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 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t llicata "By using a phospho-specific antibody, we show that abl directly phosphorylates pkd at tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of pkd" SIGNOR-99255 sirolimus chemical CHEBI:9168 ChEBI LILRB1 protein Q8NHL6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002042 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1654 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-248738 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 miR-146a mirna URS000075D8A0_9606 RNAcentral CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 20516212 f Luisa "MiR-221 strongly upregulated GAX.ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2." SIGNOR-268952 PRKCA protein P17252 UNIPROT MEP1B protein Q16820 UNIPROT "down-regulates quantity" phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 t miannu "These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate." SIGNOR-263172 FBXO6 protein Q9NRD1 UNIPROT ERO1A protein Q96HE7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 27855403 t miannu "Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex" SIGNOR-272326 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19819937 f "In addition to the JAK2–STAT5 pathway, the Ras GTPase–extracellular signal-regulated kinase (Ras–ERK) pathway has also been implicated in signaling of IL-5 and is important for IL-5-dependent cell survival, proliferation and differentiation of eosinophils." SIGNOR-254355 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT unknown phosphorylation Thr436 FHRNHTAtVRSHAEN 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-249074 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 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser813 DIYSRRLsQETGLEI 9606 1716180 t lperfetto "Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response." SIGNOR-21324 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 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 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 AGT protein P01019 UNIPROT TRPC6 protein Q9Y210 UNIPROT "up-regulates activity" 9606 24850910 f "We demonstrated that Ang II evokes concentration-dependent activation of podocyte TRPC6 channels" SIGNOR-253331 JAK2 protein O60674 UNIPROT RAF1 protein P04049 UNIPROT "up-regulates activity" phosphorylation Tyr341 GQRDSSYyWEIEASE 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-251362 E2F1 protein Q01094 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-253854 "4-(3-chloro-2-fluorophenoxy)-1-[[6-(2-thiazolylamino)-2-pyridinyl]methyl]-1-cyclohexanecarboxylic acid" chemical CHEBI:125340 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194411 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 "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 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-258187 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT "down-regulates activity" phosphorylation Thr386 IGLNQPStPTHAAGV 9606 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-236498 tRNA(Asp) smallmolecule CHEBI:29186 ChEBI Asp-tRNA(Asp) smallmolecule CHEBI:29158 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-270377 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 maraviroc chemical CHEBI:63608 ChEBI CCL4L1 protein Q8NHW4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194009 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 11875057 t gcesareni "In response to ionizing radiation (ir), atm, the gene product mutated in ataxia telangiectasia, stabilizes and activates p53 through phosphorylation of ser15 and (indirectly) ser20. Here we show that phosphorylation of p53 on ser46, a residue important for p53 apoptotic activity, as well as on ser9, in response to ir also is dependent on the atm protein kinase. one pathway involves the phosphorylation of p53 and its negative regulator mdm2 by ataxia telangiectasia mutated (atm) and chk2 causing p53 activation and stabilization." SIGNOR-115344 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2Q1 protein Q7Z7E8 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-271338 CREB1 protein P16220 UNIPROT NR2F1 protein P10589 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000152 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-253792 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 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-129324 CASP6 protein P55212 UNIPROT "Caspase 6 complex" complex SIGNOR-C228 SIGNOR "form complex" binding cleavage:Asp23 EENMTETdAFYKREM 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-256391 MAP1LC3A protein Q9H492 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 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-156353 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-268998 ATM protein Q13315 UNIPROT MCM3 protein P25205 UNIPROT unknown phosphorylation Ser535 ATDDPNFsQEDQQDT 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-126308 TAGLN2 protein P37802 UNIPROT ACTB protein P60709 UNIPROT "down-regulates activity" binding 21577206 t lperfetto "Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation." SIGNOR-265104 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 CAMK2A protein Q9UQM7 UNIPROT RIMS1 protein Q86UR5 UNIPROT up-regulates phosphorylation Ser288 NGKGALKsERKRVPK 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-103890 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 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL4A protein A6NLU0 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-271140 E protein P59637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000661 16048439 f Luana "Overexpression of SARS-CoV E protein in T-cells promoted apoptosis" SIGNOR-260208 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC10 protein Q969S8 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-262252 PSMA4 protein P25789 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-263366 DAPT chemical CHEBI:86193 ChEBI APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191292 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCG protein P05129 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190356 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR BIRC5 protein O15392 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys90 GCAFLSVkKQFEELT 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-272438 UIMC1 protein Q96RL1 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 BTO:0000150 17525342 t gcesareni "Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control" SIGNOR-155201 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 WNT9A protein O14904 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t gcesareni "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-195975 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 miR-155 mirna URS000062749E_9606 RNAcentral MEIS1 protein O00470 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 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-268040 GNAI2 protein P04899 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 19703466 t "Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)" SIGNOR-256499 ELOVL3 protein Q9HB03 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-267893 TGFB1 protein P01137 UNIPROT TGFBR2 protein P37173 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-255030 CSNK2A1 protein P68400 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-250830 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 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 8a protein Q7TFA0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001950 17597455 f Luana "Open Reading Frame 8a of the Human Severe Acute Respiratory Syndrome Coronavirus Not Only Promotes Viral Replication but Also Induces Apoptosis" SIGNOR-260206 PLK1 protein P53350 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-176079 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 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 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 F5 protein P12259 UNIPROT "Factor Va-Xa" complex SIGNOR-C318 SIGNOR "form complex" binding -1 2026608 t lperfetto "The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I" SIGNOR-263558 CSF2RA protein P15509 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 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-249502 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 GLI2 protein P10070 UNIPROT BMP2 protein P12643 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16880529 f gcesareni "The zinc finger transcription factor gli2 mediates bone morphogenetic protein 2 expression in osteoblasts in response to hedgehog signaling" SIGNOR-148346 PIAS4 protein Q8N2W9 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Ser4 sGFESYGS 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair furthermore, phosphorylation of the 34 kda subunit of rpa on ser-4 and ser-8 (ps4/ps8) in response to ir or camptothecin treatment was diminished by pias4 depletion, while pias1 depletion impaired ir-induced but not camptothecin-induced rpa phosphorylation" SIGNOR-162160 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 "SWI/SNF ACTL6B varian" complex SIGNOR-C476 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-270609 CIT protein O14578 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 t Giulio "Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation." SIGNOR-260305 "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 "HAUS complex" complex SIGNOR-C281 SIGNOR NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" relocalization 9606 19427217 t lperfetto "Under NuMA and HAUS6 codepletion conditions, NEDD1 levels on spindle microtubules remained low, suggesting that the suppression observed is not caused by more efficient localization of NEDD1 to spindle microtubules (Figure S9D). Taken together, our results suggest that HAUS and NuMA exert opposing activities necessary for robust bipolar spindle formation." SIGNOR-262331 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0000776 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-153479 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 KDM6A protein O15550 UNIPROT SPI1 protein P17947 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-260036 AZD1480 chemical CID:16659841 PUBCHEM JAK1 protein P23458 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190164 SIRT1 protein Q96EB6 UNIPROT CRTC1 protein Q6UUV9 UNIPROT up-regulates deacetylation 9606 BTO:0000938 BTO:0000142 22179316 t miannu "Sirt1 deacetylates and activates torc1" SIGNOR-191568 FBXO6 protein Q9NRD1 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 27855403 t miannu "Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex" SIGNOR-272331 NDUFB10 protein O96000 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-262163 "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 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 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 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "glutamic acid" smallmolecule CHEBI:18237 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-270381 CDK1 protein P06493 UNIPROT NUP210 protein Q8TEM1 UNIPROT "up-regulates activity" phosphorylation Ser1881 SPPSGLWsPAYASH -1 8672508 t miannu "In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210." SIGNOR-262699 RPL29 protein P47914 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-262471 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 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 PIM1 protein P11309 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 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-128264 NR2E3 protein Q9Y5X4 UNIPROT ESR1 protein P03372 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 22174013 t Luana "NR2E3 directly regulates expression of ESR1 | Furthermore, overexpression of exogenous NR2E3 further increased expression of ESR1 and its downstream targets as well as its transcriptional activity in MCF-7 cells (Fig S1 of Supporting Information), strongly demonstrating that NR2E3 regulates ESR1 expression and subsequent ESR1-mediated induction of target genes." SIGNOR-266207 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 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 YWHAQ protein P27348 UNIPROT GEM protein P55040 UNIPROT "up-regulates quantity by stabilization" binding 9534 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-261724 CBP/p300 complex SIGNOR-C6 SIGNOR EPCAM protein P16422 UNIPROT "up-regulates quantity by expression" "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-254791 RPGRIP1 protein Q96KN7 UNIPROT RPGR protein Q92834 UNIPROT "down-regulates activity" binding 9606 20631154 t miannu "The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. As RPGRIP1 appears to link RPGR to the cilium, it is possible that RPGR's effect on RAB8A function may occur in distinct subcellular compartments of photoreceptors and that RPGRIP1 and other interacting proteins may modulate targeting of RPGR to such compartments." SIGNOR-253031 VKORC1 protein Q9BQB6 UNIPROT "Reduced Vitamin K" smallmolecule CHEBI:8784 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-265901 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ERO1A protein Q96HE7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 27855403 t miannu "Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex" SIGNOR-272332 ETS1 protein P14921 UNIPROT ECE1 protein P42892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000396 9595399 f miannu "Endothelial expression of endothelin-converting enzyme-1 beta mRNA is regulated by the transcription factor Ets-1. We conclude that Ets-1 is involved in transcriptional upregulation of ECE-1 beta mRNA in E.A. hy 926 cells induced by phorbol ester." SIGNOR-254080 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 TGFB1 protein P01137 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7592908 f gcesareni "The steadystate level of p15ink4b mrna was induced 30-fold upon tgf-beta treatment, implicating p15ink4b as a primary effector of the tgf-beta-mediated cell cycle arrest" SIGNOR-29582 PRKCA protein P17252 UNIPROT GJB1 protein P08034 UNIPROT "up-regulates activity" phosphorylation Ser229 QRRSNPPsRKGSGFG -1 8390988 t lperfetto "Phosphorylation of connexin-32 by protein kinase C prevents its proteolysis by mu-calpain and m-calpain. |In agreement with other authors (see Saez et al., 1990b), we have found that phosphorylation of connexin-32 by protein kinase A and protein kinase C occurs in serine residues, although we have detected trace amounts of phosphothreonine in connexin-32 phosphorylated by protein kinase C (results not shown). Indeed, Se233 has been shown to be the major phosphorylation site catalyzed by protein kinase A. However, Ser233, Ser239, and perhaps other serines are phosphorylated by protein kinase C (Saez et al., 1990b)." SIGNOR-248919 ELF2 protein Q15723 UNIPROT VCP protein P55072 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000093 18544453 f "These findings indicate that ELF2 transactivates VCP promoter through binding to two motifs, with a predominant contribution of the upstream one." SIGNOR-254283 CSNK2A1 protein P68400 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" phosphorylation Thr155 DSTPPPGtRVRAMAI -1 12628923 t llicata "CK2 phosphoryl ates Thr155, which targets p53 to degradation by the Ub system." SIGNOR-250968 mTORC1 complex SIGNOR-C3 SIGNOR ATP6V1A protein P38606 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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 TLN1 protein Q9Y490 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 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-257634 "glutamic acid" smallmolecule CHEBI:18237 ChEBI "NMDA receptor_2D" complex SIGNOR-C350 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-264131 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 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 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-131634 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 PARK7 protein Q99497 UNIPROT "MTA1/DJ1 complex" complex SIGNOR-C123 SIGNOR "form complex" binding 9606 BTO:0000567 21368136 t 1 miannu "we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3." SIGNOR-239448 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 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" binding 10029 12242332 t miannu "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. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis." SIGNOR-256210 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT up-regulates phosphorylation Thr488 GAEDSGDtEDELRRV 9606 20471329 t lperfetto "Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair" SIGNOR-165427 HOXB4 protein P17483 UNIPROT IGFBP1 protein P08833 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12489992 t Luana "These data showed that Hox genes selectively activate the transcription of theIGFBP-1" SIGNOR-261636 PRKCA protein P17252 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates activity" phosphorylation Ser37 TASEHRKsSKPIMEK -1 9389649 t lperfetto "Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro." SIGNOR-248992 FBLN5 protein Q9UBX5 UNIPROT ELN protein P15502 UNIPROT up-regulates binding 9606 19570982 t miannu "Our data show that fibulin-5 can interact with tropoelastin or with fibrillin-1, implying a chaperone role for fibulin-5 in directing elastin onto microfibrils" SIGNOR-186603 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 nilotinib chemical CHEBI:52172 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-258259 CDC25C protein P30307 UNIPROT CDK1 protein P06493 UNIPROT up-regulates dephosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 19574738 t gcesareni "Cdk1/cdc2 activation involves tyr15/thr14 dephosphorylation by cdc25c" SIGNOR-186621 metformin chemical CHEBI:6801 ChEBI CRTC2 protein Q53ET0 UNIPROT down-regulates 9606 20577053 f gcesareni "It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm" SIGNOR-166361 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr496 HIIENPQyFSDACVH 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47167 linifanib chemical CHEBI:91435 ChEBI FLT4 protein P35916 UNIPROT "down-regulates activity" "chemical inhibition" -1 16648571 t Gianni "ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families" SIGNOR-262207 TBX2 protein Q13207 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 24470334 f "TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells" SIGNOR-251563 CHRM4 protein P08173 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-256965 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 CSMD1 protein Q96PZ7 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 22538441 t miannu "CSMD1 co-immunoprecipitated with SMAD3, confirming our results that CSMD1 interacts with Smad3 in A375 cells. CSMD1 interacts with Smad3 and induces phosphorylation (p-Smad3). Phosphorylated Smad3 promotes Smad2 phosphorylation and Smad2/3/4 complex formation." SIGNOR-265151 MAPK14 protein Q16539 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-249199 P2RY2 protein P41231 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-265342 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding -1 12620238 t lperfetto "This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral iap repeat (bir3) of xiap at 2.4 a resolution. X-linked inhibitor-of-apoptosis protein (xiap) interacts with caspase-9 and inhibits its activity." SIGNOR-98988 CSNK2A1 protein P68400 UNIPROT FAF1 protein Q9UNN5 UNIPROT "down-regulates activity" phosphorylation Ser289 ITDVHMVsDSDGDDF 9534 12832043 t llicata "We previously identified the Fas-associated factor FAF1 as an in vitro substrate of protein kinase CK2 and determined Ser289 and Ser291 as phosphorylation sites.|Therefore we assume that CK2‐mediated FAF1 phosphorylation influences the nuclear localization of FAF1 | it implies that the major function of FAF1 might not be in the cytoplasm as an interacting partner of Fas." SIGNOR-250863 WDR5 protein P61964 UNIPROT HMT complex SIGNOR-C19 SIGNOR "form complex" binding 9606 17500065 t lperfetto "The evolutionarily conserved hdpy-30, ash2l, rbbp5, and wdr5 likely constitute a subcomplex that is shared by all human set1-like hmt complexes." SIGNOR-154766 NTRK1 protein P04629 UNIPROT SH2B1 protein Q9NRF2 UNIPROT up-regulates binding 9606 BTO:0000938 15082760 t lperfetto "The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons." SIGNOR-124198 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 CERK protein Q8TCT0 UNIPROT "ceramide 1-phosphate(2-)" smallmolecule CHEBI:84404 ChEBI "up-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-268499 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 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 PPARG protein P37231 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20303941 f gcesareni "The results from mammalian one-hybrid experiments showed that functional ppar gamma was necessary for ligand-dependent inhibition of beta-catenin transactivation." SIGNOR-164516 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1721 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-248754 ZNF165 protein P49910 UNIPROT SMURF2 protein Q9HAU4 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-266095 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 RPS6KA3 protein P51812 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 BTO:0001286 17404396 t gcesareni "Our data indicated that phosphorylation of pkr at thr(451) is mediated through erk2 and rsk2, but not through p38 kinase." SIGNOR-154183 Ub:E2 complex SIGNOR-C497 SIGNOR RNF223 protein E7ERA6 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-271259 CREB5 protein Q02930 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" binding -1 8440710 t 2 miannu "CRE-BPa binds to CRE with higher affinity than to the 12-O-tetradecanoylphorbol-13-acetate response element as a homodimer or a CRE-BPa/c-Jun or CRE-BPa/CRE-BP1 heterodimer." SIGNOR-240397 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT up-regulates 9606 23994464 t apalma "Activation of those receptors triggers the dissociation of the GPCR-specific GŒ± subunit from the shared GŒ≤Œ≥ dimer and concomitant activation of various signal transduction pathways by both G-protein fragments" SIGNOR-255009 YAP1 protein P46937 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates binding 9606 14765127 t "Regulation of Runx activity by TAZ or YAP affects mesenchymal stem cell differentiation." gcesareni "Here we show that the endogenous yes-associated protein (yap), a mediator of src/yes signaling, interacts with the native runx2 protein, an osteoblast-related transcription factor, and suppresses runx2 transcriptional activity in a dose-dependent manner." SIGNOR-121803 CDH5 protein P33151 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-265867 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 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-88744 AKT proteinfamily SIGNOR-PF24 SIGNOR PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 t lperfetto "Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation" SIGNOR-234441 DPM2 protein O94777 UNIPROT "DPM complex" complex SIGNOR-C289 SIGNOR "form complex" binding 9606 10835346 t lperfetto "Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3." SIGNOR-262564 GEM protein P55040 UNIPROT ROCK2 protein O75116 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-261711 HLX protein Q14774 UNIPROT CDKN1C protein P49918 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-261620 "bisphenol A" chemical CHEBI:33216 ChEBI ESR2 protein Q92731 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-268739 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 GTF2F1 protein P35269 UNIPROT TFIIF complex SIGNOR-C394 SIGNOR "form complex" binding -1 18218714 t lperfetto "Human general transcription factor IIF (TFIIF), a component of the transcription pre-initiation complex (PIC) associated with RNA polymerase II (Pol II), was characterized by size-exclusion chromatography (SEC), electrospray ionization mass spectrometry (ESI-MS), and chemical cross-linking. Recombinant TFIIF, composed of an equimolar ratio of alpha and beta subunits, was bacterially expressed, purified to homogeneity, and found to have a transcription activity similar to a natural one in the human in vitro transcription system." SIGNOR-266194 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 9606 17804415 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-157725 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 CHKA protein P35790 UNIPROT PLIN3 protein O60664 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr251 ERLRQHAyEHSLGKL 9606 BTO:0000527 34929314 t lperfetto "In addition, as a protein kinase, CHKα2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth " SIGNOR-267650 sapitinib chemical CHEBI:132986 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190152 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1247 AMQSNSPsQEQQQQQ 9606 15173573 t lperfetto "Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp" SIGNOR-125077 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 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 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 CAMK2G protein Q13555 UNIPROT ATF1 protein P18846 UNIPROT "up-regulates activity" phosphorylation Ser63 GILARRPsYRKILKD 8663317 t llicata "Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, 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-250692 CSF2RA protein P15509 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "form complex" binding 9606 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-255582 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR BAD protein Q92934 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000938 15231831 t lperfetto "Casp3 cleaves bad at asp-61. In addition, caspases convert bad(l) into a pro-death fragment that resembles the short splice variant." SIGNOR-256455 "AX/b2 integrin" complex SIGNOR-C171 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-269020 3b protein P59633 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 21561061 f Luana "3b Augments c-Fos Levels by Activating the ERK Pathway. | An increase of∼2.0-fold inphospho ERK (Thr-202/Tyr-204) levels in 3b-expressing Huh7cells as compared to GFP-transfected control cells (Figure 4a)was observed. This increase in phospho ERK levels was also" SIGNOR-260763 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 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000785 16847353 t lperfetto "C-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma" SIGNOR-209593 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1626 SPSYSPTsPSYSPTS -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-248769 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 PICALM protein Q13492 UNIPROT CLTC protein Q00610 UNIPROT up-regulates binding 9606 16491119 t miannu "Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro" SIGNOR-144683 KCNMA1 protein Q12791 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "down-regulates quantity" relocalization 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." SIGNOR-269198 CARS1 protein P49589 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-270805 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Thr17 RVSSYRRtFGGAPGF -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. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro." SIGNOR-100115 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 "leukotriene D4(1-)" smallmolecule CHEBI:63166 ChEBI CYSLTR2 protein Q9NS75 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-257476 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 MAPK14 protein Q16539 UNIPROT SUZ12/EZH2 complex SIGNOR-C77 SIGNOR up-regulates phosphorylation 9606 21902831 t lperfetto "P38 can phosphorylate the histone-lysine n-methyltransferase ezh2, the catalytic subunit of the polycomb repressive complex 2 (prc2), with phosphorylation of ezh2 necessary for prc2s association with the transcriptional repressor yy1 and subsequent chromatin remodelling." SIGNOR-217676 SCF-betaTRCP complex SIGNOR-C5 SIGNOR PER2 protein O15055 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 17876059 t miannu "Here, the authors show that the F-box protein beta-transducin repeat containing protein 1 (beta-TrCP1) as part of the E3 ubiquitin ligase complex is an essential component of the mammalian circadian oscillator. Down-regulation of endogenous beta-TrCP1 as well as expression of a dominant-negative form both result in lengthening of the circadian period in oscillating fibroblasts. These phenotypes are due to an impaired degradation of PERIOD (PER) proteins, since expression of beta-TrCP interaction-deficient PER2 variants--but not wild-type PER2--results in a dramatic stabilization of PER2 protein as well as in the disruption of circadian rhythmicity." SIGNOR-268055 FERMT2 protein Q96AC1 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" binding 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-266101 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 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 CHD4 protein Q14839 UNIPROT ChAHP complex SIGNOR-C407 SIGNOR "form complex" binding 10090 BTO:0002896 29795351 t miannu "Here we show that ADNP interacts with the chromatin remodeller CHD4 and the chromatin architectural protein HP1 to form a stable complex, which we refer to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. In conclusion, CHD4, ADNP and HP1β/γ form a stable protein complex, which we refer to as ChAHP." SIGNOR-266752 PTPRB protein P23467 UNIPROT KDR protein P35968 UNIPROT "down-regulates activity" dephosphorylation Tyr1175 AQQDGKDyIVLPISE 9606 19136612 t "VE-PTP/VEGFR2 complex formation resumes with time, leading to dephosphorylation and deactivation of VEGFR2 (right). B) In VE-PTP-deficient cells, such as after siRNA treatment, VEGFR2 activation (middle) is exaggerated, leading to increased phosphorylation at the Y951 and Y1175 phosphorylation sites" SIGNOR-248441 RAPGEF5 protein Q92565 UNIPROT NRAS protein P01111 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-183738 TP53 protein P04637 UNIPROT TBXAS1 protein P24557 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14586398 f miannu "We demonstrate that p53 and ets-1 coregulate TXSA in an antagonistic and inter-related manner, with ets-1 being a potent transcriptional activator and p53 inhibiting ets-1-dependent transcription." SIGNOR-254086 PRKCE protein Q02156 UNIPROT TICAM2 protein Q86XR7 UNIPROT up-regulates phosphorylation Ser16 NSCPLSLsWGKRHSV 9606 16757566 t llicata "Here we show that tram is transiently phosphorylated by pkcepsilon on serine-16 our study provides a possible target for these molecules in lps signaling. Dag may activate pkc?, Leading to the phosphorylation and activation of tram." SIGNOR-146991 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 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-258001 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR BORA protein Q6PGQ7 UNIPROT "up-regulates activity" phosphorylation 9606 18521620 t gcesareni "Our data additionally identify the cdk1 site s252 as critical for the recruitment of plk1 to hbora. collectively, our findings lead us to propose that hbora contributes to integrate the functions of three major mitotic kinases, cdk1, plk1, and aurora a." SIGNOR-178799 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 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser1068 HKNETMLsPREKIFY 9606 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-104667 TGFB1 protein P01137 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18586026 f gcesareni "These data show that tgf-beta-induced nf-kappab activation is through tak1/mek-mediated aktactivation, which is essential for tgf-beta to support of osteoclast survival" SIGNOR-179179 CSRP3 protein P50461 UNIPROT MYOD1 protein P15172 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-241116 ASXL2 protein Q76L83 UNIPROT PPARG protein P37231 UNIPROT "up-regulates activity" binding 9606 21047783 t miannu "ASXL2, which does not bind HP1, promotes differentiation by binding to PPARγ and increasing the level of methylated H3K4, leading to the elevation of PPARγ activity. Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ." SIGNOR-260063 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 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR ACLY protein P53396 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0002552 27664236 t miannu "Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. " SIGNOR-272335 STON2 protein Q8WXE9 UNIPROT SYT1 protein P21579 UNIPROT "up-regulates quantity" binding 9606 BTO:0000938 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 .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval.  the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively." SIGNOR-264115 PPM1B protein O75688 UNIPROT IKBKB protein O14920 UNIPROT down-regulates dephosphorylation Ser181 DQGSLCTsFVGTLQY 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-181667 piroxicam chemical CHEBI:8249 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-258608 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 APC protein P25054 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "form complex" binding 9606 9734785 t lperfetto "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-227296 MAPK8 protein P45983 UNIPROT RCSD1 protein Q6JBY9 UNIPROT "down-regulates activity" phosphorylation Ser83 PKFKVKSsPLIEKLQ -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-263086 MITF protein O75030 UNIPROT BEST1 protein O76090 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004595 14982938 f miannu "These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression." SIGNOR-254586 LMP1 protein P03230 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" 9606 26428373 f scontino "AP1 is a dimeric transcription factor composed of members of the Jun and Fos protooncoprotein families. AP1 was found induced by LMP1 through the JNK signaling cascade, involving JNK1-mediated phosphorylation and activation of c-Jun. JNK1 activation critically relies on CTAR2 and its P379VQLSYY motif. It has long been unclear which signaling mediators at CTAR2 are involved in JNK activation." SIGNOR-267617 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 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 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 IL20 protein Q9NYY1 UNIPROT IL20RB protein Q6UXL0 UNIPROT up-regulates binding 9606 11163236 t gcesareni "An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis." SIGNOR-151874 MAPK1 protein P28482 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates 9606 BTO:0000130 16709866 f gcesareni "The role of members of the arrestin family to mediate kinase activation is also a well-established phenomenon, including activation of members of the src family, erk1/2, and jnk3. Activation often includes the recruitment and interaction of arrestins with upstream mapks (ask1, mek3, mkk3, and mek kinase-2)." SIGNOR-146751 N protein P59595 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" 9534 15294014 f Luana "Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways." SIGNOR-261131 3b protein P59633 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" 9606 21561061 f Luana "An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260760 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 CDK18 protein Q07002 UNIPROT AQP2 protein P41181 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser261 RQSVELHsPQSLPRG 9606 BTO:0000007 32164329 t lperfetto "CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance" SIGNOR-264562 CYP21A2 protein P08686 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "up-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-268643 DIO3 protein P55073 UNIPROT 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "chemical modification" 9606 12746313 t scontino "Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144." SIGNOR-266942 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr1361 SYEEHIPyTHMNGGK -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-233560 N protein P59595 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9534 BTO:0000298 15294014 f Luana "Furthermore, N expression up-regulated the activity of stress-activated protein kinases, namely the JNK and p38 MAPK pathways." SIGNOR-261132 3a protein P59632 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 BTO:0001950 18632968 f Luana "Severe Acute Respiratory Syndrome Coronavirus 3a Protein Activates the Mitochondrial Death Pathway Through p38 MAP Kinase Activation" SIGNOR-260193 7a protein P59635 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9606 BTO:0000007 16378980 f Luana "While there is a low level of activated p38 normally found in 293T cells, expression of 7a-protein stimulated larger amounts of activated p38 during the 24-h time course. " SIGNOR-260754 E protein P59637 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 10090 BTO:0000763 25122212 f Luana "Interestingly, an increase in p38 MAPK activation was observed during infection with viruses containing E protein PBM, similarly to what was observed in the lungs of SARS-CoV-infected mice. These results indicated that the E protein PBM is involved in p38 MAPK activation in response to SARS-CoV infection." SIGNOR-260751 SLC9A9 protein Q8IVB4 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-265608 "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 AKT proteinfamily SIGNOR-PF24 SIGNOR NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser328 QDAYRRNsVRFLQQR 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-72137 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "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-252877 SETD1B protein Q9UPS6 UNIPROT "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "form complex" binding 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-268796 FBXO33 protein Q7Z6M2 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "up-regulates activity" binding 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-271605 IMP smallmolecule CHEBI:17202 ChEBI "5'-xanthylic acid" smallmolecule CHEBI:15652 ChEBI "up-regulates quantity" "precursor of" 9606 19480389 t miannu "IMPDH controls the gateway to guanine nucleotides, making it an ‚Äúenzyme of consequence‚Äù for virtually every organism. Humans and other mammals have two IMPDH genes, encoding hIMPDH1 and hIMPDH2. 