALNT5), and the proteasome (PSMA1-5, PSMB2-6, PSMC2-5, PSMD2, PMSD11, and PMSD14) SIGNOR-276793 0.2 WNT16 protein Q9UBV4 UNIPROT FZD3 protein Q9NPG1 UNIPROT up-regulates binding 9606 15578921 t gcesareni Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. SIGNOR-131674 0.608 PRKCA protein P17252 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 BTO:0000017 15647376 t lperfetto Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc)  in the phosphorylation of ezrin t567. SIGNOR-133223 0.537 RPS6KA3 protein P51812 UNIPROT MAD2L1 protein Q13257 UNIPROT up-regulates activity 9606 BTO:0000567 20383198 f lperfetto We also show that this kinase might also participate in the maintenance of the SAC in mammalian cells as Rsk2 knockdown in these cells prevents the kinetochore localization of Mad1, Mad2 and CENP-E under checkpoint conditions. SIGNOR-252039 0.2 ALDH1A3 protein P47895 UNIPROT retinal smallmolecule CHEBI:15035 ChEBI down-regulates quantity chemical modification 9606 21621639 t lperfetto All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes.| An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. SIGNOR-265128 0.8 fenoterol chemical CHEBI:149226 ChEBI ADRB1 protein P08588 UNIPROT up-regulates activity chemical activation 10030 BTO:0000457 20590599 t Luana Finally, comparisons of the rank order of ligands for the three different receptors provide information about relative intrinsic efficacies. Fenoterol is a full and efficacious agonist at the β1-adrenoceptor, ranking third out of the agonists studied. It was also a full agonist at the β2- and β3-adrenoceptors with the highest intrinsic efficacy (i.e. top of Tables 4 and ​and5,5, rank 1).  SIGNOR-257867 0.8 MSX1 protein P28360 UNIPROT LHX2 protein P50458 UNIPROT down-regulates activity binding -1 9697309 t 2 miannu Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity SIGNOR-241330 0.485 STAT6 protein P42226 UNIPROT GATA3 protein P23771 UNIPROT up-regulates 9606 12947222 t GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6 SIGNOR-254299 0.655 Histone H2B proteinfamily SIGNOR-PF68 SIGNOR RNF168 protein Q8IYW5 UNIPROT up-regulates binding 9606 19203578 t gcesareni Rnf168 is recruited to sites of dna damage by binding to ubiquitylated histone h2a. SIGNOR-265372 0.2 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR NF2 protein P35240 UNIPROT down-regulates quantity by destabilization polyubiquitination 9606 BTO:0000007 18332868 t miannu VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasome-mediated degradation. SIGNOR-271674 0.331 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT down-regulates quantity by destabilization cleavage Asp572 PWHSFGAdSVPANTE -1 8943232 t lperfetto FIG. 4. Schematic representation of the major cathepsin D cleavage sites in FLAG-bAPP156-bFGF and in bAPP100-FLAG. The amino acid sequences for the FLAG-bAPP156-bFGF and bAPP100-FLAG substrates are shown. Large arrows denote major cleavage sites. Unique cathepsin D cleavage sites in urea-denatured FLAG-bAPP156-bFGF are labeled (U). Small arrowheads denote minor bAPP100-FLAG cleavage sites determined by mass spectral analysis.|Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism. SIGNOR-261761 0.497 NPFFR1 protein Q9GZQ6 UNIPROT GNAZ protein P19086 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257103 0.253 CDK7 protein P50613 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Thr161 GIPIRVYtHEVVTLW 9606 8344251 t lperfetto The mo15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (cdks) through phosphorylation of thr161 and its homologues SIGNOR-38307 0.568 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1A protein P35348 UNIPROT down-regulates chemical inhibition 9606 Other t Selleck gcesareni SIGNOR-190604 0.8 FN1 protein P02751 UNIPROT SDC4 protein P31431 UNIPROT up-regulates activity binding 9606 23290138 t apalma Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells. SIGNOR-255846 0.705 TBL1X protein O60907 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates activity binding 9606 BTO:0000007 20181957 t miannu TBL1 appears to serve two roles in regulating the activity of β-catenin. Besides the initially identified role of TBL1 in recruiting β-catenin