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-267330 FOXL2 protein P58012 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19010791 f miannu "Foxl2 can directly activate the transcription of sirt1" SIGNOR-182300 "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 BRCA1 protein P38398 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 16331276 f miannu "We identified a foxa1 binding site within the brca1-responsive element of the p27(kip1) promoter and showed that foxa1 activated the promoter alone and in conjunction with brca1." SIGNOR-142888 AXIN1 protein O15169 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT up-regulates binding 9606 BTO:0000007 12878610 t gcesareni "Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation." SIGNOR-104003 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 U0126 chemical CHEBI:90693 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 9873633 t lperfetto "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-244958 POU5F1 protein Q01860 UNIPROT ZFP42 protein Q96MM3 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-254944 SRC protein P12931 UNIPROT BCAR1 protein P56945 UNIPROT "up-regulates activity" phosphorylation Tyr192 AGMGHDIyQVPPSMD 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-246393 ARID1A protein O14497 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-269818 Ub:HECT_E3 complex SIGNOR-C518 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-271382 CSNK2A1 protein P68400 UNIPROT MAPK9 protein P45984 UNIPROT unknown phosphorylation Thr404 SSMSTEQtLASDTDS 9606 11062067 t lperfetto "The phosphorylation of thr-404 and ser-407 is not increased in response to other agonists that activate mkk7 and sapk1/jnk, suggesting that phosphorylation of these residues is catalysed by another protein kinase, such as ck2, which also phosphorylates thr-404 and ser-407 in vitro." SIGNOR-83715 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI NTRK1 protein P04629 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-170617 PTK6 protein Q13882 UNIPROT ARAP1 protein Q96P48 UNIPROT "up-regulates activity" phosphorylation Tyr231 PEFDDSDyDEVPEEG 9606 BTO:0000007 20554524 t miannu "ARAP1 associated with PTK6 in an EGF/EGF receptor (EGFR)-dependent manner. In addition, the SH2 domain of PTK6, particularly the Arg(105) residue that contacts the phosphate group of the tyrosine residue, was essential for the association. Moreover, PTK6 phosphorylated residue Tyr(231) in the N-terminal domain of ARAP1. Expression of ARAP1, but not of the Y231F mutant, inhibited the down-regulation of EGFR in HEK293 cells expressing PTK6. These results demonstrate that PTK6 enhances EGFR signaling by inhibition of EGFR down-regulation through phosphorylation of ARAP1 in breast cancer cells." SIGNOR-263188 PPARGC1A protein Q9UBK2 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 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-217966 MCC complex SIGNOR-C382 SIGNOR APC-c complex SIGNOR-C150 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265977 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 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1696 SPSYSPTsPSYSPTS -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-248774 PTGS2 protein P35354 UNIPROT GSK3B protein P49841 UNIPROT down-regulates 9606 BTO:0000586 16293724 f lperfetto "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-141783 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-266532 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser383 IHFWSTLsPIAPRSP 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, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235455 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 PRKACA protein P17612 UNIPROT CACNG2 protein Q9Y698 UNIPROT "down-regulates activity" phosphorylation Thr321 NTANRRTtPV 9534 11805122 t miannu "phosphorylation of stargazin at T321 by PKA inhibits its interaction with PSD-95." SIGNOR-250342 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 "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "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-270925 pazopanib chemical CHEBI:71219 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-258261 PPP1CA protein P62136 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-248564 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 MAP2K3 protein P46734 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation 9606 11062067 t fstefani "Mkk3, mkk4 and mkk6 all show a strong preference for phosphorylation of the tyrosine residue of the thr-gly-tyr motifs in their known substrates sapk2a/p38, sapk3/p38 gamma and sapk4/p38 delta. we therefore examined the phosphorylation of sapk2a/p38, sapk3/p38? And sapk4/p38? By mkk3, mkk4 and mkk6, which are all known to be capable of activating these enzymes in vitro." SIGNOR-83718 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 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 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-257985 INSR protein P06213 UNIPROT IRS2 protein Q9Y4H2 UNIPROT "down-regulates activity" phosphorylation Tyr632 YHPYPEDyGDIEIGS -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-251319 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser139 RRGLLYDsDEEDEER 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-143988 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one chemical CHEBI:91348 ChEBI SYK protein P43405 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-258295 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 APOH protein P02749 UNIPROT cardiolipin smallmolecule CHEBI:28494 ChEBI "down-regulates quantity by destabilization" binding 9606 9596664 t lperfetto "The most relevant physiological role of beta2GPI is supposed to be the regulation of the function of anionic phospholipids like cardiolipin (CL). |Anticardiolipin antibodies or lupus anticoagulants are strongly associated with thrombosis. In these autoimmune diseases with anti-phospholipid antibody syndrome, beta2GPI is a cofactor in the recognition of the phospholipid antigen, CL, by anti-CL antibodies." SIGNOR-266998 EEF1A2 protein Q05639 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 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-269530 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 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 M protein P59596 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0005029 25271362 f Luana "Consistent with our previous result, we detected a reduced phosphorylated PKB/Akt level and diminished PKB/Akt activity in mammalian cells expressing M-protein." SIGNOR-260200 AGTR1 protein P30556 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-257017 PP2B proteinfamily SIGNOR-PF18 SIGNOR PPP1R1A protein Q13522 UNIPROT unknown dephosphorylation 10116 11278334 t "inferred from 70% family members" "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-269991 PLK1 protein P53350 UNIPROT PIN1 protein Q13526 UNIPROT up-regulates phosphorylation Ser65 SHLLVKHsQSRRPSS 9606 BTO:0000567 16118204 t llicata "Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1." SIGNOR-139919 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates 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-120060 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 SUN1 protein O94901 UNIPROT TERB1 protein Q8NA31 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 SIGNOR-C303 SIGNOR-C305 33015044 t lperfetto "In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex." SIGNOR-263299 PLCG2 protein P16885 UNIPROT "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 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-268453 CDK1 protein P06493 UNIPROT TPX2 protein Q9ULW0 UNIPROT "down-regulates activity" phosphorylation Thr72 NLQQAIVtPLKPVDN -1 25688093 t lperfetto "In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle" SIGNOR-265096 STAT6 protein P42226 UNIPROT MRC1 protein P22897 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-249535 CASP3 protein P42574 UNIPROT PARP1 protein P09874 UNIPROT "down-regulates activity" cleavage 10090 BTO:0000331 11907276 t 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-116178 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 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser32 RSRERSPsPLRGNVV 9606 BTO:0000671 15910284 t lperfetto "Dyrk2 (dual-specificity tyrosine-phosphorylated and -regulated protein kinase 2) phosphorylated crhsp24 at ser30, ser32 and ser41 in vitro, and ser41 was identified as a site phosphorylated in cells." SIGNOR-137478 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR SYVN1 protein Q86TM6 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-271126 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 MBTPS1 protein Q14703 UNIPROT CREB3L1 protein Q96BA8 UNIPROT up-regulates cleavage 9606 16417584 t miannu "Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes" SIGNOR-143785 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 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Ala86 PLQKQLPaFISEDAS -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-263566 linifanib chemical CHEBI:91435 ChEBI PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193663 EEF1A2 protein Q05639 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-269527 calcium(2+) smallmolecule CHEBI:29108 ChEBI PRKCZ protein Q05513 UNIPROT up-regulates "chemical activation" 9606 10777564 t gcesareni "Wnt ligands working through frizzled receptors have a differential ability to stimulate release of intracellular calcium (ca(2+)) and activation of protein kinase c (pkc)." SIGNOR-76991 HTR1A protein P08908 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-257088 MAPK11 protein Q15759 UNIPROT RPTOR protein Q8N122 UNIPROT unknown phosphorylation Ser863 LTQSAPAsPTNKGVH 9606 SIGNOR-C3 21757713 t llicata "Arsenite treatment of cells activates p38_ and induces interaction between p38_ and raptor, a regulatory component of mtorc1, resulting in phosphorylation of raptor on ser(863) and ser(771). The phosphorylation of raptor on these sites enhances mtorc1 activity, and contributes largely to arsenite-induced mtorc1 activation." SIGNOR-174874 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1871 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-120132 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 PPP2CA protein P67775 UNIPROT EIF4E protein P06730 UNIPROT down-regulates dephosphorylation Ser209 DTATKSGsTTKNRFV 9606 20927323 t tpavlidou "A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function." SIGNOR-168306 PRKCA protein P17252 UNIPROT KRT18 protein P05783 UNIPROT unknown phosphorylation Ser53 ISVSRSTsFRGGMGS -1 7523419 t lperfetto "Ser-52 in K18 is not glycosylated and matches consensus sequences for phosphorylation by CAM kinase, S6 kinase and protein kinase C, and all these kinases can phosphorylate K18 in vitro predominantly at that site." SIGNOR-248894 HCFC1 protein P51610 UNIPROT ZBTB17 protein Q13105 UNIPROT "down-regulates activity" binding 9534 BTO:0001538 12244100 t miannu "We show here that HCF-1 directly binds to the Myc-interacting protein Miz-1. HCF-1 Represses Gal4-Miz-1-mediated Transcriptional Activation" SIGNOR-223590 NOTCH proteinfamily SIGNOR-PF30 SIGNOR PAX7 protein P23759 UNIPROT "up-regulates quantity by expression" 9606 BTO:0001103;BTO:0002314 22493066 f 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-254343 BLOC-1 complex SIGNOR-C381 SIGNOR histamine smallmolecule CHEBI:18295 ChEBI "up-regulates quantity" relocalization 9606 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules" SIGNOR-265998 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 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 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 SNX5 protein Q9Y5X3 UNIPROT DOCK1 protein Q14185 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18596235 t miannu "SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding." SIGNOR-269441 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TOB1 protein P50616 UNIPROT down-regulates phosphorylation 9606 12050114 t "inferred from 70% family members" gcesareni "Tob is rapidly phosphorylated at Ser 152, Ser 154, and Ser 164 by Erk1 and Erk2 upon growth-factor stimulation." SIGNOR-270210 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 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 9606 15611135 t gcesareni "We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines." SIGNOR-132551 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 TULP3 protein O75386 UNIPROT GPR161 protein Q8N6U8 UNIPROT "up-regulates activity" relocalization 10090 23332756 t "Upon knockdown of Tulp3 using siRNA in IMCD3 cells, ciliary localization of Gpr161 was severely reduced" SIGNOR-259938 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 CDK13 protein Q14004 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-176844 C1QA protein P02745 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-263390 PAK1 protein Q13153 UNIPROT PA2G4 protein Q9UQ80 UNIPROT up-regulates phosphorylation Thr261 QYGLKMKtSRAFFSE 9606 BTO:0000150 18283314 t llicata "We found that pak1 phosphorylated ebp1 in vitro and mapped the phosphorylation site to threonine 261. these studies demonstrate for the first time that ebp1 is a substrate of pak1 and the importance of the pak1 phosphorylation site for the functional activity of ebp1 in breast cancer cells." SIGNOR-160963 MAPK14 protein Q16539 UNIPROT SLC9A1 protein P19634 UNIPROT up-regulates phosphorylation Ser726 IDPASPQsPESVDLV 9606 18701649 t gcesareni "Such results suggest that during apoptosis, oxidative stress could activate p38 mapk, phosphorylating nhe1 at s726 and s729." SIGNOR-180044 ECM stimulus SIGNOR-ST20 SIGNOR "A9/b1 integrin" complex SIGNOR-C166 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-259048 AURKC protein Q9UQB9 UNIPROT TACC1 protein O75410 UNIPROT "up-regulates activity" phosphorylation Ser228 ELVPSRRsKLRKPKP -1 21531210 t miannu "Aurora-C interacts with and phosphorylates the transforming acidic coiled-coil 1 protein. The results demonstrated that TACC1 is phosphorylated by Aurora-C on a serine at position 228. although the patho-physiological meaning of TACC1 phosphorylation by Aurora-C in normal and in malignant somatic cells remains to be fully investigated, our observations suggest that Aurora-C has a role in the later stage of mitosis, when an interaction with TACC1 may be relevant for the correct progression of the cell cycle." SIGNOR-262663 "A1/b1 integrin" complex SIGNOR-C159 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-269008 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 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1675 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-120012 MED18 protein Q9BUE0 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-266672 RAR proteinfamily SIGNOR-PF45 SIGNOR RXR proteinfamily SIGNOR-PF44 SIGNOR "up-regulates activity" binding 9606 1310351 t miannu "Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins." SIGNOR-256198 APC-c complex SIGNOR-C150 SIGNOR DTYMK protein P23919 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 16103219 t miannu "We demonstrate that TMPK is recognized and degraded by APC/C-Cdc20/Cdh1-mediated pathways from mitosis to the early G1 phase, whereas TK1 is targeted for degradation by APC/C-Cdh1 after mitotic exit. " SIGNOR-272653 FZR1 protein Q9UM11 UNIPROT ANLN protein Q9NQW6 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 16040610 t miannu " Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin." SIGNOR-272654 "SAM complex" complex SIGNOR-C422 SIGNOR "Insertion into mitochondrial membrane" phenotype SIGNOR-PH193 SIGNOR up-regulates 33408415 f lperfetto "The mitochondrial outer membrane contains so-called β-barrel proteins, which allow communication between the cytosol and the mitochondrial interior1-3. Insertion of β-barrel proteins into the outer membrane is mediated by the multisubunit mitochondrial sorting and assembly machinery (SAM, also known as TOB)" SIGNOR-267687 ERC1 protein Q8IUD2 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates binding 9606 15218148 t lperfetto "Elks likely functions by recruiting ikappabalpha to the ikk complex and thus serves a regulatory function for ikk activation." SIGNOR-217448 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 YY1 protein P25490 UNIPROT GDAP1 protein Q8TB36 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19720140 f miannu "Overexpression of YY1 activated the GDAP1 promoter in a reporter gene system as well as increased the level of endogenous mRNA." SIGNOR-255618 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 LRFN5 protein Q96NI6 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu "The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons." SIGNOR-264093 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 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-262992 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser425 SIRCSSVs 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto "A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus" SIGNOR-235380 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 EDNRB protein P24530 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-257379 SIRT3 protein Q9NTG7 UNIPROT CYP11A1 protein P05108 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys148 LKKSAAWkKDRVALN 9606 BTO:0002588 22585829 t lperfetto "Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis." SIGNOR-268717 GABRB1 protein P18505 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-263751 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI TAL2 protein Q16559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24816818 f irozzo "These results demonstrate for the first time that atRA induces Tal2 expression in P19 cells, and suggest that TAL2 commits to the acquisition of neural fate in brain development." SIGNOR-259087 RPS6KA1 protein Q15418 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser52 TRRTRTFsATVRASQ 9606 BTO:0000671 15910284 t lperfetto "These and other results demonstrate that crhsp24 is phosphorylated at ser52 by pkbalpha in response to igf-1, at ser52 by pkbalpha and rsk in response to egf" SIGNOR-137482 JARID2 protein Q92833 UNIPROT NPPA protein P01160 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0003324 15542826 f 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-224790 E2F1 protein Q01094 UNIPROT RRM1 protein P23921 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-253852 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 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one chemical CID:56593482 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258321 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 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT "up-regulates activity" cleavage Arg494 CAKTKQLrVVNGIPT -1 12372819 t miannu "the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain." SIGNOR-256514 PTEN protein P60484 UNIPROT PINK1 protein Q9BXM7 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-260056 DLGAP2 protein Q9P1A6 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-264589 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 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 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI1 protein P08151 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni "Gant58 is a gli antagonist that inhibits gli1-induced transcription" SIGNOR-188863 CDK2 protein P24941 UNIPROT USP37 protein Q86T82 UNIPROT "up-regulates activity" phosphorylation Ser628 MVNSCITsPSTPSKK 9606 SIGNOR-C83 21596315 t lperfetto "There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity" SIGNOR-265045 CRHR1 protein P34998 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 22869609 t lperfetto "Previous studies have indicated that CRHR could couple to multiple Galpha proteins including Gs, Gi, and Gq/11 and then go on to induce changes in AC activity and activation of PLC-beta3" SIGNOR-268617 TAB3 protein Q8N5C8 UNIPROT MAP3K7 protein O43318 UNIPROT "up-regulates activity" binding 9606 14670075 t lperfetto "We have identified a new binding partner of the tgfbeta (transforming growth factor-beta)-activated protein kinase (tak1), termed tab.two distinct tak1 complexes are present in cells. One comprises tak1 complexed with tab1 and tab2, and the other tak1 complexed with tab1 and tab3 (tak1-binding protein-3). Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1." SIGNOR-120325 ropinirole chemical CHEBI:8888 ChEBI DRD3 protein P35462 UNIPROT "up-regulates activity" "chemical activation" -1 9057850 t miannu "Compound (R)-6, the most active compound, showed dopaminergic D2 activity and also had affinity for the 5HT1A serotonin receptor subtype. Its dopaminergic activity was more selective for the D2 receptor subtype (259-fold D2/D3 selectivity) than propylamine analogue (R)-2 (14-fold selectivity) or other dopaminergic standards (e.g., pergolide, lisuride, bromocriptine, and ropinirole, 1.0-, 3.4-, 8.7-, and 2.6-fold selectivities, respectively)" SIGNOR-258601 NMBR protein P28336 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-257047 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI GNG12 protein Q9UBI6 UNIPROT up-regulates "chemical activation" 9606 16293724 t gcesareni "Although pge2 promotes nucleotide exchange on gas and subsequent dissociation of gtp-bound gas from gbg subunits." SIGNOR-141820 RAC1 protein P63000 UNIPROT BAIAP2 protein Q9UQB8 UNIPROT up-regulates binding 9606 11130076 t gcesareni "Here we demonstrate that irsp53, a substrate for insulin receptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex." SIGNOR-85302 TLRs proteinfamily SIGNOR-PF20 SIGNOR TIRAP protein P58753 UNIPROT "up-regulates activity" binding 9606 20404851 t lperfetto "These differences are explained by the discovery of TIR domain’containing adaptor molecules, including MyD88, TIRAP (Mal), TRIF and TRAM, which are recruited by distinct TLRs and activate distinct signaling pathways" SIGNOR-216298 GNB/GNG complex SIGNOR-C202 SIGNOR PLCB2 protein Q00722 UNIPROT up-regulates 23994464 t apalma "However, it was later shown that other PLCβ isoforms (particularly PLCβ2 and PLCβ3) can also be directly activated by Gβγ subunits" SIGNOR-255015 AKT1 protein P31749 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 9373175 t gcesareni "Evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9" SIGNOR-252546 TLE2 protein Q04725 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates binding 9606 19460168 t gcesareni "Mapping studies reveal that groucho/tle binds two regions in lef-1." SIGNOR-185736 CSNK1A1L protein Q8N752 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation 9606 19293931 t gcesareni "Ck1 also phosphorylates lrp6 at the second ser residue in the pppspxs motif ck1_ in the lrp5/e-cadherin/p120-catenin complex temporally coincides with p120-catenin phosphorylation in ser268. moreover, and considering the close similarity between the catalytic domains of ck1_ and ck1_, it is possible that ck1_ is indeed responsible for the phosphorylation at ser1420 and ser1430 in lrp5/6 that negatively affects wnt signaling by still not defined mechanisms" SIGNOR-184699 SLC1A6 protein P48664 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-264805 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 TLR9 protein Q9NR96 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-266748 vorinostat chemical CHEBI:45716 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-257917 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr70 RNSPVTKtPPRDLPT 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-101127 Ub:E2 complex SIGNOR-C497 SIGNOR RNF212B protein A8MTL3 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-271257 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 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 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT "down-regulates activity" phosphorylation Thr715 PMRFRSAtTSGAPGV 10090 SIGNOR-C469 21148297 t miannu "RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase" SIGNOR-269799 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 MC5R protein P33032 UNIPROT GNAS protein Q5JWF2 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-268712 ODC1 protein P11926 UNIPROT spermidine smallmolecule CHEBI:16610 ChEBI "up-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-256038 GATA2 protein P23769 UNIPROT TRH protein P20396 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000318 33201916 t scontino "The rat prepro-TRH gene is activated by GATA2." SIGNOR-267259 RPS6KA3 protein P51812 UNIPROT H2BC3 protein P33778 UNIPROT unknown phosphorylation Ser33 DGKKRKRsRKESYSI 9606 21646345 t lperfetto "Here, we studied the histone h2b core domain and found that phosphorylation of h2b serine 32 occurs in normal cycling and mitogen-stimulated cells. Notably, this phosphorylation is elevated in skin cancer cell lines and tissues compared with normal counterparts. We identified ribosomal s6 kinase 2 (rsk2) as the kinase responsible for h2bs32 phosphorylation." SIGNOR-174026 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 NDUFA8 protein P51970 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 ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added" SIGNOR-262159 FOXL2 protein P58012 UNIPROT Cell_death phenotype SIGNOR-PH109 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-256643 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 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 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 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCG protein P05129 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191499 zotepine chemical CHEBI:32316 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-258554 BBC3 protein Q9BXH1 UNIPROT MCL1 protein Q07820 UNIPROT down-regulates binding 9606 15694340 t gcesareni "Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1." SIGNOR-133817 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Ser187 RIMEKADsNKTRIDE 9606 12459461 t lperfetto "This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C" SIGNOR-249178 GRHL2 protein Q6ISB3 UNIPROT ZEB1 protein P37275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 23814079 f miannu "we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells." SIGNOR-255624 DRD4 protein P21917 UNIPROT GNB5 protein O14775 UNIPROT "up-regulates activity" binding 9606 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-264995 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 UBE2N protein P61088 UNIPROT TRIM63 protein Q969Q1 UNIPROT "up-regulates activity" ubiquitination -1 19240029 t miannu "We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s." SIGNOR-272737 N-[(2S)-1-[[(2S)-1-[[3-[4-(Aminomethyl)piperidine-1-carbonyl]phenyl]methylamino]-3-methyl-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]-1,2-oxazole-5-carboxamide chemical CID:49843508 PUBCHEM F2RL1 protein P55085 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20873792 t "Simone Vumbaca" "Agonist GB110 (19, EC50 0.28 μM) selectively induced PAR2-, but not PAR1-, mediated intracellular Ca2+ release in HT29 human colorectal carcinoma cells." SIGNOR-261125 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 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 TNFSF11 protein O14788 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-253044 PRKCA protein P17252 UNIPROT TRPM4 protein Q8TD43 UNIPROT up-regulates phosphorylation Ser1145 RDKRESDsERLKRTS 9606 15590641 t gcesareni "Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites." SIGNOR-132243 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 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 CREB1 protein P16220 UNIPROT NR2F6 protein P10588 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-253793 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244862 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 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 "HIRA complex 1" complex SIGNOR-C461 SIGNOR H3-3A protein P84243 UNIPROT "up-regulates quantity by stabilization" 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-269439 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 Ub:E2 complex SIGNOR-C497 SIGNOR SMURF1 protein Q9HCE7 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-271290 CDK1 protein P06493 UNIPROT PAPOLA protein P51003 UNIPROT "up-regulates activity" phosphorylation Ser545 PTSATKTsPLNSSGS 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-268339 CDK5 protein Q00535 UNIPROT LMTK2 protein Q8IWU2 UNIPROT up-regulates phosphorylation Ser1450 LQTSKYFsPPPPARS 9606 BTO:0000938 BTO:0000142 22220831 t gcesareni "Here, we demonstrate that lmtk2 is phosphorylated on serine-1418 (lmtk2ser ) by cdk5/p35 and present evidence that this regulates its ability to phosphorylate pp1cthr __" SIGNOR-195329 glyburide chemical CHEBI:5441 ChEBI CFTR protein P13569 UNIPROT "down-regulates activity" "chemical inhibition" 10090 BTO:0000944 1281220 t miannu "The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively." SIGNOR-258344 GABRG2 protein P18507 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-263752 "Neuronal AP-3" complex SIGNOR-C445 SIGNOR Platelet_dense_granule_formation phenotype SIGNOR-PH181 SIGNOR up-regulates 9606 BTO:0000132 12019270 f miannu "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-268523 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 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 WDR5 protein P61964 UNIPROT "MLL/SET subcomplex" complex SIGNOR-C87 SIGNOR "form complex" binding 9606 24680668 t miannu "Dimethylation of h3k4 requires a sub-complexincluding 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-204828 STAT1 protein P42224 UNIPROT S100A10 protein P60903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567;BTO:0002923 12645529 f miannu "IFN-gamma induced a rapid tyrosine phosphorylation and nuclear translocation of STAT1 protein, which is involved in the binding to the GAS-2 site in the p11 promoter by EMSA analysis. These data suggest that IFN-gamma-induced p11 expression is mediated through the binding of STAT1 to GAS sites in the p11 promoter." SIGNOR-255237 SLBP protein Q14493 UNIPROT H2BC5 protein P58876 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-265378 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 GHSR protein Q92847 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-257054 Ub:E2 complex SIGNOR-C497 SIGNOR PHRF1 protein Q9P1Y6 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-271075 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 SPOP protein O43791 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 15897469 t miannu "Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30)." SIGNOR-272659 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "long-chain fatty acid anion" smallmolecule CHEBI:57560 ChEBI "up-regulates quantity" "precursor of" 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-269658 CDK2 protein P24941 UNIPROT MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Ser577 RKPGLRRsPIKKVRK 9606 SIGNOR-C83 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-62353 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 SYCP3 protein Q8IZU3 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "form complex" binding 9606 22394509 t miannu "The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region." SIGNOR-264200 CDK1 protein P06493 UNIPROT NINL protein Q9Y2I6 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser589 NRHSPSWsPDGRRRQ 9606 20890132 t miannu "In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation." SIGNOR-259831 HAX1 protein O00165 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 18971376 t lperfetto "The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels." SIGNOR-262052 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr900 FGLSRDVyEEDSYVK 9606 16928683 t gcesareni "Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation" SIGNOR-148992 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20570526 t Luana "Sunitinib [inhibits KDR, PDGFR2, PDGFRβ, c-KIT and FLT3; approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors]," SIGNOR-257850 MGluR proteinfamily SIGNOR-PF55 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." SIGNOR-264930 "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 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 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 GART protein P22102 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 ChEBI "up-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-267304 MSH6 protein P52701 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "form complex" binding 9606 15064730 t miannu "The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors." SIGNOR-123708 PIM proteinfamily SIGNOR-PF34 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 10837473 t gcesareni "Similar to pim1, pim2 phosphorylates bad, which antagonizes the pro-apoptotic function of bax" SIGNOR-259418 EIF3_complex complex SIGNOR-C401 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-269162 IL4R protein P24394 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 20824124 t "Several cytokine receptors share subchains and targets. For example, the common gamma chain (CGC) is shared by IL2, IL4, IL7, IL9 and IL15 receptors that lead to the activation of STAT5" SIGNOR-254298 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 BTO:0001253 9811851 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-61549 RPS28 protein P62857 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-262423 ETV6 protein P41212 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002883 16828711 f miannu "Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma." SIGNOR-254138 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 ADCY7 protein P51828 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-265007 IKBKE protein Q14164 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 BTO:0000150 19940156 t lperfetto "Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna." SIGNOR-161834 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 CAST protein P20810 UNIPROT CAPN3 protein P20807 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-251603 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 DPF3 protein Q92784 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-270730 D-glucopyranose smallmolecule CHEBI:4167 ChEBI AMP smallmolecule CHEBI:456215 ChEBI down-regulates 9606 10409121 f gcesareni "The activation in response to glucose removal appeared to be due to changes in the concentration of the known regulators of the cascade, i.e. Amp and atp, since ampk activation was associated with a large increase in the cellular amp." SIGNOR-69249 HSPA1B protein P0DMV9 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-252198 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 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-271308 IFNG protein P01579 UNIPROT RIPK2 protein O43353 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-252410 CIITA protein P33076 UNIPROT HLA-DRA protein P01903 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-254008 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1784 TPTSPNYsPTSPSYS 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-203556 MAPK3 protein P27361 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252759 PPP2CA protein P67775 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 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-269918 AIMP1 protein Q12904 UNIPROT SMURF2 protein Q9HAU4 UNIPROT "up-regulates activity" binding 9606 18448069 t lperfetto "Here, we report that AIMP1 negatively regulates TGF-_ signaling via stabilization of Smurf2." SIGNOR-227470 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000801 10973958 t lperfetto "The pathway restricted (r)Smads (e.g. Smad1, 2, 3, and 5) are serine/threonine kinase activated proteins that interact in an unphosphorylated state with a TGF-b superfamily receptor. Upon ligand binding they are phosphorylated by the receptor and released." SIGNOR-249549 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 CDX2 protein Q99626 UNIPROT UGT1A10 protein Q9HAW8 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-253968 CUL5 protein Q93034 UNIPROT ARIH2 protein O95376 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-268843 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001412 8394219 f "We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death." SIGNOR-255722 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 "(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 MGluR proteinfamily SIGNOR-PF55 SIGNOR up-regulates "chemical activation" 9606 Other t "Selleck|inferred from family member" gcesareni SIGNOR-270281 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "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) and p38 subs of map kinases, respectively. 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-83721 PLK1 protein P53350 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser30 EADSPSDsGQGSYET 9606 16885021 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-148442 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 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 PTPN1 protein P18031 UNIPROT MET protein P08581 UNIPROT down-regulates dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 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-145141 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide chemical CHEBI:125619 ChEBI HTR1A protein P08908 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207779 STARD8 protein Q92502 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-260520 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr283 YQPYQSIyVGGMMEG 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-45343 GABARAP protein O95166 UNIPROT GPHN protein Q9NQX3 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 25882190 t miannu "The GABA(A)R-associated protein GABARAP was found to bind to the gamma2 subunit of GABA(A)Rs. Here we show that GABARAP interacts with gephyrin in both biochemical assays and transfected cells. Our data indicate that GABARAP-gephyrin interactions are not important for postsynaptic GABA(A)R anchoring but may be implicated in receptor sorting and/or targeting mechanisms." SIGNOR-264971 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" 9606 BTO:0000093 8415704 t "PML-RAR alpha chimera cooperates with c-Jun and, strikingly, with c-Fos to stimulate the transcription of both synthetic and natural reporter genes containing an AP-1 site" SIGNOR-259940 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 MRPS10 protein P82664 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-267731 RARA protein P10276 UNIPROT RXRG protein P48443 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1310351 f gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16469 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT "down-regulates activity" phosphorylation Ser52 EDNVQYVsMRKALKV -1 23954429 t miannu "the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters." SIGNOR-266371 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 t miannu "FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8." SIGNOR-271634 GLS2 protein Q9UI32 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-266911 JNK proteinfamily SIGNOR-PF15 SIGNOR HNRNPK protein P61978 UNIPROT up-regulates phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t lperfetto "Using modified jnk and its atp analogue enables the detection of novel jnk substrates. Among substrates identified using this approach is heterogeneous nuclear ribonucleoprotein k, which is involved in transcription and post-transcriptional mrna metabolism. The newly identified substrate can be phosphorylated by jnk on amino acids 216 and 353, which contribute to heterogeneous nuclear ribonucleoprotein k mediated transcriptional activities." SIGNOR-105758 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 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-121705 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1878 SPKYSPTsPTYSPTT 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-203572 Gbeta proteinfamily SIGNOR-PF4 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 t "inferred from 70% family members" lperfetto "Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein" SIGNOR-270099 EXOSC3 protein Q9NQT5 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-261382 CIITA protein P33076 UNIPROT IL4 protein P05112 UNIPROT down-regulates "transcriptional regulation" 9606 BTO:0000782 10946277 f "We identified two domains of CIITA that interact with two distinct domains of CBP/p300 that are also recognized by NF-AT. CIITA mutants that retain the ability to interact with CBP/p300 are sufficient to inhibit NF-AT-mediated IL-4 gene expression" SIGNOR-254499 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" -1 24015967 t Gianni "This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation" SIGNOR-262204 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 JAK2 protein O60674 UNIPROT CSF2RA/CSF2RB complex SIGNOR-C212 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000801 8977526 t irozzo "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-256001 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 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-169841 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Ser360 RKTQTSMsLGTTREK 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-266428 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 Ub:E2 complex SIGNOR-C497 SIGNOR RNFT1 protein Q5M7Z0 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-271262 ARAP1 protein Q96P48 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-260452 PRKCD protein Q05655 UNIPROT C5AR1 protein P21730 UNIPROT down-regulates phosphorylation Ser334 SVVRESKsFTRSTVD 9606 10636859 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-73967 EGR1 protein P18146 UNIPROT FAP protein Q12884 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000567 20515787 f "Down-regulation of EGR1 resulted in a significant reduction in endogenous FAP mRNA expression. These findings identify the basal transcriptional requirements of FAP gene expression and show EGR1 is an important regulator of FAP expression." SIGNOR-254248 JNK proteinfamily SIGNOR-PF15 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser230 PEGATPTsPVGHFAK 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-252953 Ub:E2 complex SIGNOR-C497 SIGNOR RNF125 protein Q96EQ8 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-271212 CCN4 protein O95388 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 10116 11782444 t "Here it is shown that WISP-1 can activate the antiapoptotic Akt/PKB signaling pathway." SIGNOR-256269 FKBP5 protein Q13451 UNIPROT YY1 protein P25490 UNIPROT "up-regulates activity" 9606 BTO:0000848 34589486 f miannu "FKBP51 Affects the Binding of YY1 Repressor to DR5 Gene. These results suggest that reduced YY1 DNA-binding activity in FKBP51-silenced cells corresponds to reduced YY1 acetylation." SIGNOR-268792 CCL21 protein O00585 UNIPROT CCR7 protein P32248 UNIPROT up-regulates binding 9606 BTO:0000671 11970971 t gcesareni "The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7." SIGNOR-117566 3-isobutyl-1-methylxanthine chemical CHEBI:48518 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-106478 ibuprofen chemical CHEBI:5855 ChEBI PTGS1 protein P23219 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-258605 APH1A protein Q96BI3 UNIPROT PSEN2 protein P49810 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 t gcesareni "Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. 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-93265 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 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 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 ADRA1A protein P35348 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-257195 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 NHS protein Q6T4R5 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 20332100 f miannu "We demonstrate that NHS is essential for maintaining cell morphology through the regulation of actin cytoskeletal dynamics and suggest that an important mechanism of remodelling of the actin cytoskeleton during development would therefore be lost in patients with NHS." SIGNOR-253565 "tacrolimus (anhydrous)" chemical CHEBI:61049 ChEBI PPP3CB protein P16298 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127242 RPL10 protein P27635 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-262501 FZD1 protein Q9UP38 UNIPROT CEBPA protein P49715 UNIPROT down-regulates 9606 BTO:0000222 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-80595 FOXO3 protein O43524 UNIPROT TSC1 protein Q92574 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 20371605 t "FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1" SIGNOR-259382 CHFR protein Q96EP1 UNIPROT HLTF protein Q14527 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 20388495 t miannu "CHFR functions as a ubiquitin ligase for HLTF to regulate its stability and functions. CHFR negatively regulates and ubiquitinates HLTF. Taken together, this is the first report identifying the regulatory mechanism of HLTF by CHFR, suggesting that CHFR-mediated downregulation of HLTF may help protect against cancer." SIGNOR-271460 "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 TNPO1 protein Q92973 UNIPROT FUS protein P35637 UNIPROT "up-regulates activity" relocalization -1 23056579 t lperfetto "The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1)." SIGNOR-262101 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 RPS6KA1 protein Q15418 UNIPROT 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-69171 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 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 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 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 FBXW11 protein Q9UKB1 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates ubiquitination Lys22 GPRDGLKkERLLDDR 9606 7479976 t gcesareni "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-26577 USF2 protein Q15853 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-222608 LRRK2 protein Q5S007 UNIPROT DVL3 protein Q92997 UNIPROT up-regulates binding 9606 23754980 t gcesareni "Subsequent assays confirmed a direct interaction between the lrrk2 roccor domain and all three human dvl proteins, these data are consistent with a role for lrrk2 in the activation of canonical wnt signaling bringing dvl proteins to cellular membranes." SIGNOR-202187 CCAR2 protein Q8N163 UNIPROT SUV39H1 protein O43463 UNIPROT "down-regulates activity" binding 26158765 t lperfetto "Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation." SIGNOR-267664 FANCD2 protein Q9BXW9 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-263255 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 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 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 KLF8 protein O95600 UNIPROT CTBP2 protein P56545 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 10756197 t miannu "Here we report the characterisation of KLF8/ZNF741/BKLF3 (KLF8). We demonstrate that this protein is able to bind CACCC-boxes in DNA and can repress gene expression by associating with CtBP co-repressors." SIGNOR-236962 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 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser552 VVRTPPKsPSSAKSR 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-251590 CHEK2 protein O96017 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser376 PLLPRVSsYLVPIQF 9606 BTO:0001938 17101782 t lperfetto "Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein" SIGNOR-150746 CLOCK protein O15516 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-253631 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTTG1 protein O95997 UNIPROT up-regulates phosphorylation 9606 10906323 t "inferred from 70% family members" 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-270155 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 GRM3 protein Q14832 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-264934 MYC protein P01106 UNIPROT DHODH protein Q02127 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003291 18628958 t miannu "PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria." SIGNOR-267382 SMO protein Q99835 UNIPROT GNAT1 protein P11488 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-148496 CEP135 protein Q66GS9 UNIPROT SASS6 protein Q6UVJ0 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-269676 RELA protein Q04206 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR "form complex" binding 9606 BTO:0000671 9056676 t miannu "Tnf-alpha induces the formation of a specific kappab binding complex, mainly composed of nf-kappab subunits rela and c-rel." SIGNOR-46948 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 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Thr27 KFRFRKEtNNAAIIM -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-248961 GSK3A protein P49840 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-159390 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 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 amitriptyline chemical CHEBI:2666 ChEBI CHRM5 protein P08912 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-258701 PRKCA protein P17252 UNIPROT UNC5A protein Q6ZN44 UNIPROT "down-regulates quantity" phosphorylation Ser352 TSGFQPVsIKPSKAD 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-268180 "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 (S)-selisistat chemical CHEBI:90371 ChEBI SIRT1 protein Q96EB6 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191511 PTCHD1 protein Q96NR3 UNIPROT DLG4 protein P78352 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-266652 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 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 APOBEC3H protein Q6NTF7 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-261330 FBXO3 protein Q9UK99 UNIPROT SMURF1 protein Q9HCE7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272441 LRRK2 protein Q5S007 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-260267 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CSF2RB protein P32927 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0005248 8758906 t irozzo "We demonstrated that Bcr-Abl co-immunoprecipitates with, and constitutively phosphorylates, the common βc,subunit of the interleukin 3 and granulocyte/macrophage-colony stimulating factor receptors.We demonstrate that Bcr-Abl interacts with the common βc subunit of the IL-3 family of receptors and phosphorylates it on tyrosine." SIGNOR-255814 SPRY4 protein Q9C004 UNIPROT TESK1 protein Q15569 UNIPROT "down-regulates activity" binding 9606 15584898 t miannu "Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4" SIGNOR-253032 ULK1 protein O75385 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit." SIGNOR-173050 TUBGCP6 protein Q96RT7 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-262330 PLK1 protein P53350 UNIPROT TPT1 protein P13693 UNIPROT down-regulates phosphorylation Ser46 TEGNIDDsLIGGNAS 9606 12167714 t lperfetto "Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase" SIGNOR-91344 GRK5 protein P34947 UNIPROT ADRB2 protein P07550 UNIPROT unknown phosphorylation Thr384 LCEDLPGtEDFVGHQ -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-251199 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 AKT proteinfamily SIGNOR-PF24 SIGNOR VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 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-145288 PSMB6 protein P28072 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-263361 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1015 MMVKRRDyLDLAAST 9606 14981541 t llicata "Opn upregulation depended on the integrity of the ret/ptc kinase and tyrosines y1015 and y1062, two major ret/ptc autophosphorylation sites. ret signalling mainly depends on three key tyrosine residues: tyrosine 905, in the activation loop, whose phosphorylation stabilizes the active conformation of the catalytic domain , tyrosine 1015, a docking site for phospholipase citalic gamma and tyrosine 1062." SIGNOR-122915 IL23R protein Q5VWK5 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates 9606 BTO:0000782 12023369 f 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-87838 RET protein P07949 UNIPROT RET protein P07949 UNIPROT unknown phosphorylation Tyr687 AQAFPVSySSSGARR 9534 BTO:0004055 8621380 t lperfetto "Based on the phosphopeptide maps, we can identify six tyrosine phosphorylation sites in RET: Tyr-687, Tyr-826, Tyr-1062, Tyr-1096, Tyr-1015, and Tyr-1029. By comparing the peptide map of each mutant to the wild-type receptor, we can tentatively assign each tryptic peptide containing phosphorylation sites to individual P-labeled spots on the two-dimensional map " SIGNOR-248941 PEX3 protein P56589 UNIPROT PEX19 protein P40855 UNIPROT "up-regulates activity" binding -1 15007061 t miannu "PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes." SIGNOR-253026 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 9534 BTO:0000298 10212258 t "C-Abl phosphorylates Rad51 in vitro and in vivo. phosphorylation of Rad51 by c-Abl enhances complex formation between Rad51 and Rad52, which cooperates with Rad51 in recombination and repair. c-Abl phosphorylates Rad51 Tyr315" SIGNOR-251434 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 "Caspase 9 complex" complex SIGNOR-C229 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-256448 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 MAPK14 protein Q16539 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 25056917 t "P38α promotes multi‐site GATA‐2 phosphorylation, increasing its localization in nuclear foci enriched in an active form of RNA polymerase II and its capacity to regulate endogenous target genes." SIGNOR-259946 FGF8 protein P55075 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002314 BTO:0000887;BTO:0001103 24209627 f gcesareni "Loss of fgf signaling in fgf24 and fgf8 double-deficient zebrafish" SIGNOR-203148 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 "Host translation inhibitor nsp1" protein P0C6X7-PRO_0000037309 UNIPROT IRF7 protein Q92985 UNIPROT "down-regulates activity" 9606 17715225 f miannu "SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7." SIGNOR-262504 SYK protein P43405 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 11331248 t gcesareni "Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k." SIGNOR-107046 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 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser383 ELPRRVNsASSSNPP 9606 15341740 t llicata "Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites." SIGNOR-128495 FGFR3 protein P22607 UNIPROT FGFR3 protein P22607 UNIPROT "up-regulates activity" phosphorylation Tyr577 RRPPGLDySFDTCKP 9606 BTO:0000007 11294897 t lperfetto "Ligand stimulation leads to autophosphorylation of fgfr3 the absence of y577 (3y-577f) or y760 (3y-760f) resulted in a modest decrease in activity." SIGNOR-106726 CLTCL1 protein P53675 UNIPROT "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-260673 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 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 Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR Neutrophil_degranulation phenotype SIGNOR-PH212 SIGNOR up-regulates 9606 BTO:0000133 2161532 f lperfetto "ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation." SIGNOR-270582 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 RPS18 protein P62269 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-262433 AP1M1 protein Q9BXS5 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-260686 N protein P59595 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling." SIGNOR-260342 3b protein P59633 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling." SIGNOR-260343 6 protein P59634 UNIPROT Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "down-regulates quantity by repression" "transcriptional regulation" 17108024 f miannu "The data presented here indicate that N protein inhibits interferon production, while ORF 3b and ORF 6 proteins are able to inhibit both interferon production and interferon signaling." SIGNOR-260344 fentanyl chemical CHEBI:119915 ChEBI OPRD1 protein P41143 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-258938 SMC1A protein Q14683 UNIPROT "RAD21L Cohesin complex" complex SIGNOR-C355 SIGNOR "form complex" binding 10090 BTO:0000534 21242291 t miannu "RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21." SIGNOR-264538 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 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 PDP1 protein Q9P0J1 UNIPROT PDHA1 protein P08559 UNIPROT "up-regulates activity" dephosphorylation Ser293 TYRYHGHsMSDPGVS -1 7782287 t "Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism" SIGNOR-252054 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22863277 t miannu "Lats1/2 inhibit yap by direct phosphorylation at s127, which results in yap binding to 14-3-3 and cytoplasmic sequestration" SIGNOR-198514 PAK1 protein Q13153 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser75 EIRSRHSsYPAGTED 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-73529 dabigatran chemical CHEBI:70752 ChEBI F2 protein P00734 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190314 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 (R)-(+)-sulpiride chemical CHEBI:64122 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-258735 PTPRJ protein Q12913 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1365 NVKCVAPyPSLLSSE 9606 BTO:0000007 12475979 t "When co-expressed in 293 cells, the full-length substrate-trapping mutant form of DEP-1 formed a stable complex with the chimeric receptor colony stimulating factor 1 (CSF)-Met and wild type DEP-1 dephosphorylated CSF-Met. Furthermore, we observed that DEP-1 preferentially dephosphorylated a Gab1 binding site (Tyr(1349)) and a COOH-terminal tyrosine implicated in morphogenesis (Tyr(1365))," SIGNOR-248703 NOTCH1 protein P46531 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001454 10933396 f gcesareni "Activation of notch1 signaling in dp thymocytes and thymoma cell lines results in the upregulation of cd25 and cd44 expression" SIGNOR-80333 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SMURF1 protein Q9HCE7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272443 GLI2 protein P10070 UNIPROT GLI1/GLI2 complex SIGNOR-C450 SIGNOR "form complex" binding 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." SIGNOR-269210 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 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser619 RELTNRHsLPFSLPS 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-249054 STAT4 protein Q14765 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-255246 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation Ser218 ISGYLVDsVAKTMDA 9606 19920149 t lperfetto "Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7" SIGNOR-161763 RNF182 protein Q8N6D2 UNIPROT ATP6V0C protein P27449 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002574 18298843 t miannu "The data indicated that RNF182 targeted ATP6V0C for degradation by the ubiquitin-proteosome pathway." SIGNOR-271771 HOXC11 protein O43248 UNIPROT S100B protein P04271 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17488478 t Luana "HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells." SIGNOR-261647 ATP7B protein P35670 UNIPROT copper(1+) smallmolecule CHEBI:49552 ChEBI "up-regulates quantity" relocalization 24706876 t lperfetto "WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans-Golgi network (TGN) and exports excess copper out of cells by trafficking from the TGN to the plasma membrane." SIGNOR-272297 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser36 PSEGRQPsPSPSPTE 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124240 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 EIF4E2 protein O60573 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-261008 "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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CABLES1 protein Q8TDN4 UNIPROT unknown phosphorylation Ser273 PGQGGSTsAFEQLQR -1 11733001 t llicata "Here, we report that Ser274 of p70ik3-1 is phosphorylated by cdk2 or cdk3 bound to cyclin A and to cyclin E in vitro. We also found that in COS7 cells in which cyclin E and cdk3 were ectopically overexpressed, the phosphorylation level of Ser274 in coexpressed p70ik3-1 is upregulated. We therefore conclude that p70ik3-1 is a substrate for cdk3-mediated phosphorylation." SIGNOR-250756 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr418 LSGEDDAyCTFPSRD -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-251378 MAPK14 protein Q16539 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 10085140 t gcesareni "On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38." SIGNOR-65601 Ub:E2 complex SIGNOR-C497 SIGNOR RNF20 protein Q5VTR2 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-271111 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 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 NMBR protein P28336 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-257373 STAT3 protein P40763 UNIPROT HGF protein P14210 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11278729 t lperfetto "Coexpression of activated c-Src and Stat3 synergistically induced strong HGF promoter activity in SP1 cells" SIGNOR-251742 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 CASZ1 protein Q86V15 UNIPROT EGFL7 protein Q9UHF1 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001176 24150064 t miannu "We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis." SIGNOR-266858 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 "DNA primase complex" complex SIGNOR-C261 SIGNOR "DNA polymerase alpha:primase complex" complex SIGNOR-C262 SIGNOR "form complex" binding -1 24043831 t 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-261341 PTGER1 protein P34995 UNIPROT GNAS protein Q5JWF2 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-256811 CDK1 protein P06493 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser104 FSFDTDRsPAPMSCD 9606 22071694 t lperfetto "Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal." SIGNOR-267985 4E2RCat chemical CID:2287236 PUBCHEM EIF4E protein P06730 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000414 21507972 t miannu "Characterization of 4E2RCat, an inhibitor of eIF4E-eIF4G interaction. Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers." SIGNOR-260187 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 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 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 ILK protein Q13418 UNIPROT "IPP complex" complex SIGNOR-C380 SIGNOR "form complex" binding 16493410 t lperfetto "Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton." SIGNOR-265762 RIPK1 protein Q13546 UNIPROT MAP3K1 protein Q13233 UNIPROT "up-regulates activity" phosphorylation Ser970 HSQCLNSsPLSHHSQ 9606 11369754 t lperfetto "These findings strongly suggest that rip phosphorylates mekk1 at ser-957 and ser-994." SIGNOR-108257 KNTC1 protein P50748 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-265015 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, Wnt1 induced expression of the MRF Myf5, whereas Wnt7a or Wnt6 preferentially activated the MRF MyoD" SIGNOR-198849 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 NEDD4L protein Q96PU5 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates ubiquitination 9606 19917253 t gcesareni "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-161713 panobinostat chemical CHEBI:85990 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-257752 Ub:E2 complex SIGNOR-C497 SIGNOR PCGF6 protein Q9BYE7 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-271037 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser83 PTIPGVTsPSSDEPP 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-249391 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Thr306 LKGAILTtMLATRNF 9606 1324926 t lperfetto "After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314" SIGNOR-17316 PRKACA protein P17612 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-259402 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 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f "Alessandro Palma" "It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits" SIGNOR-254955 "AP-2 complex" complex SIGNOR-C245 SIGNOR SYNJ1 protein O43426 UNIPROT "up-regulates activity" binding 10116 15496985 t Giorgia "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-260396 PRKG1 protein Q13976 UNIPROT SEPTIN3 protein Q9UH03 UNIPROT "up-regulates activity" phosphorylation Ser91 SQVSRKAsSWNREEK -1 15107017 t miannu "Mutation of Ser-91 to Ala in recombinant Sept3 also abolished PKG phosphorylation, confirming that Ser-91 is the major site in vitro. Therefore Sept3 is phosphorylated on Ser-91 in nerve terminals and its phosphorylation may contribute to the regulation of its subcellular localization in neurons." SIGNOR-263183 citrate(3-) smallmolecule CHEBI:16947 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "precursor of" 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-267100 PMS2 protein P54278 UNIPROT MLH1/PMS2 complex SIGNOR-C59 SIGNOR "form complex" binding 9606 10542278 t miannu "Hmlh1 and hpms2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hmutl_" SIGNOR-71777 PRKACA protein P17612 UNIPROT HMGN1 protein P05114 UNIPROT "down-regulates activity" phosphorylation Ser7 sSAEGAAK 9606 11438671 t miannu "PKA preferentially phosphorylates serine 6 in human HMGN1. specific phosphorylation of the NBD of HMGN proteins serves to prevent the interaction of these proteins with their chromatin targets during mitosis." SIGNOR-249993 DSN1 protein Q9H410 UNIPROT "MIS12 complex" complex SIGNOR-C362 SIGNOR "form complex" binding -1 27881301 t lperfetto "Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits" SIGNOR-265189 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 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 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 DCAF4 protein Q8WV16 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 32014991 t miannu "DCAF4-mediated ubiquitination of OPTN facilitates the degradation of DBR-exposed SOD1. OPTN is involved in degradation of DBR-exposed SOD1. These data demonstrate that DCAF4-including CRL4 complex mediates OPTN ubiquitination at lysine 501, and this ubiquitination is absent in the ALS-related OPTNmut." SIGNOR-272211 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 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 PTPRG protein P23470 UNIPROT PDGFRA protein P16234 UNIPROT "up-regulates activity" dephosphorylation Tyr754 ERKEVSKySDIQRSL -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-254714 MAPK14 protein Q16539 UNIPROT ELAVL1 protein Q15717 UNIPROT up-regulates phosphorylation 9606 19528229 t gcesareni "P38 mapk phosphorylates the mrna binding protein hur on thr118, which results in cytoplasmic accumulation of hur and its enhanced binding to the p21cip1 mrna." SIGNOR-186138 F2 protein P00734 UNIPROT F2RL3 protein Q96RI0 UNIPROT up-regulates binding 9606 22318735 t gcesareni "Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4)." SIGNOR-196003 TLR4 protein O00206 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 f miannu "S100A9 induces differentiation of acute myeloid leukemia cells through TLR4." SIGNOR-261923 PRKCE protein Q02156 UNIPROT NLRP5 protein P59047 UNIPROT "up-regulates activity" phosphorylation Ser331 MQRKKESsVTEFISR 9606 BTO:0000007 19542546 t miannu "MATER protein as substrate of PKCepsilon in human cumulus cells. we performed coimmunoprecipitation experiments using HEK293T cells expressing human MATER; a similar approach was then followed in human cumulus/follicular cells. In MATER(+)HEK293T cells, we observed that this protein acts as a phosphorylation substrate of PKCepsilon. Since PKCepsilon is known to collaborate with antiapoptotic signalling pathways, this suggests a novel mechanism for the function of MATER in follicular maturation." SIGNOR-263175 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Ser171 RILNHDTsFAKTFVG 9606 17197699 t gcesareni "Enzymatic activity, induced;" SIGNOR-151755 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 EEF1A1P5 protein Q5VTE0 UNIPROT Arg-tRNA(Arg) smallmolecule CHEBI:18366 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-269545 VAV1 protein P15498 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-260581 ASNS protein P08243 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 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-267535 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 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-259808 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 ARHGEF28 protein Q8N1W1 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-260546 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 MAPK11 protein Q15759 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation 9606 20820849 t gcesareni "Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (map) kinaseslinker region phosphorylation can prevent nuclear translocation of smads and inhibit tgf-_ signalling, potentially leading to oncogenesis." SIGNOR-167848 MAPK3 protein P27361 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 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-34657 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 CAPN2 protein P17655 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Gly71 FSASVLTgKLTTVFL -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-263581 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr387 VYFTYDPySEEDPDE -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-251377 Ub:E2 complex SIGNOR-C497 SIGNOR PLAGL1 protein Q9UM63 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-270997 UBE3A protein Q05086 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). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP." SIGNOR-272745 CUL3 protein Q13618 UNIPROT KCTD13 protein Q8WZ19 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-264233 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 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 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 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR up-regulates relocalization 9606 25627476 t lperfetto "One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP. " SIGNOR-267006 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 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 seliciclib chemical CHEBI:45307 ChEBI TP53 protein P04637 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206577 DCTN2 protein Q13561 UNIPROT Cytoplasmic_Dynein proteinfamily SIGNOR-PF67 SIGNOR "up-regulates activity" relocalization 25364732 t lperfetto "ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores" SIGNOR-265018 SP1 protein P08047 UNIPROT RHO protein P08100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 15781457 f miannu "Sp4 and Sp1 are activators of the rod opsin promoter" SIGNOR-225385 BMP2 protein P12643 UNIPROT SHH protein Q15465 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19855020 f gcesareni "On the other hand, bmp activity negatively regulates shh transcription and a bmp-shh nega-tive-feedback loop serves to confine shh expression during limb development." SIGNOR-188853 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 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 GLUL protein P15104 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "down-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-267824 progesterone smallmolecule CHEBI:17026 ChEBI Corticotropin protein P01189-PRO_0000024969 UNIPROT down-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 (Viau and Meaney, 1991). In the same study, it was shown that progesterone inhibits the sensitizing effects of estrogen on ACTH release during stress, as the ACTH levels and HPA output decreased with increasing amounts of progesterone in the estrous and diestrous phases." SIGNOR-268727 MICU2 protein Q8IYU8 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-270877 HDLBP protein Q00341 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" binding 9606 BTO:0000150 33941620 t miannu "We show that vigilin interacts with the DNA damage response (DDR) proteins RAD51 and BRCA1, and vigilin depletion impairs their recruitment to DSB sites." SIGNOR-266697 DDX58 protein O95786 UNIPROT MAVS protein Q7Z434 UNIPROT "up-regulates activity" binding 9606 19052324 t miannu "Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ." SIGNOR-260139 NUMA1 protein Q14980 UNIPROT TUBB4A protein P04350 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-117025 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 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 P2RY2 protein P41231 UNIPROT H3-3A protein P84243 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-264307 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 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194922 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 3142692 t irozzo "The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun." SIGNOR-256366 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 KLHL17 protein Q6TDP4 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9534 BTO:0000298 17062563 t miannu "Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation." SIGNOR-271613 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 NAT8L protein Q8N9F0 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI "up-regulates quantity" "chemical modification" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267523 MAPK1 protein P28482 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 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-249392 CARM1 protein Q86X55 UNIPROT MDH1 protein P40925 UNIPROT "down-regulates activity" acetylation Arg230 FVTTVQQrGAAVIKA 9606 27840030 t lperfetto "Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization" SIGNOR-267639 NFY complex SIGNOR-C1 SIGNOR TOP2A protein P11388 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25328138 t lperfetto "The expression of human TOP2A is controlled by its promoter region that contains two GC boxes and five CCAAT boxes. NF-Y recognizes and binds to the ICBs. This binding of NF-Y to the TOP2A promoter can be promoted by HMGB1/2 and inhibited by pRb." SIGNOR-242526 PHKA2 protein P46019 UNIPROT PHKG1 protein Q16816 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-267404 TG101209 chemical CHEBI:90304 ChEBI JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207263 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 AKT proteinfamily SIGNOR-PF24 SIGNOR S1PR1 protein P21453 UNIPROT "up-regulates activity" phosphorylation Thr236 RTRSRRLtFRKNISK 9606 11583630 t lperfetto "Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis" SIGNOR-110845 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1616 TPQSPSYsPTSPSYS -1 17157258 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-248767 PPARA protein Q07869 UNIPROT AQP3 protein Q92482 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255045 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 1178183 t lperfetto "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-16043 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 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 HTR2A protein P28223 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-256885 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT "down-regulates activity" phosphorylation Thr80 MARKMKDtDSEEEIR -1 26675311 t miannu "Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third." SIGNOR-266356 PRKCI protein P41743 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 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-172886 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251469 SMURF1 protein Q9HCE7 UNIPROT BMPR1A protein P36894 UNIPROT down-regulates ubiquitination 9606 22298955 t 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-195651 SMAD3 protein P84022 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 19701891 t "TGF-beta1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-beta1-induced-Treg generation from Smad3(-/-) mice is markedly reduced and abolished by inactivating Smad2" SIGNOR-254362 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser618 APTPPKRsSSFREMD 9606 18161990 t lperfetto "The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl." SIGNOR-160215 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 BTF3 protein P20290 UNIPROT SSPN protein Q14714 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-253951 PPAT protein Q06203 UNIPROT "5-phospho-α-D-ribose 1-diphosphate" smallmolecule CHEBI:58017 ChEBI "down-regulates quantity" "chemical modification" 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-267293 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 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 PAX7 protein P23759 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR down-regulates 9606 BTO:0001103;BTO:0002314 22493066 f lperfetto "Constitutive Notch Activation Upregulates Pax7 and Promotes the Self-Renewal of Skeletal Muscle Satellite Cells" SIGNOR-219371 COMMD5 protein Q9GZQ3 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" 9606 30021164 f miannu "We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling.We found that RhoA activity is decreased following COMMD5 depletion, suggesting that COMMD5 regulates cytoskeleton organization through RhoA signaling. However, the dynamics of Rho GTPase activities are highly complex and tightly regulated in order to achieve their specific subcellular localization (Marjoram et al., 2014); thus, the mechanism by which COMMD5 directly or indirectly regulates the activity of RhoA needs to be investigated further." SIGNOR-261690 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 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 MAPK3 protein P27361 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-219345 ZEB1 protein P37275 UNIPROT EPCAM protein P16422 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000584 23667256 f miannu "We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter." SIGNOR-255622 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 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR DYSF protein O75923 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-136497 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 PKN1 protein Q16512 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser637 VDLSKVTsKCGSLGN 9606 BTO:0000938 BTO:0000975 11104762 t "The effect has been demonstrated using P10636-8" lperfetto "Phosphorylation of tau is regulated by pknthere is a pkn-specific phosphorylation site, ser-320, in mbdsthus pkn serves as a regulator of microtubules by specific phosphorylation of tau, which leads to disruption of tubulin assembly." SIGNOR-84958 HTR1D protein P28221 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-257208 MT-CO1 protein P00395 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-267746 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 MAPK1 protein P28482 UNIPROT MCL1 protein Q07820 UNIPROT up-regulates phosphorylation Thr163 TDGSLPStPPPAEEE 9606 18676833 t gcesareni "We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage." SIGNOR-179808 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 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 BTO:0000567 19789335 t lperfetto "we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1." SIGNOR-109684 MYC protein P01106 UNIPROT HNRNPA2B1 protein P22626 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20010808 t "We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2," SIGNOR-268691 CTDSP1 protein Q9GZU7 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-236839 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation 21443865 t "The MAPT H1 haplotype and subhaplotypes may be associated with sporadic tauopathies including AD. And that, tau's phosphorylation is regulated by many protein kinases, including glycogen synthase kinase 3beta (GSK3B)." SIGNOR-255486 ACIN1 protein Q9UKV3 UNIPROT Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 10490026 f "Cleaved by CASP3" amattioni "Acinus induces apoptotic chromatin condensation after cleavage by caspase-3 without inducing dna fragmentation." SIGNOR-70797 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 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-244696 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 15574335 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-131442 "cyclosporin A" chemical CHEBI:4031 ChEBI PPP3CA protein Q08209 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127225 SLC5A5 protein Q92911 UNIPROT iodide smallmolecule CHEBI:16382 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-266960 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 NANOG protein Q9H9S0 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-266080 "erlotinib hydrochloride" chemical CHEBI:53509 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191502 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 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 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr395 AKHHQDAyIRIVLEN 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-138150 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 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR up-regulates binding 9606 BTO:0001253 7673243 t lperfetto "We have isolated a cdna encoding a novel transmembrane serine/threonine kinase from human skin fibroblasts which we demonstrate here to be a type ii receptor that binds bmp-4. This receptor (brk-3) is distantly related to other known type ii receptors and is distinguished from them by an extremely long carboxyl-terminal sequence following the intracellular kinase domain." SIGNOR-217535 VAC14 protein Q08AM6 UNIPROT FIG4 protein Q92562 UNIPROT "up-regulates quantity by stabilization" binding 9534 BTO:0000298 20630877 t miannu "Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction." SIGNOR-253534 SIRT1 protein Q96EB6 UNIPROT EP300 protein Q09472 UNIPROT down-regulates deacetylation Lys1024 TELKTEIkEEEDQPS 9606 BTO:0000150 19047049 t gcesareni "Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024" SIGNOR-182511 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "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-255972 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 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 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-271359 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 G3BP2 protein Q9UN86 UNIPROT Stress_granules phenotype SIGNOR-PH124 SIGNOR up-regulates 9606 23279204 f SARA "G3BP1 and G3BP2 form homo‐ and hetero‐multimers to induce SGs" SIGNOR-260983 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 IKBKB protein O14920 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation Ser511 DSPFYRDsLPGSQRK 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-183692 CHD8 protein Q9HCK8 UNIPROT SOX3 protein P41225 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-268920 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys126 DNEKDLVkLAKRLKK -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-272746 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 "CHEVI complex" complex SIGNOR-C269 SIGNOR Platelet_aggregation phenotype SIGNOR-PH81 SIGNOR up-regulates 9606 27319744 f lperfetto "VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles" SIGNOR-261833 RASGEF1B protein Q0VAM2 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-183832 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 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-252743 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR DOT1L protein Q8TEK3 UNIPROT "up-regulates activity" binding 9606 BTO:0005014 27856324 t 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-255882 MCHR2 protein Q969V1 UNIPROT GNAS protein Q5JWF2 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-256795 SHMT1 protein P34896 UNIPROT "glycine zwitterion" smallmolecule CHEBI:57305 ChEBI "up-regulates quantity" "chemical modification" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269689 SIK3 protein Q9Y2K2 UNIPROT CRTC2 protein Q53ET0 UNIPROT "down-regulates activity" phosphorylation Ser70 RSSHYGGsLPNVNQI 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-249171 HIC1 protein Q14526 UNIPROT EFNA1 protein P20827 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20154726 f miannu "we show that HIC1 is a direct transcriptional repressor of the gene encoding ephrin-A1, a cell surface ligand implicated in the pathogenesis of epithelial cancers." SIGNOR-254240 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 10037602 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-64964 "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 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 cabazitaxel chemical CHEBI:63584 ChEBI TUBB1 protein Q9H4B7 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-259341 CD47 protein Q08722 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266016 CDK2 protein P24941 UNIPROT CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 SIGNOR-C83 9889196 t lperfetto "Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2." SIGNOR-63895 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 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 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 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 ESR1 protein P03372 UNIPROT CYP19A1 protein P11511 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 11973645 t lperfetto "By binding to S1, ERalpha down-regulates the aromatase promoter activity." SIGNOR-271683 PTPRR protein Q15256 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 11493009 t "Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.|PTP-SL dephosphorylates the regulatory phosphotyrosine on the active loop of ERK1/2. Tyrosine dephosphorylation of ERK1/2 causes the inactivation of ERK1/2 and its retention in the cytoplasm" SIGNOR-248840 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 7a protein P59635 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 16303160 f Luana "Expression of SARS-CoV ORF7a block cell cycle arrest in G0/G1" SIGNOR-260207 MYF6 protein P23409 UNIPROT DES protein P17661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 8382796 t lperfetto "Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression" SIGNOR-241497 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 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 RB1 protein P06400 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8242749 t gcesareni "A domain in the c-terminus of rb, outside of the a/b pocket, binds to the atp-binding lobe of the c-abl tyrosine kinase, resulting in kinase inhibition." SIGNOR-37139 lenvatinib chemical CHEBI:85994 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191454 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 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-200902 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 azelastine chemical CHEBI:2950 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-257790 MYOD1 protein P15172 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-241122 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser248 DLDILHNsSQMKSMS 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265227 P2RY11 protein Q96G91 UNIPROT GNAS protein Q5JWF2 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-256788 CCND1 protein P24385 UNIPROT HDAC2 protein Q92769 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5." SIGNOR-134053 Nalmefene chemical CHEBI:7457 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-258811 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 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser486 DDEITEAKsGTATPQRS 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256110 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser27 GGSTTSGsRRSRRRS 9606 20534587 t llicata "We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30." SIGNOR-166040 SMAD3 protein P84022 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 11331591 t lperfetto "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-235902 GLI2 protein P10070 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 33125874 f SimoneGraziosi "Inhibition of Gli1 with simultaneous increase in Gli2 promotes migration of vNSC-derived cells to demyelinated lesions" SIGNOR-269223 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CACNB1 protein Q02641 UNIPROT "up-regulates activity" phosphorylation Ser161 CEVGFIPsPVKLDSL 9534 BTO:0000298 16406008 t miannu "Thus, Ser-447 on Ca(v)2.2 and Ser-161 and Ser-348 of Ca(v)beta1b appear to be both necessary and sufficient for ERK-dependent modulation of these channels. Together, our data strongly suggest that modulation of neuronal N-type VDCCs by ERK involves phosphorylation of Ca(v)2.2alpha1 and to a lesser extent possibly also Ca(v)beta subunits. On the basis of the evidence presented here, it is therefore suggested that ERK-dependent up-regulation of Cav2.2 channels is primarily mediated by phosphorylation of Ser-447 on the I–II loop of Cav2.2 and possibly also the two SP sites conserved on Cavβs." SIGNOR-262966 RACK1 protein P63244 UNIPROT LARP4B protein Q92615 UNIPROT "up-regulates activity" binding 9606 BTO:0005238 20573744 t miannu "Here we show that LARP4B is a cytoplasmic protein that co-sediments with polysomes and accumulates upon stress induction in stress granules. Biochemical studies further show that the protein interacts with two key factors of the translational machinery, namely, the cytoplasmic poly(A) binding protein (PABPC1) and the receptor for activated C Kinase (RACK1). The biochemical and functional data of LARP4B presented in this study suggest a possible mode of action of LARP4B in translation. Assuming that LARP4B interacts with mRNA-associated PABPC1 and RACK1 simultaneously, it may form a bridge between the 3′ end of mRNAs and the initiating ribosome. This process would lead to mRNA circularization, possibly in an analogous way as it has been described for PABPC1 and eIF4G, the scaffold protein of the cap-binding complex." SIGNOR-260941 AKT2 protein P31751 UNIPROT GLI1 protein P08151 UNIPROT up-regulates 9606 17845852 f gcesareni "Ras and akt signaling enhances the nuclear localization of gli1, counteracting its suppression by other modifiers that retain it in the cytoplasm, such as suppressor of fused (sufu)." SIGNOR-157770 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates binding 9606 BTO:0001130 1010227 t gcesareni "Progressive increase in akt activation during prostate cancer progression led to increase phosphorylation of foxo3a and binding with 14-3-3, which potentially affected its transcriptional activity in age-specific manner." SIGNOR-252819 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 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr36 LPPGDYStTPGGTLF 10090 BTO:0002572 SIGNOR-C3 20670887 t lperfetto "Specifically as part of mTORC1, mTOR directly phosphorylates the ribo- somal 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-167180 PRKG2 protein Q13237 UNIPROT PTS protein Q03393 UNIPROT up-regulates phosphorylation Ser19 AQVSRRIsFSASHRL 9606 10531334 t gcesareni "Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps. Addition of cgmp stimulated phosphotransferase activity 2-fold. Extracts from transfected cos-1 cells overexpressing cgkii stimulated ser(19) phosphorylation more than 100-fold.In assays with purified enzymes, wild-type but not ptps-s19a was a specific substrate for the cgmp-dependent protein kinase (cgk) type i and ii. Upon expression in cos-1 cells, ptps-s19a was stable but not phosphorylated and had a reduced activity of approximately 33% in comparison to wild-type ptps" SIGNOR-71751 RNF31 protein Q96EP0 UNIPROT NR0B1 protein P51843 UNIPROT "up-regulates quantity by stabilization" monoubiquitination 9606 BTO:0002588 19237537 t miannu "RNF31 promotes monoubiquitination of DAX-1 in an RBR domain-dependent manner. In conclusion, our results suggest that the major DAX-1 modification observed in different experimental settings is likely to be monoubiquitination at one or more lysine residues (multiubiquitination) possibly located within the LBD of DAX-1. RNF31 stabilizes endogenous DAX-1." SIGNOR-271786 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 PTPRE protein P23469 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 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-248449 "Elongator complex" complex SIGNOR-C466 SIGNOR TUBA3E protein Q6PEY2 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-269718 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 SB-202190 chemical CHEBI:79090 ChEBI MAPK11 protein Q15759 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206694 AKT proteinfamily SIGNOR-PF24 SIGNOR TBX3 protein O15119 UNIPROT "up-regulates activity" phosphorylation Ser719 AEKEAATsELQSIQR 9606 25595898 t lperfetto "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-244353 INVS protein Q9Y283 UNIPROT DVL1 protein O14640 UNIPROT down-regulates ubiquitination 9606 15852005 t gcesareni "Inversin inhibits the canonical wnt pathway by targeting cytoplasmic dishevelled (dsh or dvl1) for degradation" SIGNOR-135766 BBS1 protein Q8NFJ9 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-262558 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 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 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage Phe709 ENPTYKFfEQMQN -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-261778 ROCK1 protein Q13464 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-198840 KMT2A protein Q03164 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-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-268626 PLK1 protein P53350 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates activity" phosphorylation Ser126 PILVDTAsPSPMETS 9606 BTO:0000567 11242082 t lperfetto "Phosphorylation of cyclin b1 is central to its nuclear translocationduring cell-cycle progression in hela cells, a change in the kinase activity of endogenous plk1 toward s147 and/or s133 correlates with a kinase activity in the cell extractsa mutant cyclin b1 in which s133 and s147 are replaced by alanines remains in the cytoplasm, whereas wild-type cyclin b1 accumulates in the nucleus during prophase.Together, these results suggest that phosphorylation of s133 and s147 is necessary for the nuclear translocation of cyclin b1 during prophase, and that phosphorylation of s126 and s128 may stimulate the nuclear translocation." SIGNOR-105707 N-[4-[(4-Ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[(E)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-5-yl)ethenyl]-4-methylbenzamide chemical CID:53302361 PUBCHEM BRAF protein P15056 UNIPROT "down-regulates activity" "chemical inhibition" -1 32069833 t lperfetto "HG6-64-1 is a specific BRAF inhibitor" SIGNOR-261986 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 histidine smallmolecule CHEBI:27570 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-264762 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr487 SLSNIDFyAQVSDIT 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-248419 HCRTR2 protein O43614 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-257216 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 7901013 t "The effect has been demonstrated using P07101-3" gcesareni "Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant 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" SIGNOR-34686 BUB1 protein O43683 UNIPROT CENPE protein Q02224 UNIPROT "up-regulates activity" relocalization 11402067 t lperfetto "Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity" SIGNOR-252016 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 BDP1 protein A6H8Y1 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "form complex" binding 29378333 t lperfetto "Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1)." SIGNOR-266189 ADORA1 protein P30542 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-256697 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 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 G6PD protein P11413 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-267052 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 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 CUL3 protein Q13618 UNIPROT KCTD10 protein Q9H3F6 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-264234 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 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr423 NSLNEEWyVSYITRP 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42972 PRKCA protein P17252 UNIPROT GRIA1 protein P42261 UNIPROT unknown phosphorylation Ser832 LIEFCYKsRSESKRM 9606 8663994 t lperfetto "In addition, protein kinase C specifically phosphorylates Ser-831 of GluR1 in HEK-293 cells and in cultured neurons." SIGNOR-248950 ANKRD1 protein Q15327 UNIPROT NPPA protein P01160 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 18273862 t "In vitro calpain-mediated degradation assays, coupled to reporter gene analysis in transfected HeLa cells, strongly suggested that this mutation enhances both the stability of the ANKRD1/CARP protein and its transcriptional repression activity upon the cardiac-specific atrial natriuretic factor (ANF) promoter." SIGNOR-253647 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 GSK3B protein P49841 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser106 PLNSVSPsPLMLLHP 9606 16076840 t gcesareni "The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex." SIGNOR-139320 USP7 protein Q93009 UNIPROT CHFR protein Q96EP1 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 17442268 t miannu "In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell.  USP7 mediates deubiquitination of Chfr." SIGNOR-271462 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 RLF protein Q13129 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-220799 LEF1 protein Q9UJU2 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254550 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 SPDYA protein Q5MJ70 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 33015044 t lperfetto "Speedy/RINGO A, a noncanonical activator of CDK2, was recently identified as a key regulator for CDK2 recruitment to meiotic telomeres" SIGNOR-263310 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 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 NFYB protein P25208 UNIPROT PHGDH protein O43175 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18378410 f miannu "Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y." SIGNOR-255210 (2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzazepin-5-yl]amino]-1-oxopropan-2-yl]butanamide chemical CHEBI:131158 ChEBI APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206850 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 RNF7 protein Q9UBF6 UNIPROT PMAIP1 protein Q13794 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-271446 DAPK1 protein P53355 UNIPROT RPL5 protein P46777 UNIPROT unknown phosphorylation 9606 18283219 t lperfetto "Here we adapted this strategy to successfully screen for dapk substrates. We report the identification of two substrates, ribosomal protein l5 and mcm3." SIGNOR-160954 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 PRKCA protein P17252 UNIPROT TNNI3 protein P19429 UNIPROT "down-regulates activity" phosphorylation Ser166 LGARAKEsLDLRAHL -1 11121119 t lperfetto "In addition to the established phosphorylation sites (S22 and S23) we found that S38 and S165 were the other two main sites of phosphorylation. | Overphosphorylation of troponin I reduced its affinity for troponin C, as measured by isothermal titration microcalorimetry. Phosphorylation of S22/23A also decreased its affinity for troponin C indicating that phosphorylation of S38 and/or S165 impedes binding of troponin I to troponin C. Formation of a troponin I/troponin C complex prior to cAMP-dependent protein kinase treatment did not prevent overphosphorylation." SIGNOR-249069 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr1166 DIYETDYyRKGGKGL -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-246268 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 CDK7 protein P50613 UNIPROT RARA protein P10276 UNIPROT up-regulates phosphorylation Ser77 EIVPSPPsPPPLPRI 9606 BTO:0000567 9230306 t llicata "However, only the coexpression of cdk7 stimulated ser-77 phosphorylation in vivo and enhanced transactivation by rar alpha, but not by a s77a rar mutant." SIGNOR-49693 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9534 BTO:0004055 8137421 t lperfetto "The jnk-mediated phosphorylation of both ser63 and ser73 within the transactivation domain of c-jun potentiates its transcriptional activity." SIGNOR-252354 FKBP5 protein Q13451 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 30685540 f Luana "Loss of FKBP5 Affects Neuron Synaptic Plasticity | In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways." SIGNOR-265798 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 MMP12 protein P39900 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-272380 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 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 "Spike protein-ACE2" complex SIGNOR-C240 SIGNOR "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 18554741 f miannu "Endocytosis of the Receptor-Binding Domain of SARS-CoV Spike Protein Together With Virus Receptor ACE2. Here, we demonstrate that the RBD spike protein alone can be internalized together with ACE2. We propose that after binding to ACE2, the RBD spike protein activates the ACE2 mediated cellular endocytosis signal pathway, by which SARS-CoV enters the susceptible cells." SIGNOR-260289 KLF4 protein O43474 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 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." SIGNOR-270544 "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9606 32221306 f miannu "We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease." SIGNOR-260743 "CoV2 spike protein-NRP1" complex SIGNOR-C267 SIGNOR "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 10090 BTO:0000108 33082293 t Luana "NRP mediates entry of nanoparticles coated with SARS-CoV-2 (SARS-2) S–derived CendR peptides into cultured cells, olfactory epithelium, and the central nervous system of mice." SIGNOR-262316 FGF2 protein P09038 UNIPROT HBA1 protein P69905 UNIPROT "down-regulates quantity by repression" "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-251796 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SREBF1 protein P36956 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000599 10915800 t "inferred from 70% family members" 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-270081 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 "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32231345 f doi.org/10.1101/2020.03.09.983247 miannu "Unlike SARS-CoV, live SARS-CoV-2-infected cells were found to form typical syncytium, suggesting that SARS-CoV-2 may mainly utilize the plasma membrane fusion pathway to enter and replicate inside host cells. Consistently, in the cell-cell fusion system, SARS-CoV-2 S protein could effectively mediate the formation of syncytium between the effector cell and the target cell in the absence of an exogenous proteolytic enzyme, e.g., trypsin, while SARS-CoV S protein could not. Actually, the plasma membrane fusion pathway is more efficient than the endosomal membrane fusion pathway for most viruses because the latter is more prone to activating the host cell antiviral immunity." SIGNOR-260741 "CoV2 Spike protein-ACE2" complex SIGNOR-C254 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 SIGNOR up-regulates 9606 32221306 f miannu "We demonstrated that SARS-CoV-2 S protein entry on 293/hACE2 cells is mainly mediated through endocytosis, and that PIKfyve, TPC2, and cathepsin L are critical for virus entry. We further found that SARS-CoV-2 S protein could trigger syncytia in 293/hACE2 cells independent of exogenous protease." SIGNOR-260744 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 MPHOSPH10 protein O00566 UNIPROT IMP4 protein Q96G21 UNIPROT "up-regulates activity" binding -1 28813493 t miannu "Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA." SIGNOR-261174 UBQLN2 protein Q9UHD9 UNIPROT HNRNPA1 protein P09651 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-262270 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 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 DDX17 protein Q92841 UNIPROT DDX5/DDX17 complex SIGNOR-C40 SIGNOR "form complex" binding 9606 12595555 t miannu "The highly related dead box rna helicases p68 and p72 exist as heterodimers in cells" SIGNOR-98403 CAMK2G protein Q13555 UNIPROT PEA15 protein Q15121 UNIPROT unknown phosphorylation Ser116 KDIIRQPsEEEIIKL BTO:0000099 9721757 t llicata "Partly purified PEA-15 was a substrate in vitro for CaMKII, but not for casein kinase II. Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin. CaMKII phosphorylated selectively Ser116 and had no effect on Ser104, but in vitro phosphorylation by CaMKII appeared to facilitate further phosphorylation by protein kinase C. " SIGNOR-250701 AKT3 protein Q9Y243 UNIPROT 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-186780 PPM1L protein Q5SGD2 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000142;BTO:0000671 17456047 t gcesareni "Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation" SIGNOR-154554 CSNK2A1 protein P68400 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser154 FLWSPFEsLCEIGEK 9606 21209074 t lperfetto "We report here that phosphorylation of cdc27, a core subunit of apc, in response to tgf- signaling can facilitate the activation of apc.we have demonstrated that casein kinase ii (ckii) is involved in the phosphorylation of cdc27 in response to tgf- signaling." SIGNOR-170872 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 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 CBL protein P22681 UNIPROT LRIG1 protein Q96JA1 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 15282549 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-127289 EGFR protein P00533 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 14967450 t lperfetto "The egf-r coimmunoprecipitated with p85 alpha" SIGNOR-252672 MAPK10 protein P53779 UNIPROT BCL2L11 protein O43521 UNIPROT "up-regulates activity" phosphorylation Ser77 PGPFATRsPLFIFMR 10090 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-250131 "GABA-B receptor" complex SIGNOR-C336 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR "up-regulates activity" binding 9606 BTO:0000938 20655485 t miannu "The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release." SIGNOR-265068 JUN protein P05412 UNIPROT SMAD4 protein Q13485 UNIPROT "up-regulates activity" binding 9615 9312063 t lperfetto "Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter." SIGNOR-236139 TCAP protein O15273 UNIPROT Sarcomere_organization phenotype SIGNOR-PH165 SIGNOR "up-regulates activity" binding 9606 BTO:0001103 9804419 t lperfetto "The giant muscle protein titin (connectin) is essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres (contractile units) of striated muscle. " SIGNOR-264855 RPS6K proteinfamily SIGNOR-PF26 SIGNOR METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 BTO:0000007;BTO:0000567 15861136 t gcesareni "Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro." SIGNOR-252800 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 EPHA3 protein P29320 UNIPROT EPHA3 protein P29320 UNIPROT "up-regulates activity" phosphorylation Tyr596 KLPGLRTyVDPHTYE 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-251115 TNK2 protein Q07912 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Tyr176 EKATGRYyAMKILKK 10090 BTO:0002021 20333297 t gcesareni "Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation." SIGNOR-252457 HTR6 protein P50406 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-257395 RET protein P07949 UNIPROT FRS2 protein Q8WU20 UNIPROT up-regulates binding 9606 11360177 t gcesareni "Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret" SIGNOR-108244 MAVS protein Q7Z434 UNIPROT IKBKE protein Q14164 UNIPROT "up-regulates activity" binding 9606 25636800 t miannu "After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively." SIGNOR-260144 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT down-regulates dephosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 16778204 t gcesareni "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). in line with this finding, adoptive ptprj expression reduced the oncogenic activity of ret" SIGNOR-147161 ATP6AP1 protein Q15904 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" 9606 28296633 f miannu "Depletion or inhibition of the V-ATPase stabilises HIF1α in aerobic conditions." SIGNOR-261347 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 16023596 t gcesareni "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." SIGNOR-138603 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256549 SRC protein P12931 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15695828 t llicata "These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity." SIGNOR-133870 CDK1 protein P06493 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-100877 CEBPB protein P17676 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 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-250572 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTPN7 protein P35236 UNIPROT "up-regulates activity" phosphorylation -1 16226275 t "inferred from 70% family members" lperfetto "First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|" SIGNOR-270202 ULK2 protein Q8IYT8 UNIPROT PRKAA2 protein P54646 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t miannu "We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I" SIGNOR-173089 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 MAPK1 protein P28482 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Thr451 KRTRSKGtLRYMSPE 9606 9528799 t gcesareni "Our results provide strong evidence that dsrna binding is required for dimerization of full-length pkr molecules in vivo, leading to autophosphorylation in the activation loop and stimulation of the eif2alpha kinase function of pkr." SIGNOR-56337 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 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1868 SPTSPKYsPTSPKYS 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-176797 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 NFYC protein Q13952 UNIPROT NFY complex SIGNOR-C1 SIGNOR "form complex" binding 9606 BTO:0000801;BTO:0000876 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-63019 USF1 protein P22415 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 9677331 f "inferred from family member" 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-267797 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 PRKCG protein P05129 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 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-249091 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 TWIST1 protein Q15672 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-255518 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Thr310 GTARRTGtPSDPRRR -1 12885254 t "GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro" SIGNOR-251235 EGLN1 protein Q9GZT9 UNIPROT HIF1A protein Q16665 UNIPROT "down-regulates quantity by destabilization" hydroxylation 9606 BTO:0000567 32755251 t lperfetto "Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.|Oxygen-dependent hydroxylation by the prolyl hydroxylase domain-2 (PHD2) protein marks HIF-1alpha for ubiquitination by the von Hippel Lindau (VHL) tumor suppressor protein, leading to proteasomal degradation" SIGNOR-261994 AKT1 protein P31749 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto "Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212" SIGNOR-252500 PIM proteinfamily SIGNOR-PF34 SIGNOR MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr90 AIKIIDKtQLNPTSL 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-259431 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 17189255 t gcesareni "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster." SIGNOR-151449 "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI UDP-alpha-D-glucose(2-) chemical CHEBI:58885 ChEBI "up-regulates quantity" "precursor of" 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-267924 "MLL2 complex" complex SIGNOR-C88 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-268799 CAMK2A protein Q9UQM7 UNIPROT NOS1 protein P29475 UNIPROT "down-regulates activity" phosphorylation Ser852 SYKVRFNsVSSYSDS 10400690 t llicata "It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation." SIGNOR-250635 DGC complex SIGNOR-C217 SIGNOR NRXN3 protein Q9HDB5 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-265450 BCAR1 protein P56945 UNIPROT PKN3 protein Q6P5Z2 UNIPROT "up-regulates activity" binding 10090 BTO:0002572 30422386 t lperfetto "Taken together, the data suggest that p130Cas expression induces PKN3 activation and this activation is independent of p130Cas–PKN3 interaction." SIGNOR-264573 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 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr221 IRAKIQDyHILTRKR 9606 BTO:0000007 15143187 t lperfetto "Autophosphorylation of jak2 on tyrosines 221 and 570 regulates its activity with phosphorylation of tyrosine 221 increasing kinase activity" SIGNOR-236506 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 IL31 protein Q6EBC2 UNIPROT IL31RA protein Q8NI17 UNIPROT up-regulates binding 9606 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-125313 ITSN1 protein Q15811 UNIPROT CDC42 protein P60953 UNIPROT up-regulates binding 9606 15824104 t gcesareni "Full-length intersectin-l exhibited little ability to stimulate nucleotide exchange on cdc42" SIGNOR-135377 Gbeta proteinfamily SIGNOR-PF4 SIGNOR CIITA protein P33076 UNIPROT down-regulates phosphorylation 9606 18245089 t "inferred from 70% family members" gcesareni "In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-270067 TNF protein P01375 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates activity" 9606 9204951 f miannu "The de novo synthesis of 6-BH4 depends on the induction of GTP-CH-1, e.g., by tumor necrosis factor-alpha (TNF alpha)." SIGNOR-252210 PRKACG protein P22612 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser275 LSAFRRTsLAGGGRR 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-163784 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 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation 9606 19230643 t gcesareni "Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1." SIGNOR-184130 CRH protein P06850 UNIPROT CRHR1 protein P34998 UNIPROT up-regulates binding 9606 11416224 t gcesareni "Crf and ucn bind and activate crf-r1 with similarly high affinities." SIGNOR-108713 Laminin-8 complex SIGNOR-C181 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-253220 NFIB protein O00712 UNIPROT NEUROD4 protein Q9HD90 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-268898 PTPN1 protein P18031 UNIPROT TYK2 protein P29597 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-134564 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 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser38 SVPEFPLsPPKKKDL 9606 10913145 t gcesareni "We find that, in vitro, pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays." SIGNOR-79955 RHOA protein P61586 UNIPROT DIAPH1 protein O60610 UNIPROT "up-regulates activity" 9606 BTO:0000815 22820501 t lperfetto "We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells." SIGNOR-253108 NFKB1 protein P19838 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-253648 NDUFS3 protein O75489 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-262177 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 MAPK14 protein Q16539 UNIPROT TCF3 protein P15923 UNIPROT "up-regulates activity" phosphorylation Ser139 LNSPGPLsPSGMKGT 9606 BTO:0000887 15719023 t lperfetto "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" SIGNOR-134194 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 MAP2K3 protein P46734 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9534 BTO:0000298 7839144 t Luana "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-260723 AGTR1 protein P30556 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-256738 SUZ12 protein Q15022 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-241900 SH2B1 protein Q9NRF2 UNIPROT CD79A protein P11912 UNIPROT "down-regulates activity" dephosphorylation 9606 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268457 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB6 protein P18564 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-259007 HGF protein P14210 UNIPROT MET protein P08581 UNIPROT up-regulates binding 9606 8380735 t gcesareni "Hgf is the ligand for p190met, the receptor tyrosine kinase encoded by the met proto-oncogene." SIGNOR-38429 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI EPHB4 protein P54760 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194916 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 FGF2 protein P09038 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 11781339 f gcesareni "In these collagen gel cultures, p38 activation was induced more potently by fgf-2 treatment compared with that in proliferating cultures" SIGNOR-113649 pemetrexed chemical CHEBI:63616 ChEBI DHFR protein P00374 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205819 PPP2CA protein P67775 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 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-243424 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 PTPRG protein P23470 UNIPROT CTTN protein Q14247 UNIPROT "down-regulates activity" dephosphorylation Tyr470 AYATEAVyESAEAPG -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-254696 PRKAA1 protein Q13131 UNIPROT RPTOR protein Q8N122 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C15 SIGNOR-C3 21460634 t lperfetto "Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2." SIGNOR-173035 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser152 PASSVSSsPSPPFGH 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-88716 RXRA protein P19793 UNIPROT RARA protein P10276 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-16665 "GABA-A (a2-b1-g2) receptor" complex SIGNOR-C331 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-268601 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 DCC protein P43146 UNIPROT CACNA1D protein Q01668 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-268292 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 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI INSR protein P06213 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192871 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 GATA1 protein P15976 UNIPROT MPL protein P40238 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-254162 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 PRSS2 protein P07478 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-263603 HNF1A protein P20823 UNIPROT UGT1A10 protein Q9HAW8 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-253971 CHD2 protein O14647 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates quantity" relocalization 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-264527 PRKCQ protein Q04759 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" phosphorylation Ser716 HILERFGsLTMDGGL 9606 31792381 t "TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation" SIGNOR-272472 TRIM31 protein Q9BZY9 UNIPROT KIF21B protein O75037 UNIPROT "up-regulates activity" binding 24086586 t "Here we show that the ubiquitin E3 ligase TRIM3, also known as BERP, interacts with KIF21B via its RBCC domain ||he E3-ligase function of TRIM3 is not involved in KIF21B degradation, however TRIM3 depletion reduces the motility of the motor. Together, our data suggest that TRIM3 is a regulator in the modulation of KIF21B motor function" SIGNOR-272479 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2620 QGTLQTRtQEGSLSA -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-249158 IGF1R protein P08069 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" 10090 11715022 f lperfetto "We show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy." SIGNOR-235373 MAPK8 protein P45983 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 jnk directly regulated nuclear factor of activated t-cell (nfat) activation in culture and in transgenic mice containing an nfat-dependent luciferase reporter." SIGNOR-118217 COL6A2 protein P12110 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-254674 DVL1 protein O14640 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" binding 9606 SIGNOR-C110 20837657 t gcesareni "In canonical wnt signaling, dsh phosphorylation inhibits the apcaxingsk3 complex, leading to beta-catenin stabilization." SIGNOR-167957 SIRT1 protein Q96EB6 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity" deacetylation 10090 BTO:0002572 27776347 t "SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis." SIGNOR-256208 4-(trimethylammonio)butanoate smallmolecule CHEBI:16244 ChEBI carnitine smallmolecule CHEBI:17126 ChEBI "up-regulates quantity" "precursor of" 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-269701 miR-155 mirna URS000062749E_9606 RNAcentral JUN protein P05412 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255761 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 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-265814 Ub:E2 complex SIGNOR-C497 SIGNOR ZNF598 protein Q86UK7 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-271185 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 CTNNB1 protein P35222 UNIPROT SOX2 protein P48431 UNIPROT "down-regulates activity" binding 9606 BTO:0000093 24291232 t flangone "The interaction between Sox2 and _-catenin provides a novel mechanism underlying the functional dichotomy of BC cells, which carries potential therapeutic implications." SIGNOR-241994 SEC24B protein O95487 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-265290 "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 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 CDH23 protein Q9H251 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-262579 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 RNF5 protein Q99942 UNIPROT STING1 protein Q86WV6 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys150 EISAVCEkGNFNVAH 9606 BTO:0000007 19285439 t miannu "The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection." SIGNOR-271484 APH1A protein Q96BI3 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR "form complex" binding 9606 25610395 t lperfetto "-Secretase is a four subunit, 19-pass transmembrane enzymeBiochemical studies indicated that -secretase activity is catalyzed by the presenilin (PS)-containing macromolecular complex (Li et al., 2000a). The search for other components of the complex revealed three additional proteins: nicastrin (Nct), anterior pharynx-defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)" SIGNOR-209714 E2F4 protein Q16254 UNIPROT BIRC5 protein O15392 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 18504435 t lperfetto "This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter." SIGNOR-271678 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 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 PTK2B protein Q14289 UNIPROT PTK2B protein Q14289 UNIPROT up-regulates phosphorylation Tyr402 CSIESDIyAEIPDET 9606 15105428 t llicata "Overexpression of pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of stat5b, indicated by the reporter gfp-stat5b. These effects were completely dependent upon tyr(402), the autophosphorylation site of pyk2, which allows recruitment of src family members for further activating phosphorylations at other sites on pyk2." SIGNOR-124339 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 HBA1 protein P69905 UNIPROT CD163 protein Q86VB7 UNIPROT "up-regulates activity" binding 9606 16522161 t Regulation miannu "These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells." SIGNOR-251747 GDNF protein P39905 UNIPROT NCAM1 protein P13591 UNIPROT "up-regulates activity" binding 10116 BTO:0002881 15212950 t miannu "Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable." SIGNOR-252189 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 UNIPROT "up-regulates activity" binding 9534 10712517 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-219291 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 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr349 EEPPDHQyYNDFPGK 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-59623 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 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 12970777 t gcesareni "The raf inhibitor l-779,450. This raf inhibitor was less effective on b-raf- or mek1-responsive cells, demonstrating the specificity of this drug." SIGNOR-100358 dactolisib chemical CHEBI:71952 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21803746 t "ATP-competitive inhibitor of PI3K and mTOR" gcesareni "The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific" SIGNOR-175715 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 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 LRIG1 protein Q96JA1 UNIPROT CBLC protein Q9ULV8 UNIPROT up-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-127301 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 "Adalimumab (Imraldi)" antibody DB00051 DRUGBANK TNF protein P01375 UNIPROT "down-regulates activity" binding 9606 33125196 t "Adalimumab is a recombinant human immunoglobulin monoclonal antibody that specifically binds to tumor necrosis factor α (TNF-α)" SIGNOR-272493 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 MECOM protein Q03112 UNIPROT GATA2 protein P23769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000565 15889140 t Luana "Evi1 directly binds to the promoter region of GATA-2 and thus enhances the GATA-2 transcription." SIGNOR-266062 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser486 RPLSRAQsSPAAPAS -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-249276 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 PPP2CA protein P67775 UNIPROT STK4 protein Q13043 UNIPROT down-regulates dephosphorylation Thr183 DTMAKRNtVIGTPFW 9606 23431053 t gcesareni "Rassf1a apparently protects mst1/2 against inactivation by pp2a , the phosphatases that dephosphorylate the stimulatory thr-183 and thr-180 of mst1 andmst2, respectively." SIGNOR-201270 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT "up-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-272514 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 ITGB1BP1 protein O14713 UNIPROT ITGB4 protein P16144 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-257658 EGR1 protein P18146 UNIPROT HSD11B2 protein P80365 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15659537 f miannu "Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50." SIGNOR-253876 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser142 AVSDSLPsNSLKKSS 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-99135 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR DUSP1 protein P28562 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0001103 17158101 f Andrea "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-255744 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR GRIK2 protein Q13002 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 17062563 t miannu "Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation." SIGNOR-271614 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 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 L-thyroxine smallmolecule CHEBI:18332 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-267492 KIF11 protein P52732 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-272521 KIF1A protein Q12756 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-272522 KIF16B protein Q96L93 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-272527 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 KCNC2 protein Q96PR1 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-265585 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 GNB2 protein P62879 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 f 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-199132 AKAP5 protein P24588 UNIPROT PPP3CC protein P48454 UNIPROT "up-regulates activity" relocalization 10116 BTO:0004553 20694001 t "Using a viral-mediated molecular replacement strategy in rat hippocampal slices, we found that AKAP is required for NMDA receptor-dependent long-term depression solely because of its interaction with calcineurin" SIGNOR-261291 PHA-665752 chemical CHEBI:90197 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206088 EGR1 protein P18146 UNIPROT CYP2B6 protein P20813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18303024 f miannu "The CYP2B6 enzyme metabolizes commonly used therapeutics and also activates pro-drugs. The CAR directly binds to the distal enhancer element of the CYP2B6 promoter, which is essential in converging to its drug-sensing function onto promoter activity. However, this binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter." SIGNOR-253874 ATR protein Q13535 UNIPROT ATM protein Q13315 UNIPROT "up-regulates activity" phosphorylation Ser1981 SLAFEEGsQSTTISS 9606 17124492 t lperfetto "Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment" SIGNOR-150870 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 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 PSMA6 protein P60900 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-263368 EEF1A1P5 protein Q5VTE0 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-269554 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 TGFB1 protein P01137 UNIPROT HBA1 protein P69905 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-251798 SHANK3 protein Q9BYB0 UNIPROT GRIA1 protein P42261 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-264601 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 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 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 9753485 t "Crohn's Disease" gcesareni SIGNOR-251703 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser180 GSSASFIsDTFSPYT 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-252327 "AP-2/clathrin vescicle" complex SIGNOR-C249 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-267861 CDK14 protein O94921 UNIPROT TAGLN2 protein P37802 UNIPROT "down-regulates activity" phosphorylation Ser83 PVKKIQAsTMAFKQM 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-265103 SMAD7 protein O15105 UNIPROT TGFBR1 protein P36897 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3." SIGNOR-64088 PRKCA protein P17252 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-248962 GNAS protein P63092 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-256529 UMPS protein P11172 UNIPROT Pyrimidine_nucleotide_metabolic_process phenotype SIGNOR-PH85 SIGNOR up-regulates 26059768 f miannu "The bifunctional enzyme UMP synthase leads to the synthesis of uridine 5′-monophosphate (UMP). UMP could be considered one of the hub molecules in pyrimidine metabolism because it is the precursor of other pyrimidine nucleotides." SIGNOR-253582 ZWINT protein O95229 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-265194 MINK1 protein Q8N4C8 UNIPROT PRICKLE1 protein Q96MT3 UNIPROT "up-regulates activity" phosphorylation Thr370 LSGNADDtLSRKLDD -1 22037766 t miannu "We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle." SIGNOR-263095 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 LARP7 protein Q4G0J3 UNIPROT HEXIM1 protein O94992 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 30824372 t Monia "To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system." SIGNOR-261183 CSNK1A1 protein P48729 UNIPROT SNCA protein P37840 UNIPROT "down-regulates activity" phosphorylation Ser129 NEAYEMPsEEGYQDY 9606 10617630 t lperfetto "In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2.| together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of alpha-synuclein could affect its binding to membranes." SIGNOR-73795 Ub:E2 complex SIGNOR-C497 SIGNOR RNF41 protein Q9H4P4 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-271090 ATR protein Q13535 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-177805 PIK3C3 protein Q8NEB9 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 10090 19270693 t lperfetto "The beclin 1-vps34 interaction regulates autophagy." SIGNOR-184521 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM15 protein Q9C019 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-271215 HDAC1 protein Q13547 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 9606 BTO:0000887 11684023 t gcesareni "Interaction of myod with hdac1 in undifferentiated myoblasts mediates repression of muscle-specific gene expression." SIGNOR-111243 STAT5A protein P42229 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15003515 f "Flt3 Mutation Activates p21WAF1/CIP1 Gene Expression Through the Action of STAT5. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a -692/-684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site." SIGNOR-261518 RARB protein P10826 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" 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-267807 KIF21B protein O75037 UNIPROT "Plus-end directed sliding movement" phenotype SIGNOR-PH216 SIGNOR up-regulates 9606 28290984 f "In this study, we showed that KIF21B is a highly processive MT plus-end directed motor, which can potently induce pausing of MT plus ends. This activity depends on several regions of this large motor protein." SIGNOR-272515 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 MBP protein P02686 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates 31066630 f SimoneGraziosi "Myelin basic protein (MBP) is essential for the compaction of the two adjacent cytoplasmic membrane surfaces into the major dense line of myelin." SIGNOR-269230 CDK2 protein P24941 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 17361108 t gcesareni "Our results demonstrate that cdk2 is capable of autophosphorylation at thr160." SIGNOR-153636 HOXA10 protein P31260 UNIPROT PHGDH protein O43175 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19778996 f miannu "PHGDH is expressed in both endometrial epithelial and stromal cells. HOXA10 represses endometrial PHGDH expression." SIGNOR-254468 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 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 MDFI protein Q99750 UNIPROT MYF5 protein P13349 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-240433 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 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT "down-regulates activity" dephosphorylation Tyr796 GGTGGSVyTEDNDDD 9606 BTO:0000007 10364224 t "Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs." SIGNOR-248460 DUSP6 protein Q16828 UNIPROT MAPK3 protein P27361 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-103149 YES1 protein P07947 UNIPROT YES1 protein P07947 UNIPROT "up-regulates activity" phosphorylation Tyr426 RLIEDNEyTARQGAK 9606 9794236 t lperfetto "Autophosphorylation of Src and Yes blocks their inactivation by Csk phosphorylation" SIGNOR-247014 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 SLC24A1 protein O60721 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-264395 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser324 RDLELPLsPSLLGGP 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, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency." SIGNOR-235459 PRKACA protein P17612 UNIPROT ADD1 protein P35611 UNIPROT "down-regulates activity" phosphorylation Ser408 REKSKKYsDVEVPAS -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-250329 "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 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 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 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 DRD4 protein P21917 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-256982 IKBKE protein Q14164 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 23691078 t lperfetto "Ikbke phosphorylation and inhibition of foxo3a: a mechanism of ikbke oncogenic functionhere we report that ikbke regulates foxo3a through phosphorylation of foxo3a-ser644. The phosphorylation of foxo3a resulted in its degradation and nuclear-cytoplasmic translocation." SIGNOR-202054 CAMK2A protein Q9UQM7 UNIPROT CALD1 protein Q05682 UNIPROT down-regulates phosphorylation Ser656 RAEFLNKsVQKSSGV 9606 2170388 t gcesareni "Smooth muscle caldesmon was phosphorylated by smooth muscle calmodulin-dependent protein kinase. Ii" SIGNOR-22635 POT1 protein Q9NUX5 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR "form complex" 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-152324 MAP3K7 protein O43318 UNIPROT PTPN3 protein P26045 UNIPROT unknown phosphorylation Ser359 PAMRRSLsVEHLETK 9606 9341175 t gcesareni "Mutation of ser359 and ser853 to alanine significantly reduced the association between 14-3-3beta and ptph1. Furthermore, association of ptph1 and 14-3-3beta was detected in several cell lines and was regulated in response to extracellular signals" SIGNOR-52781 FZD3 protein Q9NPG1 UNIPROT RHOA protein P61586 UNIPROT "up-regulates activity" binding 9606 20828404 t gcesareni "Upon ligand binding, non-canonical wnt signaling controls tissue polarity and cell movement through the activation of rhoa, c-jun n-terminal kinase (jnk), and nemo-like kinase (nlk) signaling cascades." SIGNOR-167865 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 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT "down-regulates activity" sumoylation 9606 BTO:0000007 16061479 t miannu "Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP" SIGNOR-225481 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 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 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 AVPR1B protein P47901 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-257264 BST1 protein Q10588 UNIPROT NADP(+) smallmolecule CHEBI:18009 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-264251 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 ROCK1 protein Q13464 UNIPROT LPP protein Q93052 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001260 22886954 f miannu "Inactivation of rho kinase (rok) with rok inhibitors significantly inhibited lpp mrna expression" SIGNOR-198118 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 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 SRC protein P12931 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Tyr188 SFVGTLQyLAPELLE 9606 SIGNOR-C14 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-100784 sabcomeline chemical CHEBI:134846 ChEBI CHRM2 protein P08172 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-258674 MDM2 protein Q00987 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" 9606 18292944 f amattioni "Overexpression of hdm2 resulted in a decrease in the level of p21waf1" SIGNOR-160977 AZD1480 chemical CID:16659841 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190167 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 CAMK2A protein Q9UQM7 UNIPROT OPRM1 protein P35372 UNIPROT down-regulates phosphorylation Thr372 STRIRQNtRDHPSTA 9606 BTO:0000671 10908300 t gcesareni "The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microm [d-ala(2),n-mephe(4),gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative ca(2+)/calmodulin-dependent protein kinase ii (camk ii) phosphorylation sites, s261 and s266, by alanines in the third intracellular loop of the rat mu-opioid receptor (rmor1) confers resistance to camk ii-induced receptor desensitization." SIGNOR-79686 PRKCE protein Q02156 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser99 PFRGRSRsAPPNLWA 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-163916 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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR MYBL2 protein P10244 UNIPROT up-regulates phosphorylation Thr494 TPLHRDKtPLHQKHA 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/cdk4" SIGNOR-217264 