to the SCF(TBL1) complex, it has also been shown to function as a transcriptional co-activator of β-catenin in recruiting it to the promoter site of Wnt target genes. Our results indicated that TBL1 can inhibit the polyubiquitination of β-catenin by Siah-1 in vitro (Fig. 3) and stabilize β-catenin in cells by protecting it from Siah-1-mediated ubiquitination and proteasomal degradation (Fig. 4). SIGNOR-271954 0.649 PTEN protein P60484 UNIPROT STAT5A protein P42229 UNIPROT down-regulates dephosphorylation 9606 20596030 t miannu The forced expression of pten in the eol-1r cells dephosphorylated akt, erk and stat5 /eol-1r cells showed epigenetic silencing of the phosphatase and tensin homolog deleted on chromosome ten (pten) gene. Exposure of eol-1r cells to imatinib failed to dephosphorylate akt, erk and stat5, although pdgfr? Was effectively inactivated. The forced expression of pten negatively regulated these signal pathways and sensitized eol-1r cells to imatinib. SIGNOR-166481 0.446 GPC4 protein O75487 UNIPROT WNT3A protein P56704 UNIPROT up-regulates binding 9606 22302992 t gcesareni Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways SIGNOR-195749 0.354 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKACA protein P17612 UNIPROT up-regulates 9606 BTO:0000938 16537363 f gcesareni Indicating that akt positively regulates shh signaling by controlling pka-mediated gli inactivation. SIGNOR-145113 0.2 KAT6A protein Q92794 UNIPROT CCL3 protein P10147 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 BTO:0000661 12771199 t lperfetto We further demonstrate that the histone acetyltransferase, MOZ, can activate the MIP-1a promoter in T-cells and that this activation is largely dependent upon the proximal RUNX site. Moreover, we show that co-expression of MOZ and RUNX1 can activate the MIP-1a promoter. SIGNOR-251726 0.2 TCL1A protein P56279 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 10983986 t miannu Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation SIGNOR-81683 0.537 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 10606744 t gcesareni Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. SIGNOR-73266 0.567 PRKAB1 protein Q9Y478 UNIPROT RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 t gcesareni Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2. SIGNOR-173041 0.452 EDNRB protein P24530 UNIPROT GNAI3 protein P08754 UNIPROT up-regulates activity binding 9606 BTO:0002524 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257166 0.421 QRICH1 protein Q2TAL8 UNIPROT EARS2 protein Q5JPH6 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269402 0.2 BLK protein P51451 UNIPROT BCR-Mk complex SIGNOR-C433 SIGNOR up-regulates activity phosphorylation 9606 BTO:0000776 32323266 t scontino The CD79 molecules contain signaling molecules called immunoreceptor tyrosine-based activation motifs (ITAMs) in their intracellular portion. ITAMs are bound by the SRC kinases such as LYN, FYN and B-lymphoid tyrosine kinase (BLK). The crosslinking of BCR by specific antigens induces phosphorylation of ITAM tyrosines by these SRC kinases. SIGNOR-268208 0.639 RB1 protein P06400 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates activity binding 9606 8255752 t amattioni E2f binds rb. E2f activation domain is the target for rb-induced repression. Rb can silence the 57 residue e2f activation domain. Rb can mask e2f residues involved in the activation process, possibly by mimicking a component of the transcriptional machinery SIGNOR-37305 0.919 MAPK8 protein P45983 UNIPROT CDT1 protein Q9H211 UNIPROT up-regulates quantity by stabilization phosphorylation Ser391 LRSAAPSsPGSPRPA 9606 BTO:0000567 21930785 t miannu  We discovered that human Cdt1, an essential origin licensing protein whose activity must be restricted to G(1) phase, is a substrate of the stress-activated mitogen-activated protein (MAP) kinases p38 and c-Jun N-terminal kinase (JNK). These MAP kinases phosphorylate Cdt1 both during unperturbed G(2) phase and during an acute stress response. Phosphorylation renders Cdt1 resistant to ubiquitin-mediated degradation during S phase and after DNA damage by blocking Cdt1 binding to the Cul4 adaptor, Cdt2.  SIGNOR-276361 0.374 CFH protein P08603 UNIPROT C3 protein P01024 UNIPROT down-regulates activity binding 9606 19050261 t miannu As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity) SIGNOR-252141 0.917 GNAI1 protein P63096 UNIPROT PLD2 protein O14939 UNIPROT down-regulates binding 9606 9148895 t gcesareni The results of this study suggest that membrane phospholipase d activity can be negatively regulated via gi SIGNOR-48256 0.31 ATF4 protein P18848 UNIPROT AARS1 protein P49588 UNIPROT up-regulates quantity by expression transcriptional regulation 9606 33384352 t miannu QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress. SIGNOR-269414 0.2 PRKCA protein P17252 UNIPROT ARRB1 protein P49407 UNIPROT up-regulates activity phosphorylation Ser163 EKIHKRNsVRLVIRK 9606 BTO:0000661 24502978 t miannu  We demonstrate that β-arrestin-1 recruitment to the TCR, and bystander TCR and CXCR4 downregulation, are mechanistically mediated by the TCR-triggered PKC-mediated phosphorylation of β-arrestin-1 at Ser163.  SIGNOR-276619 0.2 YAP1 protein P46937 UNIPROT GINS1 protein Q14691 UNIPROT up-regulates quantity by expression transcriptional regulation BTO:0001939 30224758 f lperfetto By gene expression, exogenous YAP turns on its targets, but not in cells treated with JQ1 or depleted of BET-proteins (Fig. 3b and Supplementary Fig. 3e), indicating that BRD4 operates downstream of YAP/TAZ. SIGNOR-276566 0.2 KLF4 protein O43474 UNIPROT STAT6 protein P42226 UNIPROT up-regulates 9606 BTO:0000801 22378047 f lperfetto KLF4 cooperates with Stat6 to induce M2 genes (Arg-1, Mrc1, Fizz1, PPAR?) and inhibit M1 genes (TNFa, Cox-2, CCL5, iNOS) via sequestration of coactivators required for NF-kappaB activation. SIGNOR-249569 0.35 WARS1 protein P23381 UNIPROT tRNA(Trp) smallmolecule CHEBI:29181 ChEBI down-regulates quantity chemical modification 9606 14660560 t miannu Aminoacyl-tRNA synthetases (aaRSs)1 are a family of ancient enzymes that catalyze amino acid activation by ATP and the subsequent aminoacylation to its cognate tRNA. Alternative splicing produces two forms of hTrpRS in human cells: full-length hTrpRS (residues 1-471) and mini-hTrpRS (residues 48-471) SIGNOR-270509 0.8 MSL acetyltransferase complex SIGNOR-C344 SIGNOR Histone H2B proteinfamily SIGNOR-PF68 SIGNOR down-regulates activity monoubiquitination 9606 BTO:0000567 21726816 t miannu MSL1/2 ubiquitylates histone H2B on K 34. Importantly, only mono-ubiquitylation of H2B by MSL1/2 was detected in cells (data not shown), suggesting that MSL1/2, like RNF20/RNF40, was mainly a mono-ubiquitylase under physiological conditions.the MOF-MSL complex functions to promote both H4 K16ac and H2B K34ub. H2B K34ub, in turn, promotes H2B K120ub, H3 K4me3 and K79me2 to facilitate transcription elongation. SIGNOR-271978 0.2 FAS protein P25445 UNIPROT FADD protein Q13158 UNIPROT up-regulates activity binding 9606 21959933 t lperfetto Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd. SIGNOR-176651 0.908 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr95 DKTQLNPtSLQKLFR 9606 15319445 t gcesareni Here we show that the protein kinase cdc25 c-associated kinase 1 (c-tak1) is a binding partner and a substrate of pim-1. SIGNOR-259430 0.2 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Thr116 SCDKSTQtPSPPCQA 9606 18498746 t gcesareni Jnk is the physiogically relevant uv-stimulated kinase that phosphorylates bimel on thr-112/jnk-induced bim apoptotic activity SIGNOR-178683 0.682 PTPRS protein Q13332 UNIPROT EGFR protein P00533 UNIPROT down-regulates activity dephosphorylation 9606 12018405 t miannu Similarly, Pestana et al. (89) have reported that overexpression of RPTPsigma in human A431 carcinoma cells partially inhibits EGFR activation, whereas antisense mediated suppression of RPTPsigma expression enhances EGFR activation, substrate phosphorylation, and signalling.