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 PHA-680632 chemical CID:11249084 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206100 XL147 chemical CHEBI:71957 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252659 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 DNMT3B protein Q9UBC3 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 22808286 f miannu "EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex." SIGNOR-254145 BDKRB2 protein P30411 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-256838 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 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM56 protein Q9BRZ2 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-270961 GNRHR protein P30968 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-256935 CIITA protein P33076 UNIPROT HLA-DQB1 protein P01920 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 11332992 f "The class II transactivator (CIITA) regulates expression of the classical and non-classical MHC class II genes, HLA-DR, -DP, -DQ and -DM," SIGNOR-254017 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 GOT2 protein P00505 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 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-267513 WNT1 protein P04628 UNIPROT FZD3 protein Q9NPG1 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-131571 EZH2 protein Q15910 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-241894 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 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT down-regulates phosphorylation Thr3950 GHAFGSAtQFLPVPE 9606 17189255 t gcesareni "Ir-induced dna-pkcs phosphorylation at thr-2609 and ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although dna-pkcs autophosphorylates itself at ser-2056 after ir, we have reported here that atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster." SIGNOR-151453 FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-252921 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-248085 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 CAPN1 protein P07384 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-251581 GNB5 protein O14775 UNIPROT ADCY1 protein Q08828 UNIPROT "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-264996 SP1 protein P08047 UNIPROT SLC19A1 protein P41440 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 15652157 f "Collectively, these results identify transcriptionally important regions in the hRFC-C minimal promoter that include a GC-box and CCAAT-box, and suggest that cooperative interactions between Sp1 and C/EBP beta are essential for hRFC-C transactivation." SIGNOR-254064 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 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 CUL1 protein Q13616 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "form complex" binding 9606 10023660 t gcesareni "The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin." SIGNOR-64502 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 POLR3A protein O14802 UNIPROT Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 19631370 t miannu "Here we show that the cytosolic poly(dA-dT) DNA is converted into 5′-ppp RNA to induce IFN-β through the RIG-I pathway. Biochemical purification led to the identification of DNA-dependent RNA polymerase III (Pol-III) as the enzyme responsible for synthesizing 5′-ppp RNA from the poly(dA-dT) template. Inhibition of RNA Pol-III prevents IFN-β induction by transfection of DNA or infection with DNA viruses." SIGNOR-265563 ERK1/2 proteinfamily SIGNOR-PF1 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-270140 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 HIF1A protein Q16665 UNIPROT EPO protein P01588 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 8756616 t "We demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells" SIGNOR-256593 MAPK1 protein P28482 UNIPROT PPARG protein P37231 UNIPROT down-regulates relocalization 9606 18596912 t fspada "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-179400 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 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu "AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250321 MAPK3 protein P27361 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-48355 PLK1 protein P53350 UNIPROT FBXO5 protein Q9UKT4 UNIPROT down-regulates phosphorylation 9606 16439210 t gcesareni "We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity." SIGNOR-142949 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 GEMIN4 protein P57678 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-253118 SMARCA2 protein P51531 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-263890 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 AKT2 protein P31751 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" 9606 BTO:0000150 12697749 f lperfetto "Our data indicate that akt2 inhibits cisplatin-induced jnk/p38 and bax activation through phosphorylation of ask1" SIGNOR-100591 CIITA protein P33076 UNIPROT HLA-A protein P04439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000776 10329350 f "Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression." SIGNOR-254020 FBXW7 protein Q969H0 UNIPROT MED13 protein Q9UHV7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 SIGNOR-C135 SIGNOR-C406 23322298 t miannu "The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association." SIGNOR-266690 MAP3K5 protein Q99683 UNIPROT MAP2K7 protein O14733 UNIPROT up-regulates phosphorylation 9606 19920149 t gcesareni "Ask1 is a member of a mapkkk family and functions as an upstream kinase engaged in c-jun nh2-terminal kinase (jnk)/p38 signaling via the phosphorylation and activation of mapkks, such as mkk3, -4, -6, and -7" SIGNOR-161766 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser870 KEDSAYGsQSVEQEA 10090 BTO:0000785 15084608 t lperfetto "Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52." SIGNOR-124230 F2RL1 protein P55085 UNIPROT DUSP6 protein Q16828 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-254853 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 VKORC1L1 protein Q8N0U8 UNIPROT "vitamin K epoxide" smallmolecule CHEBI:28371 ChEBI "down-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-265902 CUDC-907 chemical CID:54575456 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191212 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 ADNP protein Q9H2P0 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 12888219 f miannu "Mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment." SIGNOR-266758 dexmedetomidine chemical CHEBI:4466 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-258907 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 PRKCB protein P05771 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 9271428 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-50594 MMP13 protein P45452 UNIPROT COL2A1 protein P02458 UNIPROT "down-regulates quantity by destabilization" cleavage Gly906 EGPPGPQgLAGQRGI 9606 8609233 t miannu "Although it appears that MMP-1 and MMP-13 both cleave type II collagen initially at the same site, MMP-13 affects a secondary cleavage to produce a 1/4-size collagen fragment with an NH2 terminus three amino acids removed from the primary cleavage site.The present work has demonstrated expression of MMP-13 in human osteoarthritic cartilage and shown that MMP-13 has significant type II collagen degrading activity." SIGNOR-256340 IGF2 protein P01344 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." SIGNOR-251495 NAA38 protein Q9BRA0 UNIPROT NatC complex SIGNOR-C417 SIGNOR "form complex" binding 9606 19398576 t miannu "We here identify and characterize the human NatC (hNatC) complex, containing the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31. This complex associates with ribosomes, and hMak3 acetylates Met-Leu protein N termini in vitro, suggesting a model in which the human NatC complex functions in cotranslational N-terminal acetylation." SIGNOR-267235 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation Thr221 KDEILPTtPISEQKG 9606 19059439 t Manara "Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA" SIGNOR-260895 IKBKB protein O14920 UNIPROT ASB8 protein Q9H765 UNIPROT "up-regulates activity" phosphorylation Ser31 RTIAAIRsFPHDNVE 9606 BTO:0000007 31009856 t lperfetto "We found that ASB8 was phosphorylated at the N-terminal Ser-31 by host IkappaB kinase beta (IKKbeta). In turn, ASB8 facilitated K48-linked ubiquitination and degradation of IKKbeta via the ubiquitin-proteasome pathway, resulting in remarkable inhibition of I-kappa-B-alpha (IkappaBalpha) and of p65 phosphorylation, consequently suppressing NF-kappaB activity." SIGNOR-272242 PTGER3 protein P43115 UNIPROT GNB3 protein P16520 UNIPROT up-regulates binding 9606 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88192 "Immune complexes" stimulus SIGNOR-ST15 SIGNOR FCGR1A protein P12314 UNIPROT "up-regulates activity" 9606 BTO:0000801 18064051 f lperfetto "Immune complexes bind to activating Fc receptors (FcR) and inhibitory FcRs that are expressed by innate immune effector cells such as basophils, mast cells, neutrophils, monocytes and macrophages, in which they trigger the indicated effector responses." SIGNOR-249521 CDK5 protein Q00535 UNIPROT NOS3 protein P29474 UNIPROT down-regulates phosphorylation Ser114 RKLQGRPsPGPPAPE 9606 BTO:0000938 20213743 t llicata "Together, our data suggest that cdk5 can phosphorylate enos at the ser-113 site and down-regulate enos-derived no levels." SIGNOR-164080 CDKN2C protein P42773 UNIPROT CDK4 protein P11802 UNIPROT down-regulates binding 9606 8891723 t miannu "The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb." SIGNOR-44598 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 PPP2CA protein P67775 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0001023 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-248617 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 S protein P59594 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 16310778 f Luana "We demonstrated that the adenovirus-mediated over-expression of SARS-CoV spike (S) protein and its C-terminal domain (S2) induce apoptosis in Vero E6 cells in a time- and dosage-dependent manner" SIGNOR-260219 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 15294014 f Luana "In the present paper, we show that SARS-CoV N is capable of inducing apoptosis of COS-1 monkey kidney cells in the absence of growth factors by down-regulating ERK (extracellular-signal-regulated kinase), up-regulating JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) pathways, and affecting their downstream effectors." SIGNOR-260204 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001538 17453707 f Luana "SARS-CoV Nucleocapsid Protein Induced Apoptosis of COS-1 Mediated by the Mitochondrial Pathway" SIGNOR-260205 N protein P59595 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana "Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells." SIGNOR-260199 M protein P59596 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000161 16845612 f Luana "Co-transfection of M and N enhances the induction of apoptosis by M or N alone, which also suggests that the structural proteins of SARS-CoV may play an important role not only in the process of invasion but also in the pathogenetic process in cells." SIGNOR-260198 3a protein P59632 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR "up-regulates activity" 9534 15958670 f Luana "These results indicated that the 3a protein induced apoptosis in Vero E6 cells." SIGNOR-260195 3b protein P59633 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR "up-regulates activity" 9534 16965829 f Luana "Over-expression of severe acute respiratory syndrome coronavirus 3b protein induces both apoptosis and necrosis in Vero E6 cells" SIGNOR-260194 6 protein P59634 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 18708124 f Luana "A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis" SIGNOR-260203 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000018 15564512 f Luana "7a induces apoptosis via a caspase-dependent pathway and in cell lines derived from different organs, including lung, kidney, and liver. | The overexpression of HA-tagged 7a (7a-HA) induces apoptosis in 293T (human kidney epithelial) cells, as evidenced by an increase in caspase-3 protease activity, a hallmark of apoptosis, which is comparable to that caused by the overexpression of BAX, a proapoptotic member of the Bcl-2 family" SIGNOR-260197 7a protein P59635 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana "Cells expressing the ORF7a or ORF7b protein undergo apoptosis." SIGNOR-260209 ATAT1 protein Q5SQI0 UNIPROT TUBA1B protein P68363 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272245 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 CUDC-101 chemical CID:24756910 PUBCHEM HDAC9 protein Q9UKV0 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-262265 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 CDK2 protein P24941 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates activity" phosphorylation Thr611 ETLPISStPSKSVLP BTO:0001938 15024056 t llicata "We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins." SIGNOR-250731 AKAP11 protein Q9UKA4 UNIPROT PKA proteinfamily SIGNOR-PF17 SIGNOR "down-regulates activity" binding 26088133 t lperfetto "A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta)." SIGNOR-264818 7b protein Q7TFA1 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9534 BTO:0001444 17686858 f Luana "Cells expressing the ORF7a or ORF7b protein undergo apoptosis." SIGNOR-260210 AMPK complex SIGNOR-C15 SIGNOR MTOR protein P42345 UNIPROT "down-regulates activity" 9606 30274374 f miannu "AMPK inhibits the mTOR pathway through phosphorylation and activation of tuberous sclerosis protein 2 (TSC2) and causes direct activation of unc-51-like autophagy activating kinase 1 (ULK1) via phosphorylation of Ser555, thus promoting initiation of autophagy." SIGNOR-260096 COL1A1 protein P02452 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-253345 FOXA1 protein P55317 UNIPROT LOXL2 protein Q9Y4K0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002861 20043065 f miannu "These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells." SIGNOR-254166 EEF1A1P5 protein Q5VTE0 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-269560 CSNK2A1 protein P68400 UNIPROT SSRP1 protein Q08945 UNIPROT "down-regulates activity" phosphorylation Ser510 SSSNEGDsDRDEKKR 9606 BTO:0000007 15659405 t llicata "CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity." SIGNOR-250959 Ub:E2 complex SIGNOR-C497 SIGNOR RNF113B protein Q8IZP6 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-271193 KDM2B protein Q8NHM5 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 f miannu "Here, we show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. These results suggest that FBXL10 represses adipogenesis by targeting a noncanonical PRC1 complex to repress key genes (e.g. Pparg) that control conversion of pluripotent cells into the adipogenic lineage." SIGNOR-252243 CASK protein O14936 UNIPROT Exocytosis phenotype SIGNOR-PH157 SIGNOR up-regulates 9606 BTO:0000938 11036064 f miannu "As neurexins have been proposed to function in neuronal cell adhesion, it is possible that they define specific sites at the plasma membrane and that Mint complexes and Mint1-CASK complexes on neurexin are involved in the localized recruitment of Munc18 to the sites of exocytosis. In support of this hypothesis, both CASK and Mint1 have been reported to be localized at synapses" SIGNOR-264044 MAP2K1 protein Q02750 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000011 12270934 t lperfetto "MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis." SIGNOR-235352 GSK3B protein P49841 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser863 DPISTDAsRRSSEAS 9606 BTO:0000007 16611981 t lperfetto "The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3." SIGNOR-249590 MAPKAPK2 protein P49137 UNIPROT SRF protein P11831 UNIPROT unknown phosphorylation Ser103 RGLKRSLsEMEIGMV 9606 BTO:0000567 10318869 t llicata "Mk2 phosphorylates srf in vitro at ser-103" SIGNOR-67448 SF1 protein Q15637 UNIPROT LHB protein P01229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004467 19106114 f miannu "The human LHB promoter also contains low and high affinity SF1 binding sites. Mutation of these elements or depletion of endogenous SF1 impaired basal and ligand-induced transcription." SIGNOR-254915 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 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 CDC14B protein O60729 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates dephosphorylation 9606 18662541 t lperfetto "The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1" SIGNOR-227927 SMARCD1 protein Q96GM5 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-270734 PRKACA protein P17612 UNIPROT MBP protein P02686 UNIPROT unknown phosphorylation Ser266 FGYGGRAsDYKSAHK -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-163" SIGNOR-250013 MTOR protein P42345 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT "up-regulates activity" phosphorylation Thr388 NQAFLGFtYVAPSVL -1 11733037 t miannu "In vitro phosphorylation and activation of p70β by mTOR and PDK1. We observed that the replacement of either Thr241 or Thr401 to Ala in p70β1(T241A, T401A) severely decreased the kinase activity." SIGNOR-250295 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1626 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-269379 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR SAV1 protein Q9H4B6 UNIPROT "up-regulates activity" phosphorylation 9606 21084559 t miannu "Mst is activated by binding of salvador (sav1, sav in drosophila), which is, in turn, also phosphorylated by mst." SIGNOR-256184 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 8559144 t gcesareni "Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation" SIGNOR-39862 INHBA protein P08476 UNIPROT ACVR2B protein Q13705 UNIPROT "up-regulates activity" binding 9606 8622651 t gcesareni "Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB." SIGNOR-235142 PLK1 protein P53350 UNIPROT BORA protein Q6PGQ7 UNIPROT down-regulates phosphorylation Ser497 SSNIQMDsGYNTQNC 9606 18378770 t gcesareni "Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp)." SIGNOR-178150 GABARAP protein O95166 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" binding 9606 11146101 t lperfetto "N-terminal proline/serine rich (ps) domain of ulk1 (amino acid 287-416) is required for ulk1-gate-16 and ulk1-gabarap protein interactions" SIGNOR-219391 ABCA1 protein O95477 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 23077142 f miannu "Cholesterol efflux is the first step in the formation of HDL, which is initiated through the action of ATP binding cassette transporter (ABC) A1 on apolipoprotein (apo) A-I that produces nascent HDL (nHDL)." SIGNOR-252109 EIF2B5 protein Q13144 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-269128 CSNK1A1 protein P48729 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 20419129 t lperfetto "Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome" SIGNOR-165022 MAPK1 protein P28482 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-120112 NOSIP protein Q9Y314 UNIPROT PPP2CA protein P67775 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 25546391 t miannu " NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. " SIGNOR-271498 brimonidine chemical CHEBI:3175 ChEBI ADRA2B protein P18089 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-258901 RFX1 protein P22670 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9583676 t gcesareni "We show that rfxi and c-abl are in direct interaction, in vitro and in cell extracts, through the rfxi proline rich (pxxp) motif and the c-abl sh3 domain. Remarkably, this interaction significantly potentiates c-abl but not v-abl auto-kinase activity" SIGNOR-57516 CDK5 protein Q00535 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 BTO:0000938 17591690 t gcesareni "Here, we demonstrate for the first time that cdk5 interacts with p53 and increases its stability through posttranslational regulation, leading to accumulation of p53, particularly in the nucleus. We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 in vitro," SIGNOR-156418 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249688 ESCRT-III complex SIGNOR-C379 SIGNOR Cytoskeleton_organization phenotype SIGNOR-PH89 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-265535 CAMK4 protein Q16566 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates phosphorylation Ser91 RARPRKIsSPTGSKD 9606 BTO:0000887 21689744 t lperfetto "Here we show that calcium/calmodulin-dependent kinase iv (camk iv) specifically binds to the c terminus of phb2 and phosphorylates phb2 at serine 91. Camk iv effectively decreased phb2-mediated repression of mef2 activity through phosphorylation" SIGNOR-174437 PHLPP1 protein O60346 UNIPROT AKT2 protein P31751 UNIPROT unknown dephosphorylation 9606 BTO:0000527 15808505 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-135008 PTPRJ protein Q12913 UNIPROT MAPK3 protein P27361 UNIPROT down-regulates dephosphorylation 9606 12771128 t 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-101282 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP -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-250766 CAMK2G protein Q13555 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser273 AGTRRREsLGKKAKR 9677319 t llicata "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. By deletion and point mutation analysis we show that phosphorylation by CaMKII and PKA occurs on a single serine residue at position 273" SIGNOR-250703 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 MAP3K8 protein P41279 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 10090 "BTO:0000776; BTO:0000801" 16484370 f "Mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activation in bone marrow-derived macrophages and B cells stimulated with diverse TLR ligands" SIGNOR-256078 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 CDK2 protein P24941 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 SIGNOR-C16 18332217 t llicata "We define ser-331 as the site phosphorylated by cyclin e-cdk2, cyclin a-cdk2, and p35-cdk5 both in vitro and in cells. Importantly, phosphorylation at ser-331 inhibits the catalytic activity of sirt2." SIGNOR-177972 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 MEX3B protein Q6ZN04 UNIPROT SNUPN protein O95149 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-272079 YY1 protein P25490 UNIPROT ACTC1 protein P68032 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9171244 f miannu "Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression." SIGNOR-255616 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 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 ziprasidone chemical CHEBI:10119 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-258500 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 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1920 SPTYSPTsPKYSPTS 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-120152 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 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 ATAT1 protein Q5SQI0 UNIPROT TUBA1A protein Q71U36 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272251 KLHL25 protein Q9H0H3 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 22578813 t miannu "We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination." SIGNOR-272049 NDUFA13 protein Q9P0J0 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 ND1-module builds around the Q-module with the help of TIMMDC1/C3ORF1 [47,48], which remains bound to the Q/ND1 subassembly until the last maturation steps. MT-ND1 joins first and then NDUFA3, NDUFA8 and NDUFA13 are added" SIGNOR-262153 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 ATAT1 protein Q5SQI0 UNIPROT TUBA8 protein Q9NY65 UNIPROT "up-regulates quantity by stabilization" acetylation -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272250 PI-103 chemical CHEBI:90524 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206172 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 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-248806 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 "NMDA receptor_2C" complex SIGNOR-C349 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-264224 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 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-262221 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 SMAD6 protein O43541 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 11737269 t lperfetto "Smad6 interacts with tak1 and tab1, and smad7 with tab1" SIGNOR-112636 "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 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-217853 PTPRE protein P23469 UNIPROT KCNB1 protein Q14721 UNIPROT "down-regulates activity" dephosphorylation Tyr128 YWGIDEIyLESCCQA 9606 BTO:0000007 10921884 t "Hypomyelination and increased activity of voltage-gated K(+) channels in mice lacking protein tyrosine phosphatase epsilon" SIGNOR-248450 PABIR1 protein Q96E09 UNIPROT PPP2R2A protein P63151 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 27588481 t miannu "We demonstrate that the highly conserved protein in mammals, designated FAM122A, directly interacts with PP2A-Aα and B55α rather than B56α subunits, and inhibits the phosphatase activity of PP2A-Aα/B55α/Cα complex." SIGNOR-266379 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Tyr222 MEAPTTAyKKTTPIE -1 10066823 t "HS1 was shown to undergo a process of sequential phosphorylation both in vitro and in vivo, which is synergistically mediated by Syk and Src family protein-tyrosine kinases and essential for B cell antigen receptor-mediated apoptosis. We have now identified tyrosine 222 as the HS1 residue phosphorylated by the Src family protein kinases c-Fgr and Lyn" SIGNOR-251399 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr576 RYMEDSTyYKASKGK 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-147191 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 THOC6 protein Q86W42 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-268510 "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 PRDM1 protein O75626 UNIPROT CCL2 protein P13500 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 19915049 t lperfetto "Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression." SIGNOR-271679 PTTG1 protein O95997 UNIPROT LGALS1 protein P09382 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002428 19351864 f miannu "PTTG induced S100A4 and galectin-1 mRNA and protein expression as assessed by Western blot and reverse transcription-PCR." SIGNOR-255068 USP28 protein Q96RU2 UNIPROT MYC protein P01106 UNIPROT up-regulates deubiquitination 9606 BTO:0000150 17558397 t esanto "Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc." SIGNOR-155590 cortisol smallmolecule CHEBI:17650 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-258708 acetyl-CoA smallmolecule CHEBI:15351 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI "up-regulates quantity" "precursor of" 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-266236 PRKACB protein P22694 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." SIGNOR-81141 MAPK1 protein P28482 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-265950 MAPK1 protein P28482 UNIPROT 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-263007 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 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 THRA protein P10827 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-268550 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Thr202 HDHTGFLtEYVATRW 9606 BTO:0000142 1411546 t gcesareni "The primary structure of mek, a protein kinase that phosphorylates the erk gene product" SIGNOR-19240 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARB protein P10826 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-258137 CAMK2A protein Q9UQM7 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser142 RKILNDLsSDAPGVP 9606 9668047 t gcesareni "Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer." SIGNOR-59137 MAPK1 protein P28482 UNIPROT RSPH3 protein Q86UC2 UNIPROT "up-regulates activity" phosphorylation Thr243 QEQLRPQtPEPVEGR 9606 19684019 t miannu "ERK1/2 phosphorylate RSPH3. the extent of radiolabeled phosphate incorporation into RSPH3 T286A was much less than that into wild-type RSPH3, suggesting that threonine 286 is the major ERK1/2 phosphorylation site in cells. ERK2 also phosphorylates RSPH3 on threonine 243 to a lesser extent. Phosphorylation of the double mutant T243V/T286A RSPH3 was no more than 20% that of wild-type RSPH3 (Fig. 4, C and D). inhibiting ERK1/2 activity appears to negatively regulate the AKAP function of RSPH3." SIGNOR-262839 FZR1 protein Q9UM11 UNIPROT UBE2S protein Q16763 UNIPROT "up-regulates activity" binding 9606 19822757 t lperfetto "Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity" SIGNOR-265081 AKT proteinfamily SIGNOR-PF24 SIGNOR CELF1 protein Q92879 UNIPROT "up-regulates activity" phosphorylation Ser28 GQVPRTWsEKDLREL 10090 BTO:0000165 18570922 t miannu "CUG repeat binding protein, CUGBP1, is a key regulator of translation of proteins that are involved in muscle development and differentiation. In normal myoblasts, Akt kinase phosphorylates CUGBP1 at Ser28 and increases interactions of CUGBP1 with cyclin D1 mRNA." SIGNOR-262615 HOXC6 protein P09630 UNIPROT S100B protein P04271 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002253 17488478 t Luana "HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells." SIGNOR-261646 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 CAMK2B protein Q13554 UNIPROT ETS1 protein P14921 UNIPROT "down-regulates activity" phosphorylation Ser257 DSFESIEsYDSCDRL 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-250685 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser859 DTSSLTQsAPASPTN 9606 BTO:0000007 19346248 t lperfetto "The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo." SIGNOR-184959 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 ANKRD11 protein Q6UB99 UNIPROT BDNF protein P23560 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-266732 CSNK2A1 protein P68400 UNIPROT CASP2 protein P42575 UNIPROT down-regulates phosphorylation Ser157 LYKKLRLsTDTVEHS 9606 16193064 t gcesareni "Here we show that protein kinase (pk) ck2 phosphorylates procaspase-2 directly at serine-157. When intracellular pkck2 activity is low or downregulated by specific inhibitors, procaspase-2 is dephosphorylated, dimerized, and activated in a piddosome-independent manner." SIGNOR-140836 UQCRB protein P14927 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-262194 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 20708156 t gcesareni "Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination" SIGNOR-167513 metformin chemical CHEBI:6801 ChEBI G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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-158056 PRKACA protein P17612 UNIPROT LCK protein P06239 UNIPROT unknown phosphorylation Ser42 TLLIRNGsEVRDPLV -1 8506364 t miannu "Ser-42 can be phosphorylated by either protein kinase A or protein kinase C" SIGNOR-249999 Avagacestat chemical CID:46883536 PUBCHEM APP protein P05067 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190479 alvocidib chemical CHEBI:47344 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192449 AKT1 protein P31749 UNIPROT 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-252496 "Phenylalanyl-tRNA synthetase" complex SIGNOR-C473 SIGNOR tRNA(Phe) smallmolecule CHEBI:29184 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-270438 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 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 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 FLT3 protein P36888 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 10090 25477897 t miannu "The three miR-29 family members in mouse bone marrow cells reduced the level of TET2 as well as its metabolic by-product, 5hmC" SIGNOR-255796 "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 DCAF11 protein Q8TEB1 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 31409866 t miannu "(WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner." SIGNOR-272262 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR GEN1 protein Q17RS7 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 31409866 t miannu "(WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner." SIGNOR-272263 TNFRSF1A protein P19438 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" 10090 BTO:0002572;BTO:0000801 21232017 f lperfetto "Tnfr1-induced phosforylation and degradarionn of ikb are almost completely abolished in tradd-deficient mefs,these hallmarks of classical nf-kn signaling are only attenuated in tradd-deficient macrophage." SIGNOR-235789 TP73 protein O15350 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 17700533 f miannu "Like p53, its homolog p73 transactivates proapoptotic genes and induces cell death." SIGNOR-255473 PP1 proteinfamily SIGNOR-PF54 SIGNOR TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 9606 16501611 t lperfetto "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-264670 PRKAA1 protein Q13131 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser30 EDLQEVLsSDENGGT 10090 27650555 t Luana "Here, we report that phosphorylation of CHOP at Ser30 by AMPKα1 triggers CHOP degradation resulting in reduced macrophage apoptosis and subsequent ameliorated plaque vulnerability in vivo." SIGNOR-259864 SPI1 protein P17947 UNIPROT MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26622774 f miannu "In the present study, PU.1 siRNA was demonstrated to efficiently inhibit the transcription level of oncogene MEIS1 in the human acute myeloid non-MLL leukemia U937 cell line. In addition, PU.1, as a positive regulator of MEIS1, performed a crucial role in maintaining cell proliferation." SIGNOR-256002 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 XAV939 chemical CHEBI:62878 ChEBI AXIN1 protein O15169 UNIPROT up-regulates 9606 19759537 f gcesareni "Using a quantitative chemical proteomic approach, we discovered that xav939 stabilizes axin by inhibiting the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2" SIGNOR-188045 IFTAP protein Q86VG3 UNIPROT BTF3 protein P20290 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 18433331 t lperfetto "Furthermore, we co-immunoprecipitated HEPIS with BTF3, a component of the RNA pol II initiation complex, and observed reduced proliferation of HeLa cells transfected with the HEPIS gene." SIGNOR-260252 ZNF76 protein P36508 UNIPROT TBP protein P20226 UNIPROT "down-regulates activity" binding 9606 15280358 t miannu "We identified ZNF76 as a novel transcriptional repressor that targets TBP. ZNF76 interacts with TBP through both its N and C termini. ZNF76 targets TBP for transcriptional repression." SIGNOR-224650 HBB protein P68871 UNIPROT CD163 protein Q86VB7 UNIPROT "up-regulates activity" binding 9606 16522161 t Regulation miannu "These data suggest that hemoglobin may mediate a stimulatory effect on erythropoiesis through the activation of CD163 on hematopoietic progenitor cells." SIGNOR-251746 D-glucitol smallmolecule CHEBI:17924 ChEBI TARDBP protein Q13148 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-262817 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "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-252977 ZFYVE9 protein O95405 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" relocalization 9606 20515759 t lperfetto "Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor." SIGNOR-165786 "Set1-Ash2 HMT complex" complex SIGNOR-C352 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 