|These data indicate that LAR and RPTPsigma may have a significant role in GPCR induced EGFR signalling.Whereas in A431 cells LAR and RPTPsigma may act to suppress the EGFR in response to GPCR activation, it is possible that the converse may also be true in other cell types. SIGNOR-277145 0.436 GEM protein P55040 UNIPROT ROCK2 protein O75116 UNIPROT down-regulates activity binding 9534 16757346 t miannu We have found that Gem binds specifically to ROKβ in the coiled‐coil domain adjacent to the Rho binding site. The interaction between Gem and ROKβ leads to inhibition of MLC and MBS phosphorylation but not phosphorylation of LIMK, indicating that Gem exerts its effect by altering the substrate specificity of ROKβ SIGNOR-261707 0.292 EEF1A1 protein P68104 UNIPROT Ile-tRNA(Ile) smallmolecule CHEBI:29160 ChEBI up-regulates relocalization 9606 23699257 t lperfetto During protein synthesis, eEF1A binds to and delivers aminoacylated tRNAs (aa-tRNAs) to the elongating ribosome (Fig. 1). GTP bound to eEF1A is hydrolyzed upon codon-anticodon match between an aa-tRNA in the A site of the ribosome and mRNA bound to the ribosome. SIGNOR-269512 0.8 ERC1 protein Q8IUD2 UNIPROT CHUK protein O15111 UNIPROT up-regulates binding 9606 SIGNOR-C14 15218148 t miannu Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation. SIGNOR-126430 0.58 LYN protein P07948 UNIPROT ACLY protein P53396 UNIPROT up-regulates activity phosphorylation Tyr227 KVDATADyICKVKWG 9606 BTO:0000007 32420483 t done miannu  We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells. SIGNOR-274104 0.2 ROBO proteinfamily SIGNOR-PF14 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 15916964 t lperfetto Phosphorylation of atf2 by jnk/p38 on thr69/71 is prerequisite to its transcriptional activities SIGNOR-137635 0.2 CSNK2A1 protein P68400 UNIPROT SLBP protein Q14493 UNIPROT down-regulates quantity by destabilization phosphorylation Thr61 ERRPESFtTPEGPKP 9606 phosphorylation:Thr62 RRPESFTtPEGPKPR 18490441 t lperfetto Phosphorylation of Thr61 is necessary for subsequent phosphorylation of Thr60 by CK2 in vitro. Inhibitors of CK2 also prevent degradation of SLBP at the end of S phase. Thus, phosphorylation of Thr61 by cyclin A/Cdk1 primes phosphorylation of Thr60 by CK2 and is responsible for initiating SLBP degradation. SIGNOR-265260 0.331 STK39 protein Q9UEW8 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates activity phosphorylation Ser96 IEDLSQNsITGEHSQ -1 24043619 t miannu  We observed that in vitro activated STE20/SPS1-related proline/alanine-rich kinase (SPAK) complexed to its regulatory MO25 subunit phosphorylated KCC3 at Ser-96 and that in Xenopus laevis oocytes Ser-96 of human KCC3 is phosphorylated in isotonic conditions and becomes dephosphorylated during incubation in hypotonicity, leading to a dramatic increase in KCC3 function. SIGNOR-276597 0.581 BTG2 protein P78543 UNIPROT HOXB9 protein P17482 UNIPROT up-regulates activity binding 9606 BTO:0000567 10617598 t miannu The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. SIGNOR-220987 0.677 Difluprednate chemical CHEBI:31485 ChEBI NR3C1 protein P04150 UNIPROT up-regulates activity chemical activation -1 21182429 t Luana BMP had the highest K(i) value (8.4 × 10(-8) nmol/L), whereas DFB had the lowest (6.1 × 10(-11) nmol/L). The GCRBA of DFBA was intermediate to these 2 values (7.8 × 10(-10) nmol/L). SIGNOR-257886 0.8 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1054 FGLARDIyKDPDYVR 9606 BTO:0000801;BTO:0000876 17658244 t gcesareni Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability. SIGNOR-157081 0.2 TTK protein P33981 UNIPROT USP16 protein Q9Y5T5 UNIPROT down-regulates quantity by destabilization phosphorylation Ser415 VEDEDQDsEEEKDND 9606 BTO:0002181 28380042 t miannu  Usp16 is a TTK phosphorylation substrate.  SIGNOR-277350 0.375 Calcineurin complex SIGNOR-C155 SIGNOR IL6 protein P05231 UNIPROT up-regulates quantity by expression 10090 18177723 f lperfetto Interestingly, since IL-6 production by nerve-mediated skeletal muscle contraction has recently been shown to be partly dependent on the activation of the calcineurin pathway |The fact that IL-6 is produced not only by proliferating satellite cells but also by growing myofibers during hypertrophy SIGNOR-252340 0.255 PTPN6 protein P29350 UNIPROT SH3BP2 protein P78314 UNIPROT down-regulates activity dephosphorylation Tyr448 GDDSDEDyEKVPLPN 9606 16649996 t miannu Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling|adaptor protein 3BP2 serves as a binding protein and a physiological substrate of SHP-1. 