BTO:0000567 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-264484 SMURF proteinfamily SIGNOR-PF29 SIGNOR 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-253265 progesterone smallmolecule CHEBI:17026 ChEBI 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI "up-regulates quantity" "precursor of" 9606 BTO:0000048 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-268631 zileuton chemical CHEBI:10112 ChEBI ALOX5 protein P09917 UNIPROT "down-regulates activity" "chemical inhibition" 10116 1848634 t miannu "5-lipoxygenase inhibitory activity of zileuton." SIGNOR-258363 serotonin smallmolecule CHEBI:28790 ChEBI HTR2A protein P28223 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-264293 brimonidine chemical CHEBI:3175 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-258902 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 GSK3B protein P49841 UNIPROT ROR2 protein Q01974 UNIPROT "down-regulates activity" phosphorylation Ser864 PKPSSHHsGSGSTST 9606 SIGNOR-C110 21078818 t gcesareni "We identify ror2 ser 864 as a critical residue phosphorylated by gsk3 and required for noncanonical receptor activation by wnt5a, analogous to the priming phosphorylation of low-density receptor-related protein 6 (lrp6) in response to wnt3a." SIGNOR-169642 HBA1 protein P69905 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-251753 FGF11 protein Q92914 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-253426 PPP2CA protein P67775 UNIPROT FCAR protein P24071 UNIPROT "up-regulates activity" dephosphorylation Ser284 LTFARTPsVCK -1 30766540 t lperfetto "Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail" SIGNOR-264858 FBXW8 protein Q8N3Y1 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002572 23142081 t miannu "Defective IRS-1 degradation was due to attenuated expression and phosphorylation of the ubiquitin ligase substrate-targeting subunit, Fbw8. mTORC2 stabilizes Fbw8 by phosphorylation at Ser86, allowing the insulin-induced translocation of Fbw8 to the cytosol where it mediates IRS-1 degradation. " SIGNOR-271939 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 acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "up-regulates quantity" "precursor of" 9606 19524112 t miannu "The biosynthetic enzyme, aspartate-N-acetyltransferase (Asp-NAT; EC 2.3.1.17) is a CNS specific enzyme that catalyzes the transfer of acetate from acetyl-CoA to L-aspartate forming NAA." SIGNOR-267520 TAB1 protein Q15750 UNIPROT ROR2 protein Q01974 UNIPROT down-regulates phosphorylation 9606 18762249 t gcesareni "Tak1 (tgf-beta activated kinase 1), a map3k, interacts with ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (stp) domain" SIGNOR-180566 STK11 protein Q15831 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 SDGEFLRtSCGSPNY 9606 SIGNOR-C15 14614828 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-119179 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 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 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 CDK2 protein P24941 UNIPROT FZR1 protein Q9UM11 UNIPROT "down-regulates activity" phosphorylation Ser151 DVSPYSLsPVSNKSQ BTO:0000007 12560341 t llicata " A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus. " SIGNOR-250732 MAPK1 protein P28482 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR unknown phosphorylation 9606 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-217574 CREB1 protein P16220 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 10090 BTO:0000142 17584923 f Luana "These findings, together with studies in Aplysia and Drosophila, strongly suggest that CREB is an evolutionary conserved component of the molecular cascade of events leading to memory consolidation." SIGNOR-265773 glycine smallmolecule CHEBI:15428 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-264745 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr296 MGYDDLDyGMMSDYG -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-246500 RNF115 protein Q9Y4L5 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 23418353 t miannu "RNF126 and Rabring7 associate with the EGFR through a ubiquitin-binding zinc finger domain and both E3 ubiquitin ligases promote ubiquitylation of EGFR. In HeLa cells depleted of either RNF126 or Rabring7 the EGFR is retained in a late endocytic compartment and is inefficiently degraded." SIGNOR-272104 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 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-252450 KLHL22 protein Q53GT1 UNIPROT PLK1 protein P53350 UNIPROT "down-regulates activity" binding -1 23455478 t miannu "Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors. " SIGNOR-272108 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR PLK1 protein P53350 UNIPROT "down-regulates activity" monoubiquitination Lys492 YMSEHLLkAGANITP -1 23455478 t miannu "Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors. " SIGNOR-272110 MAP2K2 protein P36507 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 BTO:0000142 1411546 t gcesareni "The primary structure of mek, a protein kinase that phosphorylates the erk gene product" SIGNOR-19244 UNC5 proteinfamily SIGNOR-PF98 SIGNOR Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 f miannu "Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion" SIGNOR-268177 PPM1A protein P35813 UNIPROT AXIN1 protein O15169 UNIPROT down-regulates dephosphorylation 9606 SIGNOR-C110 10644691 t acerquone "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-74231 POU2F1 protein P14859 UNIPROT HOXD10 protein P28358 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25301728 f miannu "Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11" SIGNOR-205540 "HIF-1 complex" complex SIGNOR-C418 SIGNOR SLC2A1 protein P11166 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 11120745 t "Collectively these results indicate that H-Ras up-regulates the glut1 promoter, at least in part, by increasing HIF-1alpha protein levels leading to transactivation of promoter through the HIF-1 binding site." SIGNOR-267478 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 UBR4 protein Q5T4S7 UNIPROT TRPV5 protein Q9NQA5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0003913 23747339 t miannu "Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5.  UBR4/p600 ubiquitin ligase is responsible for TRPV5 ubiquitination and proteasomal degradation in response to cytomix" SIGNOR-272117 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 TNF protein P01375 UNIPROT SCN1A protein P35498 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-253478 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser249 LDILHNSsQMKSMST 9606 BTO:0000567 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265230 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 CSNK2A1 protein P68400 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser257 QIRLRRDsKEANARR -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-250945 TESK1 protein Q15569 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11294912 t lperfetto "These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that tesk1 and lim-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells." SIGNOR-106777 STK11 protein Q15831 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "up-regulates activity" phosphorylation -1 14976552 t lperfetto "We 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)." SIGNOR-242602 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 FZD9 protein O00144 UNIPROT SPRY4 protein Q9C004 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15705594 f miannu "In NSCLC cells, Wnt-7a and Fzd-9 induced both cadherin and Sprouty-4 expression and stimulated the JNK pathway, but not beta-catenin/T cell factor activity." SIGNOR-253035 MAPK1 protein P28482 UNIPROT PPP1R9B protein Q96SB3 UNIPROT unknown phosphorylation Ser15 GPGGPLRsASPHRSA 9606 15728359 t lperfetto "We have identified three sites phosphorylated by ERK2 (Ser-15 and Ser-205) and cyclin-dependent PK 5 (Cdk5) (Ser-17), within the actin-binding domain of spinophilin." SIGNOR-249435 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser389 LSPIAPRsPAKLSFQ 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-252086 RHAG protein Q02094 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266020 SMARCB1 protein Q12824 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-270725 AREG protein P15514 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t "Amphiregulin is an autocrine growth factor" lperfetto "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-236356 RXRA protein P19793 UNIPROT CPT1B protein Q92523 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 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-254582 PTPRS protein Q13332 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-264091 NTF4 protein P34130 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-31644 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 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 TFAP2C protein Q92754 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 f SimoneGraziosi "SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation." SIGNOR-269262 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 GIT1 protein Q9Y2X7 UNIPROT ARHGEF6 protein Q15052 UNIPROT "up-regulates activity" binding 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex." SIGNOR-272165 GRM5 protein P41594 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-264936 C25H27N5O4S chemical CID:66577011 PUBCHEM KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189711 CREB1 protein P16220 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" binding 9606 15126506 t lperfetto "We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity" SIGNOR-252894 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 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT "down-regulates activity" sumoylation Lys233 YKKYKKIkVERVERE 9606 14701874 t gianni "We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1." SIGNOR-268932 CAD protein P27708 UNIPROT "Pyrimidine biosynthesis" phenotype SIGNOR-PH187 SIGNOR "up-regulates activity" 9606 15096496 f "The CPSase activity of CAD is the major locus of control of de novo pyrimidine biosynthesis" SIGNOR-267196 rituximab antibody DB00073 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 20350663 t miannu "Rituximab is a class I chimeric anti-CD20 antibody that has shown efficacy in chronic lymphocytic leukemia (CLL), both as a single agent and in combination with traditional chemotherapies." SIGNOR-259902 etanercept chemical CHEBI:4875 ChEBI TNF protein P01375 UNIPROT "down-regulates activity" binding 9606 25455504 t "Etanercept is a recombinant human TNF receptor p75Fc fusion protein that binds with high affinity to the soluble and transmembrane forms of TNF, thereby acting as a decoy receptor for TNF and, prevents TNF-mediated inflammatory cellular responses by competitive inhibition" SIGNOR-272490 "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 F2R protein P25116 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-257011 Ub:E2 complex SIGNOR-C497 SIGNOR RNF135 protein Q8IUD6 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-271092 DEF6 protein Q9H4E7 UNIPROT RAP1A protein P62834 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 26483383 t lperfetto "Mechanistic studies revealed that SLAT interacts, through its PH domain, with a key component of inside-out signaling, namely the active form of the small GTPase Rap1 (which has two isoforms, Rap1A and Rap1B). This interaction has been further shown to facilitate the interdependent recruitment of Rap1 and SLAT to the T cell immunological synapse upon TCR engagement. Furthermore, a SLAT mutant lacking its PH domain drastically inhibited LFA-1 activation and CD4(+) T cell adhesion." SIGNOR-253365 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 CHEK1 protein O14757 UNIPROT WEE1 protein P30291 UNIPROT up-regulates phosphorylation 9606 20068082 t gcesareni "Chk1 also phosphorylates and stabilizes wee1." SIGNOR-163164 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 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 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 CALM1 protein P0DP23 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR 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-252337 SKP2 protein Q13309 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 10790373 t miannu " Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3." SIGNOR-272567 SEC24A protein O95486 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-265295 CDC14A protein Q9UNH5 UNIPROT MAPK6 protein Q16659 UNIPROT down-regulates dephosphorylation Ser684 IGIPQFHsPVGSPLK 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-164404 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 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA5 protein Q9Y5G8 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-265717 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates "chemical activation" 9606 10884684 t miannu "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-266333 PLK1 protein P53350 UNIPROT PINX1 protein Q96BK5 UNIPROT down-regulates phosphorylation Ser226 ATGKDVEsYLQPKAK 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-166325 PTPN7 protein P35236 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 BTO:0000007 10415025 t fstefani "Lc-ptp dephosphorylated erk2 in vitro. the complex formation of lc-ptp with erk is the essential mechanism for the suppression. Taken collectively, these results indicate that lc-ptp suppresses mitogen-activated protein kinase directly in vivo." SIGNOR-69448 PLCG1 protein P19174 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-155747 TDGF1 protein P13385 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-251938 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 lisuride chemical CHEBI:51164 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-258886 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 SMAD6 protein O43541 UNIPROT PELI1 protein Q96FA3 UNIPROT up-regulates binding 9606 19352540 t gcesareni "Mad6-pellino-1 interaction abrogated signaling mediated by a complex of irak1." SIGNOR-185128 CDC14A protein Q9UNH5 UNIPROT WEE1 protein P30291 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser123 EEGFGSSsPVKSPAA 9606 BTO:0000007 23051732 t lperfetto "In particular, we found that Cdc14A inhibits Wee1 degradation through the dephosphorylation of Ser-123 and Ser-139 residues. " SIGNOR-267469 MAPK10 protein P53779 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 14699954 t amattioni "The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53" SIGNOR-120552 CSNK2A1 protein P68400 UNIPROT ATF1 protein P18846 UNIPROT down-regulates phosphorylation Ser41 SLSESEEsQDSSDSI 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-167552 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Ser516 LSLTRGLsRTSMKPR 9606 22514276 t miannu "A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues." SIGNOR-197058 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0001516 12796379 t "FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation." SIGNOR-261516 CD3 complex SIGNOR-C432 SIGNOR ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9534 1423621 t "We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation|Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction." SIGNOR-252304 NTRK1 protein P04629 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 8384556 t gcesareni "The nerve growth factor (ngf) receptor/trk associated with and phosphorylated phospholipase c gamma (plc gamma)" SIGNOR-38538 Ub:E2 complex SIGNOR-C497 SIGNOR SH3RF2 protein Q8TEC5 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-271203 NR3C1 protein P04150 UNIPROT NR4A3 protein Q92570 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-132309 RRAGD protein Q9NQL2 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-228170 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 MAPK3 protein P27361 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000567 18211802 t gcesareni "Activates rhoa and as a result regulates actin assembly." SIGNOR-160420 idelalisib chemical CHEBI:82701 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190813 TUBB1 protein Q9H4B7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10116 17118269 f lperfetto "However, evidence suggests that the detyrosination/tyrosination cycle of alpha-tubulin may be linked in some cell types to cell division and proliferationNF-Y" SIGNOR-242138 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT "down-regulates activity" monoubiquitination Lys682 SAVSHQGkRNPKSPL 9606 21791603 t miannu "Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709)." SIGNOR-272730 SOD3 protein P08294 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-272273 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 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 GGCX protein P38435 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" carboxylation Glu72 EEAREVFeDSDKTNE -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-263673 ROS stimulus SIGNOR-ST2 SIGNOR ATF4 protein P18848 UNIPROT up-regulates "transcriptional regulation" 9606 19439225 f lperfetto "Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2alpha phosphorylation, which is responsible for Redd1 expression" SIGNOR-253729 TERF2 protein Q15554 UNIPROT "Shelterin complex" complex SIGNOR-C306 SIGNOR "form complex" binding 9606 BTO:0000567 15383534 t lperfetto "Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins." SIGNOR-263317 sirolimus chemical CHEBI:9168 ChEBI CD40 protein P25942 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 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-255474 MYD88 protein Q99836 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" binding 10090 BTO:0003432 10217414 t lperfetto "Interleukin-1 (il-1) stimulates the association of the il-1 receptor-associated protein kinase (irak) with the heterodimer of il-iri and il-iracp via the adapter protein myd88. Myd88 binds to both irak (il-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of irak with the receptor." SIGNOR-67143 ZIC1 protein Q15915 UNIPROT GLI3 protein P10071 UNIPROT up-regulates relocalization 9606 11238441 t lperfetto "Co-expression of zic1 resulted in gli1 and gli3 proteins being translocated to the nucleus in varying levels" SIGNOR-105497 SMAD1 protein Q15797 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "form complex" binding 9606 9436979 t lperfetto "Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription." SIGNOR-103615 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 AKT1 protein P31749 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000782 25336630 t miannu "stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity." SIGNOR-262227 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 P2RY1 protein P47900 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-257072 LPAR proteinfamily SIGNOR-PF2 SIGNOR GNA13 protein Q14344 UNIPROT up-regulates binding 10090 BTO:0000944 15856019 t "inferred from 70% family members" 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-269965 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr8 MTAKMETtFYDDALN 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170768 PAK2 protein Q13177 UNIPROT PAK2 protein Q13177 UNIPROT up-regulates phosphorylation Ser141 TVKQKYLsFTPPEKD 9606 BTO:0000007 16204230 t gcesareni "Pak2 is autophosphorylated at eight sites;ser-141 and ser-165 in the regulatory domain and thr-402 in the activation loop are identified as key sites in activation of the protein kinase." SIGNOR-140907 NFKBIA protein P25963 UNIPROT S100A6 protein P06703 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 12859951 f miannu "Transient expression of NF-kappaB (p65) increased S100A6 promoter activity and expression of inhibitor of NF-kappaB (IkappaBalpha) decreased TNFalpha-induced S100A6 promoter activity. " SIGNOR-254804 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "up-regulates activity" cleavage Asp390 LPQLTLPdSLTSAAS 17761173 t lperfetto "In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein" SIGNOR-260613 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2638 VAGQIRAtQQQHDFT 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-249159 UBE2L3 protein P68036 UNIPROT PRKN protein O60260 UNIPROT "up-regulates activity" ubiquitination -1 19240029 t miannu "Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1)." SIGNOR-272734 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 t "In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4." SIGNOR-251328 FUS protein P35637 UNIPROT PA2G4 protein Q9UQ80 UNIPROT "up-regulates activity" sumoylation Lys93 VCHFSPLkSDQDYIL 9606 BTO:0000007 19946338 t gcesareni "Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity €.. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity." SIGNOR-236904 AKT proteinfamily SIGNOR-PF24 SIGNOR BAX protein Q07812 UNIPROT "down-regulates activity" phosphorylation Ser184 VAGVLTAsLTIWKKM 9606 BTO:0003473 14766748 t lperfetto "Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophilsWe suggest that Bax is regulated by phosphorylation of Ser(184) in an Akt-dependent manner and that phosphorylation inhibits Bax effects on the mitochondria by maintaining the protein in the cytoplasm, heterodimerized with antiapoptotic Bcl-2 family members" SIGNOR-209651 estrone smallmolecule CHEBI:17263 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "precursor of" -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-269759 seliciclib chemical CHEBI:45307 ChEBI CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206574 HNF1A protein P20823 UNIPROT SLC22A10 protein Q63ZE4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20829431 t lperfetto "Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1 in HepG2 cells." SIGNOR-268983 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 MAPK1 protein P28482 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 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-91726 UBE2D2 protein P62837 UNIPROT VPS18 protein Q9P253 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 16203730 t miannu "VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4. " SIGNOR-271549 UCHL5 protein Q9Y5K5 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates quantity by stabilization" binding 9606 17052192 t gcesareni "Smad7 can act as an adaptor able to recruit uch37 to the type i tgf-beta receptor. Consequently, uch37 dramatically up-regulates tgf-beta-dependent gene expression by de-ubiquitinating and stabilizing the type i tgf-beta receptor." SIGNOR-150135 TRIM63 protein Q969Q1 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)." SIGNOR-272738 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 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 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 7545671 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-28796 MDGA2 protein Q7Z553 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 26206665 f miannu "MDGA2 acts as a novel tumour suppressor in gastric cancer through inhibiting cell proliferation, suppressing G1–S cell cycle transition and inducing cell apoptosis." SIGNOR-264239 WWP2 protein O00308 UNIPROT ABI3 protein Q9P2A4 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 15998807 t miannu "The AIP2 E3 ligase acts as a novel negative regulator of ABA signaling by promoting ABI3 degradation. Here, we show that ABI3 is an unstable protein and that an ABI3-interacting protein (AIP2), which contains a RING motif, can polyubiquitinate ABI3 in vitro." SIGNOR-272656 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 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 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 SPOP protein O43791 UNIPROT MACROH2A1 protein O75367 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15897469 t miannu "Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex." SIGNOR-272657 POLA1 protein P09884 UNIPROT DNA_replication phenotype SIGNOR-PH53 SIGNOR up-regulates 9606 19608746 f lperfetto "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-261275 "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 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser78 SSGSPANsFHFKEAW -1 14709557 t miannu "AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250314 HTR2A protein P28223 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-257227 CSNK2A1 protein P68400 UNIPROT FKBP4 protein Q02790 UNIPROT "down-regulates activity" phosphorylation Thr143 EFKGEDLtEEEDGGI -1 9405642 t llicata "Thr-143 in the hinge I region was identified as the major phosphorylation site for CK2. | Most importantly, CK2-phosphorylated FKBP52 did not bind to HSP90" SIGNOR-250865 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser455 HFGSTSSsPPISPAS 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-251244 TRIM63 protein Q969Q1 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)." SIGNOR-272739 VAV1 protein P15498 UNIPROT SYK protein P43405 UNIPROT up-regulates binding 9606 11331248 t lperfetto "Vav interacts with the tyrosine kinase syk" SIGNOR-107049 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCA protein P17252 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191490 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ADAM17 protein P78536 UNIPROT up-regulates phosphorylation Thr735 KPFPAPQtPGRLQPA 9606 12058067 t lperfetto "We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (tace) is phosphorylated by erk at threonine 735.These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by mapks may regulate the proteolytic function of membrane secretases." SIGNOR-89614 MED19 protein A0JLT2 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-266663 ABL1 protein P00519 UNIPROT MAP4K1 protein Q92918 UNIPROT "up-regulates activity" phosphorylation Tyr232 FLMTKSGyQPPRLKE 9606 BTO:0000007 11278340 t "C-Abl phosphorylates HPK1 in cytoplasm and stimulates HPK1 activity. the c-Abl phosphorylation site (YXXP) in HPK1 (Y232QPP; aa 232–235) is localized in HPK1-KD" SIGNOR-251429 ULK1 protein O75385 UNIPROT RB1CC1 protein Q8TDY2 UNIPROT up-regulates phosphorylation 9606 19597335 t gcesareni "Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks." SIGNOR-186992 "D-fructofuranose 6-phosphate(2-)" smallmolecule CHEBI:61527 ChEBI "2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-)" smallmolecule CHEBI:58725 ChEBI "up-regulates quantity" "precursor of" 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-268098 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 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 MIB2 protein Q96AX9 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates activity" polyubiquitination Lys377 NEPSLQSkLQDEANY 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-272662 canertinib chemical CHEBI:61399 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-258094 PPARG protein P37231 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" 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-249558 SLBP protein Q14493 UNIPROT H2BC1 protein Q96A08 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-265393 obinutuzumab antibody DB08935 DRUGBANK MS4A1 protein P11836 UNIPROT "down-regulates activity" binding 9606 BTO:0001546;BTO:0004656 28584136 t miannu "Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL)." SIGNOR-259896 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 8622669 t lperfetto "Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases." SIGNOR-40353 "Fostamatinib disodium" chemical CID:25008120 PUBCHEM SYK protein P43405 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206373 THAP12 protein O43422 UNIPROT EIF2S1 protein P05198 UNIPROT unknown phosphorylation Ser52 MILLSELsRRRIRSI -1 10542257 t lperfetto "The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the alpha subunit of the translation initiation factor eIF2. " SIGNOR-249029 PGAM proteinfamily SIGNOR-PF78 SIGNOR 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-266513 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD2 protein Q5U5R9 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-271283 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI "glycine zwitterion" smallmolecule CHEBI:57305 ChEBI "up-regulates quantity" "precursor of" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269691 KPNA1 protein P52294 UNIPROT KPNB1 protein Q14974 UNIPROT "up-regulates activity" binding 9534 17596301 t lperfetto "Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization." SIGNOR-260273 UBR5 protein O95071 UNIPROT TOPBP1 protein Q92547 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -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-272667 STK11 protein Q15831 UNIPROT STK11 protein Q15831 UNIPROT "up-regulates activity" phosphorylation Thr363 IEDDIIYtQDFTVPG 9606 BTO:0000007;BTO:0000567 12805220 t lperfetto "It was shown that thr336 and thr366 are the major autophosphorylation sites of mouse lkb1 (sapkota et al., 2002). We confirmed these data on the human orthologues thr336 and thr363. Moreover, the enhanced stoichiometry of lkb1 autophosphorylation by strad enabled us to identify two novel sites: thr185 and thr402. We show that increased lkb1 autophosphorylation of all sites correlates with the activation of its catalytic activity." SIGNOR-101848 sirolimus chemical CHEBI:9168 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 17350953 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 target 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-153608 TNFRSF10C protein O14798 UNIPROT TNFSF10 protein P50591 UNIPROT down-regulates binding 9606 BTO:0000671 20103630 t amattioni "Albeit on binding the ligand, dcr1 and dcr2 do not transduce the apoptogenic signal," SIGNOR-163611 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 CSNK2A2 protein P19784 UNIPROT MS4A1 protein P11836 UNIPROT unknown phosphorylation Thr250 KEEVVGLtETSSQPK 9606 BTO:0000776 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-251013 TRADD protein Q15628 UNIPROT FADD protein Q13158 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "Tradd recruits fadd" SIGNOR-177958 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 LSM-1231 chemical CHEBI:91471 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-258237 DVL1 protein O14640 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" binding 9534 BTO:0004055 10196136 t lperfetto "We have recently found that Dvl-1 directly binds to Axin and that the binding of Dvl-1 to Axin does not affect the interaction of GSK-3beta with Axin. It is possible that the binding of Dvl to Axin induces the structural change of the Axin complex; therefore GSK-3beta does not effectively phosphorylate Axin. This is the first demostration showing that Dvl inhibits the function of GSK-3beta directly." SIGNOR-227917 ME1 protein P48163 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-267055 SOD1 protein P00441 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR up-regulates 10090 BTO:0004488 29371591 t "P00441:p.Gly94Ala (mutation causing interaction); P00441:p.Gly86Arg (mutation causing interaction)" "Incubating SOD1G93A or SOD1G85R, another well-established misfolded SOD1 mutant, in the absence of recombinant MIF resulted in an exponential increase in thioflavin T (ThT) fluorescence (which correlates with amyloid aggregate formation)" SIGNOR-262796 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 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ABCB1 protein P08183 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 26299618 t miannu "Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro." SIGNOR-272425 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 ATR protein Q13535 UNIPROT XRCC3 protein O43542 UNIPROT "up-regulates activity" phosphorylation Ser225 PFRCEFDsQASAPRA 9606 23438602 t miannu "HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation." SIGNOR-262666 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 CDT1 protein Q9H211 UNIPROT CDT1 protein Q9H211 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 14672932 t "We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function." SIGNOR-261682 GSK3B protein P49841 UNIPROT BORA protein Q6PGQ7 UNIPROT up-regulates phosphorylation Ser278 PISSPTFsPIEFQIG 9606 23442801 t lperfetto "It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation" SIGNOR-201519 FGF4 protein P08620 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 8663044 t gcesareni "The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors." SIGNOR-42377 dabrafenib chemical CHEBI:75045 ChEBI BRAF protein P15056 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-259215 "UVB radiation" stimulus SIGNOR-ST17 SIGNOR calciol smallmolecule CHEBI:28940 ChEBI "up-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-270562 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser2 sPKRIAKR 9606 BTO:0000007 19559616 t miannu "MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets." SIGNOR-263146 CyclinD1/CDK6 complex SIGNOR-C143 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser45 GATTTAPsLSGKGNP -1 17208333 t llicata "We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade." SIGNOR-250647 ABL1 protein P00519 UNIPROT PSTPIP1 protein O43586 UNIPROT unknown phosphorylation Tyr345 PERNEGVyTAIAVQE 9606 11163214 t Manara "PSTPIP1 was phosphorylated by ABL1, and growth factor–induced PSTPIP1 phosphorylation was diminished in Abl null fibroblasts." SIGNOR-260809 PAWR protein Q96IZ0 UNIPROT WT1 protein P19544 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 8943350 t 2 miannu "We identified par-4 (for prostate apoptosis response) as a WT1-interacting protein that itself functions as a transcriptional repressor. Functionally, par-4 inhibited transcription activated by WT1" SIGNOR-240596 AKT1 protein P31749 UNIPROT 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-251622 SRC protein P12931 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Tyr151 IEFVNQYyGSFKEAK 9606 19875457 t llicata "We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells." SIGNOR-188974 TP53 protein P04637 UNIPROT PHB protein P35232 UNIPROT "up-regulates activity" binding 16918502 t lperfetto "Our previous studies have shown that prohibitin physically interacts with the marked-box domain of E2F family members and represses their transcriptional activity; in contrast, prohibitin could bind to and enhance the transcriptional activity of p53." SIGNOR-268978 TBX3 protein O15119 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 25595898 f miannu "AKT phosphorylation potentiates the ability of TBX3 to repress the transcription of the E-cadherin gene" SIGNOR-223537 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR ACIN1 protein Q9UKV3 UNIPROT up-regulates cleavage 9606 10490026 t amattioni "Induces apoptotic chromatin condensation after activation by casp3" SIGNOR-256449 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11689553 t irozzo "To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity." SIGNOR-256290 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 SP1 protein P08047 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-253350 ATG10 protein Q9H0Y0 UNIPROT ATG12/5/16L1 complex SIGNOR-C109 SIGNOR up-regulates binding 9606 18704115 t lperfetto "Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein." SIGNOR-226699 VPS11 protein Q9H270 UNIPROT RDX protein P35241 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 21148287 t Sara "Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation." SIGNOR-261312 EFNA1 protein P20827 UNIPROT EPHA2 protein P29317 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-51939 IKBKG protein Q9Y6K9 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C14 SIGNOR-C14 12192055 t lperfetto "The n-terminal domain of ikkgamma is required both for the binding of ikkalfa and ikkbeta and their assembly into a high-molecular-weight complex essential for