3BP2 is phosphorylated on tyrosyl residue 448 in response to TCR activation, and the phosphorylation is required for T c SIGNOR-277172 0.559 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT up-regulates activity cleavage Asn66 GCPKESCnLFVLKDT -1 14583471 t miannu Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Leukolysin Cleaves ProMMP-2 at Asn66-Leu and Asn109-Tyr. SIGNOR-256346 0.38 TDGF1 protein P13385 UNIPROT TGFB1 protein P01137 UNIPROT down-regulates activity binding 9606 17030617 t lperfetto Ere, we provide evidence supporting a novel mechanism in which Cripto inhibits the tumor suppressor function of TGF-beta. Cripto bound TGF-beta and reduced the association of TGF-beta with its type I receptor, TbetaRI. SIGNOR-150006 0.2 FYN protein P06241 UNIPROT GRB10 protein Q13322 UNIPROT down-regulates phosphorylation Tyr67 NASLESLySACSMQS 9606 10871840 t lperfetto Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir. SIGNOR-78702 0.384 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr654 DIHHIDYyKKTTNGR 10116 BTO:0002809;BTO:0001009 8622701 t lperfetto In this report, we describe the identification of six additional autophosphorylation sites (y-463, y-583, y-585, y-653, y-654 and y-730) on fgfr1. We demonstrate that autophosphorylation on tyrosines 653 and 654 is important for activation of tyrosine kinase activity of fgfr1 and is therefore essential for fgfr1-mediated biological responses. SIGNOR-236199 0.2 MAPK11 protein Q15759 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t llicata Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro SIGNOR-173405 0.2 PLK1 protein P53350 UNIPROT BIRC5 protein O15392 UNIPROT up-regulates phosphorylation Ser20 FLKDHRIsTFKNWPF 9606 21148584 t lperfetto Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation|SUR (survivin) SIGNOR-170460 0.573 calcium(2+) smallmolecule CHEBI:29108 ChEBI CIB2 protein O75838 UNIPROT up-regulates activity chemical activation 9606 35408910 t miannu Calcium- and integrin-binding protein 2 (CIB2) is a small EF-hand protein capable of binding Mg2+ and Ca2+ ions. SIGNOR-269667 0.8 IRS1 protein P35568 UNIPROT GRB2 protein P62993 UNIPROT up-regulates activity binding 9606 BTO:0000156 11259577 t lperfetto Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis. SIGNOR-236614 0.799 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates activity chemical inhibition -1 22037378 t Luana Our data set represents the most detailed comprehensive assessment of the reactivity of known and clinical kinase inhibitors across the kinome published to date. | The data also show that for at least 15 of the 27 kinases that are the primary, intended targets for the compounds tested and that are represented in the assay panel, selective inhibitors, as assessed by both absolute selectivity across the kinome and selectivity relative to the primary target, are among the 72 tested here. SIGNOR-258093 0.8 UHMK1 protein Q8TAS1 UNIPROT PAM protein P19021 UNIPROT unknown phosphorylation Ser946 DRLSTEGsDQEKEDD 9606 BTO:0004055 10574929 t lperfetto Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser(949) is the major site phosphorylated by P-CIP2. B SIGNOR-247009 0.452 N-tert-butyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-phenylpropanamide chemical CHEBI:104131 ChEBI HTR1A protein P08908 UNIPROT down-regulates activity chemical inhibition 10029 BTO:0000246 9550290 t miannu Together, these data show that (i) [3H]-S 15535 is a highly selective 5-HT1A receptor ligand which labels both G-protein-coupled and uncoupled 5-HT1A receptors, (ii) antagonists, such as WAY 100,635, which yield monophasic isotherms in competition with both [3H]-agonists and [3H]-antagonists, are not sensitive to the G-protein coupling state of the receptor, but (iii) spiperone and methiothepin behaved as inverse agonists, their competition isotherms with [3H]-S 15535 being modulated in an opposite manner to those of agonists. SIGNOR-258896 0.8 HCK protein P08631 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates activity phosphorylation Tyr771 IGTAEPDyGALYEGR -1 7682059 t lperfetto The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors. SIGNOR-249361 0.672 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 BTO:0000887;BTO:0001260 8702756 t gcesareni Rho-kinase phosphorylates the mlc of intact myosin and activates its mgatpase activity in a gtp_?Rho-dependent manner. SIGNOR-43031 0.638 PPP1CA protein P62136 UNIPROT CCND3 protein P30281 UNIPROT up-regulates dephosphorylation Thr283 QGPSQTStPTDVTAI 9606 16331257 t lperfetto These results support the hypothesis that pp1 constitutively keeps cyclin d3 in a stable, dephosphorylated state SIGNOR-142884 0.247 VHL protein P40337 UNIPROT CARD9 protein Q9H257 UNIPROT down-regulates activity binding 9606 BTO:0000567 17936701 t We found that pVHL associates with the NF-kappaB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. SIGNOR-257603 0.399 17beta-estradiol 3-sulfate(1-) smallmolecule CHEBI:136582 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI up-regulates quantity precursor of -1 7779757 t Luana HEST-1 maximally sulfates β-estradiol and estrone at concentrations of 20 nM. SIGNOR-269748 0.8 miR-495 mirna URS000075C517_9606 RNAcentral Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 19219026 t Luana Here we report that the c-Myc (hereafter referred to as Myc) oncogenic transcription factor, which is known to regulate microRNAs and stimulate cell proliferation, transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells.  SIGNOR-268044 0.4 FGF1 protein P05230 UNIPROT FGFR4 protein P22455 UNIPROT up-regulates binding 9606 1385111 t gcesareni Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides. SIGNOR-18454 0.823 AMPK complex SIGNOR-C15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates activity phosphorylation 9606 17900900 t lperfetto The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt. SIGNOR-252889 0.403 (R)-salbutamol chemical CHEBI:8746 ChEBI ADRB2 protein P07550 UNIPROT up-regulates activity chemical activation 9606 22182578 t Luana  Salbutamol is a well-known β2 adrenoceptor (β2AR) partial agonist. | In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human β2AR (hβ2AR). The transfected hβ2AR showed similar affinity for BCSDs and salbutamol SIGNOR-258326 0.8 ITGB4 protein P16144 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9428518 t gcesareni Stable expression of alpha6beta4 increased carcinoma invasion in a pi3k-dependent manner, and transient expression of a constitutively active pi3k increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more pi3k activity than ligation of beta1 integrins, establishing specificity among integrins for pi3k activation. SIGNOR-54530 0.401 EIF2B2 protein P49770 UNIPROT EIF2S3 protein P41091 UNIPROT up-regulates activity guanine nucleotide exchange factor 9606 15054402 t lperfetto EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity. SIGNOR-269135 0.688 GPER1 protein Q99527 UNIPROT GNG2 protein P59768 UNIPROT up-regulates activity binding 10696571 t GPCRs transduce their signal via G-protein heterotrimers (αβγ) that dissociate in free Gα-subunit protein and Gβγ-subunit protein complexes following ligand stimulation; GNG2 stands for the subunit γ, which dissociates from the receptor after the binding of GTP on α-subunit. SIGNOR-251104 0.368 MAP3K9 protein P80192 UNIPROT MAP3K9 protein P80192 UNIPROT up-regulates activity phosphorylation Thr312 TKMSAAGtYAWMAPE 10029 15610029 t lperfetto We present here biochemical and biophysical evidence that MLK1 is activated by autophosphorylation in (or near) the activation loop. The activation loops of the MLK family are highly homologous, and so one might predict that the same residues would be key to their activation. Functional data presented here, however, demonstrate that the key residue for activation of MLK1, Thr312, differs from the key residue for activation of MLK3. SIGNOR-249388 0.2 MC3R protein P41968 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates activity binding 9606 31160049 t GPCR-Ga dataset Luana Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0. SIGNOR-257407 0.251 RAC1 protein P63000 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates activity binding 10090 BTO:0000142 8107774 t gcesareni A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways. SIGNOR-248236 0.785 DVL3 protein