activation" SIGNOR-91705 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD3 protein Q5T447 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-271280 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 ATM protein Q13315 UNIPROT SMC1A protein Q14683 UNIPROT up-regulates phosphorylation Ser966 GEDSVSGsQRISSIY 9606 11877377 t lperfetto "Here we report that smc1 is a component of the dna damage response network that functions as an effector in the atm/nbs1-dependent s-phase checkpoint pathway. Smc1 associates with brca1 and is phosphorylated in response to ir in an atm- and nbs1-dependent manner. Using mass spectrometry, we established that atm phosphorylates s957 and s966 of smc1 in vivo." SIGNOR-115496 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA1A protein P35348 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-257450 PRKACA protein P17612 UNIPROT SYN2 protein Q92777 UNIPROT "down-regulates activity" phosphorylation Ser10 NFLRRRLsDSSFIAN -1 10571231 t miannu "Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I" SIGNOR-250059 RALBP1 protein Q15311 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-260513 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 STAT4 protein Q14765 UNIPROT LAMTOR5 protein O43504 UNIPROT "up-regulates activity" binding 9606 22740693 t 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. here we first report that the transcription factor STAT4 plays a role in regulating S100A4 mediated by HBXIP in breast cancer." SIGNOR-255247 FLT3 protein P36888 UNIPROT USP22 protein Q9UPT9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26049753 f "USP22 deubiquitinase was overexpressed in FLT3-ITD positive AML CD34+ cells.USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells." SIGNOR-261559 "ZM 336372" chemical CID:5730 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207911 MMP9 protein P14780 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-272376 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 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 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 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 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1784 TPTSPNYsPTSPSYS -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-248790 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MCRIP1 protein C9JLW8 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 25728771 t "inferred from 70% family members" 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-270092 MEN1 protein O00255 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 11526476 t miannu "Menin represses p65-mediated transcriptional activation on nf-kappab sites in a dose-dependent and specific manner." SIGNOR-110067 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-267638 SYMPK protein Q92797 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 16230528 f lperfetto "Reconstitution experiments reveal that symplekin, previously shown to be necessary for cytoplasmic poly(A) tail elongation and translational activation of mRNAs during Xenopus oocyte maturation, is the essential heat-labile component." SIGNOR-268368 PRKCD protein Q05655 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser715 GYRQDDPsYRSFHSG 9606 25639486 t Manara "Moreover, protein kinase Cδ, which directly phosphorylates β-catenin at Ser715, is required for the TRIM33–β-catenin interaction. | Phosphorylation of β-catenin Ser715 is critical for TRIM33-induced β-catenin degradation" SIGNOR-260897 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 RARG protein P13631 UNIPROT THR proteinfamily SIGNOR-PF84 SIGNOR up-regulates binding 9606 15650024 t "inferred from family member" lperfetto "We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-270296 TP53 protein P04637 UNIPROT PMAIP1 protein Q13794 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10807576 f "Nuclear p53" amattioni "Expression of noxa was dependent on p53. Noxa represent a mediator of p53-dependent apoptosis." SIGNOR-76152 2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide chemical CHEBI:91331 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191103 "1D-myo-inositol 1,4,5-trisphosphate" smallmolecule CHEBI:16595 ChEBI PRKCA protein P17252 UNIPROT up-regulates "chemical activation" 9606 18593525 t gcesareni "The hrh1 predominantly couples to g?q/11 proteins, leading to the activation of phospholipase c (plc) and subsequent release of the second messengers inositol trisphosphate (ip3) and diacylglycerol (dag) followed by the activation of pkc and the release of [ca2+]i." SIGNOR-179291 "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 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MITF protein O75030 UNIPROT "down-regulates quantity by destabilization" phosphorylation 10841026 t "inferred from 70% family members" 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-270029 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 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 GSK3A protein P49840 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-159398 KAT5 protein Q92993 UNIPROT SRSF2 protein Q01130 UNIPROT down-regulates acetylation Lys52 IPRDRYTkESRGFAF 9606 21157427 t miannu "In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation." SIGNOR-170594 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 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 NRG1 protein Q02297 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 t gcesareni "Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3." SIGNOR-26875 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MYC protein P01106 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser62 LLPTPPLsPSRRSGL 10116 BTO:0004725 11018017 t "Phosphorylation of Ser 62 is required for Ras-induced stabilization of Myc, likely mediated through the action of ERK." SIGNOR-252079 Dinaciclib chemical CID:46926350 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191325 SPI1 protein P17947 UNIPROT EGR2 protein P11161 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16923394 f miannu "PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation" SIGNOR-256040 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 tRNA(Ile) smallmolecule CHEBI:29174 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-270425 CHEK1 protein O14757 UNIPROT RASSF1 protein Q9NS23 UNIPROT unknown phosphorylation Ser188 PSSKKPPsLQDARRG 9606 24197116 t llicata "This study reveals that chk1-mediated phosphorylation of rassf1a, at serine 184, plays an important role in cell-cycle regulation" SIGNOR-203144 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR 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-256452 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 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR MYOD1 protein P15172 UNIPROT "down-regulates activity" binding 9606 12244043 t 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-254986 STAT3 protein P40763 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002314 25194572 f lperfetto "STAT3 signaling controls satellite cell expansion and skeletal muscle repair" SIGNOR-245048 BFAR protein Q9NZS9 UNIPROT CASP8 protein Q14790 UNIPROT down-regulates binding 9606 BTO:0000093 11733517 t gcesareni "We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2" SIGNOR-112585 L-thyroxine smallmolecule CHEBI:18332 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino "TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis." SIGNOR-267489 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207944 KLF9 protein Q13886 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-222434 SPOP protein O43791 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 20463034 t Gianni "RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins" SIGNOR-268860 AKT1 protein P31749 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" phosphorylation Ser215 SGRAREAsGAPTSSK 9534 BTO:0001538 11404460 t lperfetto "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790" SIGNOR-108504 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 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT "up-regulates activity" phosphorylation Ser486 DDAFVGFsYAPPSED 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-250278 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR LCN2 protein P80188 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15536164 f miannu "Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG." SIGNOR-254796 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 15864272 t gcesareni "The only type ii ifn, ifn-g, 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-135952 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 USP9X protein Q93008 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates deubiquitination Lys519 DYPRQSIkETPCWIE 9606 22298955 t gcesareni "Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4." SIGNOR-195697 DYRK1A protein Q13627 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 BTO:0000142 19383720 t gcesareni "Dyrk1a physically interacts with the nicd inducing its phosphorylation in the ankyrin domain, thereby attenuating notch ." SIGNOR-185494 MAPK1 protein P28482 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1032 SSSNRPFtPPTSTGG 9606 16314496 t fstefani "We demonstrate that erk phosphorylates trap220/med1 in vivo at two specific sites: threonine 1032 and threonine 1457. importantly, we found that erk phosphorylation significantly increases the stability and half-life of trap220/med1 in vivo and correlates with increased thyroid hormone receptor-dependent transcription." SIGNOR-142458 PKA proteinfamily SIGNOR-PF17 SIGNOR CAD protein P27708 UNIPROT "down-regulates activity" phosphorylation Ser1406 GAGGRRLsSFVTKGY -1 17485345 t miannu "The multifunctional protein CAD initiates de novo pyrimidine biosynthesis in mammalian cells. CAD is activated by MAP kinase (Erk1/2) just prior to the S phase of the cell cycle, when the demand for pyrimidine nucleotides is greatest, and down-regulated as the cells emerge from S phase by protein kinase A (PKA) phosphorylation. MAP kinase phosphorylates Thr456, while PKA phosphorylates Ser1406 and Ser1859, although only Ser1406 is involved in regulation. " SIGNOR-267442 SRC protein P12931 UNIPROT CAV2 protein P51636 UNIPROT down-regulates phosphorylation Tyr27 SHHSGLEyADPEKFA 9606 15504032 t lperfetto "Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1." SIGNOR-129961 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 BTO:0000007 23429703 t "Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis." SIGNOR-267197 PTEN protein P60484 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 11875759 t lperfetto "PTEN dephosphorylates PI3P, lowering its cellular levels and resulting in the down-regulation of AKT." SIGNOR-228145 wortmannin chemical CHEBI:52289 ChEBI MYLK protein Q15746 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207791 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 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 KRAS protein P01116 UNIPROT RAF1 protein P04049 UNIPROT up-regulates binding 9606 16293107 t gcesareni "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. 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.. Association of ras with the mapk kinase kinase, raf, initiates the raf mek erk map kinase cascade." SIGNOR-141641 PRKCD protein Q05655 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249254 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 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 ETV3 protein P41162 UNIPROT ETV3 protein P41162 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22028471 t miannu "ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation." SIGNOR-262778 SMAD3 protein P84022 UNIPROT CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 23032366 f lperfetto "PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A." SIGNOR-245441 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 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 PRKCD protein Q05655 UNIPROT PRKD1 protein Q15139 UNIPROT up-regulates phosphorylation Ser742 GEKSFRRsVVGTPAY 9606 15024053 t llicata "Here we show that activation of pkd in response to oxidative stress requires two sequential signaling events, i.e., phosphorylation of tyr463 by abl, which in turn promotes a second step, phosphorylation of the pkd activation loop (ser738/ser742). We show that this is mediated by pkcdelta (protein kinase cdelta)" SIGNOR-123453 miR-23a mirna URS00001CC864_9606 RNAcentral ZNF423 protein Q2M1K9 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 19800867 t "These results suggest that the anti-adipogenic effect of miR-27b in hMADS cells is due, at least in part, to suppression of PPARgamma." SIGNOR-255934 MAP3K5 protein Q99683 UNIPROT DAXX protein Q9UER7 UNIPROT up-regulates phosphorylation Ser184 QSPRTRGsRRQIQRL 9606 19789335 t gcesareni "Our data demonstrated that ask1 controls the cytoplasmic localization of daxx (fig.1). our results indicate that daxx not only activates ask1 but also is a downstream target of ask1 and that accumulated daxx further activates ask1. Thus, the daxx-ask1 positive feedback loop amplifying jnk/p38 signaling plays an important role in the cell-killing effects of stressors, such as tnfalpha." SIGNOR-188325 DDX21 protein Q9NR30 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" binding 9606 "BTO:0000007 ; BTO:0001282" 11823437 t SARA "C-Jun and RHII/Gu proteins interact in human cells at their endogenous level of expression. The helicase activity of RHII/Gu specifically facilitates c-Jun-mediated transcription." SIGNOR-260977 RUNX2 protein Q13950 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11331591 f lperfetto "Together, these results suggest that the inhibition of cbfa1 transcription by TGF-_ requires both the presence of CBFA1 and CBFA1 binding to the cbfa1 promoter." SIGNOR-235533 MEFV protein O15553 UNIPROT "Pyrin inflammasome" complex SIGNOR-C226 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-256413 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR ACTL6B protein O94805 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-136212 SAR1A protein Q9NR31 UNIPROT SEC24B protein O95487 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-265300 TGFBR1 protein P36897 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser423 SPSIRCSsVS 10090 BTO:0005493;BTO:0000165 19458083 t lperfetto "A major event leading to smad3 activation is the tgf-beta-induced, tbetari-mediated phosphorylation at two c-terminal serine residues, ser-423 and ser-425, which triggers dissociation of smad3 from its receptors to form a complex with smad4 and accumulate in the nucleus" SIGNOR-235385 RHOQ protein P17081 UNIPROT SLC2A4 protein P14672 UNIPROT up-regulates 9606 12242347 f gcesareni "Tc10 is activated afte rinsulin stimulation, and its activation is required for insulin-stimulated glucose uptake and glut4 translocation" SIGNOR-93117 FST protein P19883 UNIPROT GDF11 protein O95390 UNIPROT "down-regulates activity" binding 10090 24627466 t lperfetto "Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-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-251716 CASP3 protein P42574 UNIPROT Protein_degradation phenotype SIGNOR-PH96 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-255337 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates 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-161678 LCK protein P06239 UNIPROT Gbeta proteinfamily SIGNOR-PF4 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-269899 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 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 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 CD79A protein P11912 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000776 12324477 f gcesareni "Bcr ligation activated mitochondrial apoptotic pathways including down-regulation of bcl-x(l)." SIGNOR-93481 SNAI2 protein O43623 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-255173 TNFRSF1A protein P19438 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates 9606 10795740 t "We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation" SIGNOR-256251 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 NR1D1 protein P20393 UNIPROT NR2E3 protein Q9Y5X4 UNIPROT up-regulates 9606 15190009 f gcesareni "Our results show that nr1d1 (rev-erb?) Also functions as a transcriptional activator of rod genes in the presence of nr2e3" SIGNOR-125658 TARS1 protein P26639 UNIPROT tRNA(Thr) smallmolecule CHEBI:29180 ChEBI "down-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-270501 HSPA1A protein P0DMV8 UNIPROT GSTA4 protein O15217 UNIPROT "up-regulates activity" relocalization phosphorylation:Thr193;Ser189 VKLSNIPtIKRFLEP;QEYTVKLsNIPTIKR 21929724 t lperfetto "Model showing Ser189/Thr193 protein kinase dependent phosphorylation of GST A4‐4 has increased affinity for chaperone Hsp70 which activates mitochondrial competent import signals for GSTA4‐4. |Protein kinase A mediated phosphorylation of serine residues of CYPs increases the affinity of proteins for binding to cytoplasmic chaperones such as heat shock proteins (Hsp), Hsp70/Hsp90, resulting in increased mitochondrial translocation" SIGNOR-264799 PRKCG protein P05129 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-249094 DFFA protein O00273 UNIPROT DFFB protein O76075 UNIPROT down-regulates binding 9606 BTO:0000567 9108473 t amattioni "Dff is a heterodimer of 40 kda and 45 kda subunits." SIGNOR-29729 GP1BA protein P07359 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-261847 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 MRPL48 protein Q96GC5 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-262348 NFYB protein P25208 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-252233 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL -1 10734133 t gcesareni "Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant." SIGNOR-262291 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 GSK3B protein P49841 UNIPROT SREBF1 protein P36956 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr426 TEVEDTLtPPPSDAG 9606 BTO:0000007 19126544 t lperfetto "Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1." SIGNOR-236667 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 CRYGS protein P22914 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-253625 SPTA1 protein P02549 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-266025 regorafenib chemical CHEBI:68647 ChEBI TAP1 protein Q03518 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 ABCG3" SIGNOR-259204 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 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 "26S Proteasome" complex SIGNOR-C307 SIGNOR oligopeptide smallmolecule CHEBI:25676 ChEBI "up-regulates quantity" cleavage 9606 15571818 t scontino "The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates." SIGNOR-267768 SDC4 protein P31431 UNIPROT DVL1 protein O14640 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Like other wnt co-receptors, syndecan 4 directly interacts with dvl during pcp 1." SIGNOR-199632 DHODH protein Q02127 UNIPROT ubiquinol smallmolecule CHEBI:17976 ChEBI "up-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-267432 AKT proteinfamily SIGNOR-PF24 SIGNOR ARFIP2 protein P53365 UNIPROT unknown phosphorylation Ser260 GTRGRLEsAQATFQA 9606 BTO:0000938 15809304 t llicata "Akt phosphorylated arfaptin 2 at ser(260). we have also demonstrated that arfaptin 2 phosphorylation restores proteasome activity that is inhibited by the presence of polyq-huntingtin in cells." SIGNOR-135105 ME1 protein P48163 UNIPROT NADP(3-) smallmolecule CHEBI:58349 ChEBI "down-regulates quantity" "chemical modification" 9606 33064660 t miannu "Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP." SIGNOR-267722 P2RY4 protein P51582 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-257214 SCN11A protein Q9UI33 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-253407 C5AR1 protein P21730 UNIPROT CR1 protein P17927 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-263466 "Papain-like proteinase" protein P0C6X7-PRO_0000037311 UNIPROT TRAF3 protein Q13114 UNIPROT "down-regulates activity" deubiquitination 9606 31226023 t miannu "Overexpressing PLPro of SARS-CoV or MERS-CoV significantly reduced the expression of IFN-β and proinflammatory cytokines in MDA5-stimulated 293T cells (83).Also, SARS-CoVPLPro catalyzed deubiquitination of TNF-receptor-associated factor3 (TRAF3) and TRAF6, thereby suppressing IFN-I and proinflammatory cytokines induced by TLR7 agonist (63). The deubiquitinating activity of SARS-CoV PLPro also suppressed a constitutively active phosphomimetic IRF3, suggesting its involvement in the postactivation signaling of IRF3" SIGNOR-260246 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ELK1 protein P19419 UNIPROT up-regulates phosphorylation 9606 7618106 t lperfetto "The tcf protein elk-1 is phosphorylated by the jnk and erk groups of mitogen-activated protein (map) kinases causing increased dna binding, ternary complex formation, and transcriptional activation" SIGNOR-252081 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 cholesta-5,7-dien-3beta-ol smallmolecule CHEBI:17759 ChEBI cholesterol smallmolecule CHEBI:16113 ChEBI "up-regulates quantity" "precursor of" 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-267250 metformin chemical CHEBI:6801 ChEBI CRTC2 protein Q53ET0 UNIPROT down-regulates 9606 16308421 f gcesareni "It has been proposed that metformin stimulates crtc2 phosphorylation in response to metabolic signals such as energy stress through the lkb1-ampk/sik1 pathways, which promotes binding to 14-3-3 proteins, thereby sequestering crtc2 from the nucleus to the cytoplasm" SIGNOR-142207 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 SRSF2 protein Q01130 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27524244 t miannu "Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2." SIGNOR-260076 CAMK2A protein Q9UQM7 UNIPROT SMAD2 protein Q15796 UNIPROT down-regulates phosphorylation Ser110 SFSEQTRsLDGRLQV 9606 SIGNOR-C8 11027280 t gcesareni "Smad2 is a target substrate for cam kinase ii in vitro at serine-110, -240, and -260. furthermore, cam kinase ii blocked nuclear accumulation of a smad2 and induced smad2-smad4 hetero-oligomerization independently of tgfbeta receptor activation, while preventing tgf-beta-dependent smad2-smad3 interactions." SIGNOR-82966 PALB2 protein Q86YC2 UNIPROT BRCA2 protein P51587 UNIPROT up-regulates binding 9606 BTO:0000150 16793542 t miannu "Palb2 colocalizes with brca2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions." SIGNOR-147217 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 CEBPA protein P49715 UNIPROT HSD11B1 protein P28845 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19088256 t lperfetto "Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region." SIGNOR-268971 AMPK complex SIGNOR-C15 SIGNOR BAIAP2 protein Q9UQB8 UNIPROT down-regulates phosphorylation Ser366 KTLPRSSsMAAGLER 9606 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-216608 STX10 protein O60499 UNIPROT "LE-TGN SNARE" complex SIGNOR-C157 SIGNOR "form complex" binding 9606 BTO:0000567 18195106 t lperfetto "We show in human cells that a soluble NSF attachment protein receptor (SNARE) complex comprised of syntaxin 10 (STX10), STX16, Vti1a, and VAMP3 is required for this MPR transport" SIGNOR-253080 "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "precursor of" 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-266500 EGR2 protein P11161 UNIPROT Monocyte_differentiation phenotype SIGNOR-PH101 SIGNOR up-regulates 9606 BTO:0001412 1864967 f irozzo "Finally, we demonstrate that dexamethasone, an inhibitor of monocytic differentiation, blocks the associated increases in EGR-1 and EGR-2 expression. Taken together, the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes." SIGNOR-256089 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 "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 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 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-39159 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 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 "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 BCL2 protein P10415 UNIPROT BAX protein Q07812 UNIPROT "down-regulates activity" binding 9606 BTO:0000776;BTO:0000785 8183370 t lperfetto "Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax." SIGNOR-36898 EIF2B3 protein Q9NR50 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-269136 FBXW7 protein Q969H0 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-243766 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 SRC protein P12931 UNIPROT JUP protein P14923 UNIPROT "up-regulates activity" phosphorylation Tyr644 RNEGTATyAAAVLFR 9606 14517306 t lperfetto "Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin." SIGNOR-247310 CHEK2 protein O96017 UNIPROT PPP2R5C protein Q13362 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 15380617 t gcesareni "Found that chk2 associated with the b' regulatory subunit of protein phosphatase pp2a. In vitro kinase assays showed that b'gamma3 was a potent chk2 substrate. This phosphorylation increased the catalytic phosphatase activity of pp2a." SIGNOR-129255 dapagliflozin chemical CHEBI:85078 ChEBI SLC5A2 protein P31639 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191289 KAT5 protein Q92993 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates acetylation Lys2078 EGSYETAkVLLDHFA 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-156923 VAV1 protein P15498 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-260580 TLN1 protein Q9Y490 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 10090 BTO:0000132 SIGNOR-C167 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-257593 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 CDK2 protein P24941 UNIPROT NFYA protein P23511 UNIPROT "up-regulates activity" phosphorylation Ser320 GEGGRFFsPKEKDSP 12857729 t llicata "Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa)" SIGNOR-250742 MAPK3 protein P27361 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-120208 DUSP4 protein Q13115 UNIPROT Gbeta proteinfamily SIGNOR-PF4 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-269914 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 MMP2 protein P08253 UNIPROT Laminin-5 complex SIGNOR-C184 SIGNOR "up-regulates activity" cleavage 9211848 t lperfetto "Induction of Cell Migration by Matrix Metalloprotease-2 Cleavage of Laminin-5|MMP2 cleaved the Ln-5 gamma2 subunit at residue 587, exposing a putative cryptic promigratory site on Ln-5 that triggers cell motility. This altered form of Ln-5 is found in tumors and in tissues undergoing remodeling, but not in quiescent tissues. Cleavage of Ln-5 by MMP2 and the resulting activation of the Ln-5 cryptic site may provide new targets for modulation of tumor cell invasion and tissue remodeling." SIGNOR-253239 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation Ser350 ELKAIVSsSNQALLR 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-260794 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CASP3 protein P42574 UNIPROT "down-regulates activity" 9606 BTO:0002882 11684015 f lperfetto "BCR/ABL Tyrosine Kinase Enhances Expression of RAD51 by Stimulation of STAT5-Mediated Transactivation and Inhibition of Caspase-3-Dependent Degradation|" SIGNOR-271704 CH5132799 chemical CID:49784945 PUBCHEM PIK3C2B protein O00750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190940 WNT10B protein O00744 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-131628 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 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 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 CSNK2A1 protein P68400 UNIPROT TLE1 protein Q04724 UNIPROT up-regulates phosphorylation Ser239 KDSSHYDsDGDKSDD 9606 15367661 t lperfetto "These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation." SIGNOR-129026 TCL1B protein O95988 UNIPROT AKT2 protein P31751 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-81716 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 FLT3 protein P36888 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" 10090 14981546 f "Immunoblot analysis indicated an increased level of Foxo3a phosphorylation on residue Thr32, as shown by the appearance of additional slower-migrating phospho-species immediately after induction of FLT3-ITD4 expression" SIGNOR-261523 GSK690693 chemical CHEBI:90677 ChEBI AKT2 protein P31751 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193003 NFE2L2 protein Q16236 UNIPROT KRT16 protein P08779 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18629308 f miannu "When overexpressed in HaCaT cells, NRF2 was also directly involved in not only the up-regulation of the detoxification gene thioredoxin but also K16 gene expression." SIGNOR-254645 AURKA protein O14965 UNIPROT MAPRE3 protein Q9UPY8 UNIPROT up-regulates phosphorylation Ser176 MQTSGRLsNVAPPCI 9606 19696028 t llicata "Aurora-a and aurora-b phosphorylate eb3 at ser-176 in a spatial and cell cycle-specific manner, respectively during mitosis two kinases, aurora-a and aurora-b, phosphorylate eb3 at ser-176, and the resulting phosphorylation disrupts the eb3-siah-1 complex. Indeed, eb3 is stabilized during mitosis and facilitates cell cycle progression." SIGNOR-187657 MYC protein P01106 UNIPROT LDHA protein P00338 UNIPROT "up-regulates quantity" "transcriptional regulation" 10116 9192621 f "Our studies have linked c-Myc to the induction of LDH-A, whose expression increases lactate production and is necessary for c-Myc-mediated transformation" SIGNOR-259367 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 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 25627476 f lperfetto "Mitochondrial phospholipids are important components of this system. Phospholipids make up the characteristic outer and inner membranes that give mitochondria their shape. " SIGNOR-267005 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 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 PBX4 protein Q9BYU1 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-265806 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 BTO:0000938 21106647 f miannu "Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion." SIGNOR-268387 GRK2 protein P25098 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates phosphorylation Thr123 IVKCQKLtDDHVQFL 9606 BTO:0000801 17055984 t lperfetto "Phosphorylation of p38 by grk2 at the docking groove unveils a novel mechanism for inactivating p38mapk p38 associates with grk2 endogenously and is phosphorylated by grk2 at thr-123, a residue located at its docking groove. Mimicking phosphorylation at this site impairs the binding and activation of p38 by mkk6 and diminishes the capacity of p38 to bind and phosphorylate its substrates" SIGNOR-150152 DLG3 protein Q92796 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-270885 PP2B proteinfamily SIGNOR-PF18 SIGNOR DNM1L protein O00429 UNIPROT "up-regulates activity" dephosphorylation 9606 18838687 t "inferred from 70% family members" "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-269994 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 EDNRA protein P25101 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-257320 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257987 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 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 8342904 t ashma gcesareni SIGNOR-251698 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates activity" binding 9606 BTO:0000459 18621737 t lperfetto "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." SIGNOR-179449 GPSM3 protein Q9Y4H4 UNIPROT GNB1 protein P62873 UNIPROT "down-regulates quantity by destabilization" binding 22843681 t lperfetto "GPSM3 was found not only to modulate heterotrimeric G-protein subunit signaling through its two active GoLoco motifs, but also to affect monomeric Gbeta subunit biosynthesis and stability|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET." SIGNOR-264865 STOX1 protein Q6ZVD7 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000601 22728895 t Gianni "In this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A." SIGNOR-269065 MAP3K1 protein Q13233 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser222 LIDSMANsFVGTRSY 10090 BTO:0000944 8131746 t lperfetto "Phosphorylation at ser-218 and ser-222 by map kinase kinase kinases (raf or mekk1) positively regulates mek1 kinase activity." SIGNOR-235564 SCN4A protein P35499 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-253451 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 EGF protein P01133 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates binding 9606 11279155 t tpavlidou "To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation." SIGNOR-106497 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR MKNK1 protein Q9BUB5 UNIPROT "up-regulates activity" phosphorylation Thr250 NSCTPITtPELTTPC 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-253014 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 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Thr100 LKRLFSGtQISTIAE 9606 15073328 t lperfetto "Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)" SIGNOR-124051 MAPK1 protein P28482 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 18245089 t gcesareni "We show in this study that the nuclear localized form of ciita is a predominantly phosphorylated form of the protein, whereas cytoplasmic ciita is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear ciita, indicating that these sites are not required for nuclear import. Erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-160609 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 TXK protein P42681 UNIPROT TXK protein P42681 UNIPROT up-regulates phosphorylation Tyr91 KIQVKALyDFLPREP 9606 12081135 t lperfetto "Evidence of autophosphorylation in txk: y91 is an autophosphorylation site. the results suggest that phosphorylated txk is an active form to promote ifn-gamma synthesis" SIGNOR-89844 ADORA1 protein P30542 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-257092 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" phosphorylation Ser29 ATKAARKsAPATGGV 9606 20129940 t gcesareni "Upon activation of the erk and p38 mapk pathways, the msk1/2-mediated nucleosomal response, including h3 phosphorylation at serine 28 or 10, is coupled with the induction of immediate-early (ie) gene transcription." SIGNOR-163712 GSK3B protein P49841 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C110 SIGNOR-C110 23579495 t lperfetto "Phosphorylation by GSK3 kept Axin activated (open) for _-catenin interaction and poised for engagement of LRP6." SIGNOR-201683 DNAJC15 protein Q9Y5T4 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-267692 GRPR protein P30550 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-257314 MAPK7 protein Q13164 UNIPROT GJA1 protein P17302 UNIPROT "down-regulates activity" phosphorylation Ser255 HATSGALsPAKDCGS 9606 BTO:0000007 12637502 t miannu "Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo. These data demonstrate that BMK1 kinase activity alone is both a necessary and sufficient component in the mediation of EGF-induced Cx43 Ser-255 phosphorylation and subsequent inhibition of GJC." SIGNOR-250115 MT-ND4 protein P03905 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-262146 NME2 protein P22392 UNIPROT KCNN4 protein O15554 UNIPROT up-regulates phosphorylation His358 FRQVRLKhRKLREQV 9606 17157250 t lperfetto "Ndpk-b directly binds and activates kca3.1 by phosphorylating histidine 358 in the carboxyl terminus of kca3.1" SIGNOR-151130 TBK1 protein Q9UHD2 UNIPROT REL protein Q04864 UNIPROT up-regulates phosphorylation 9606 SIGNOR-C68 16888014 t miannu "The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel." SIGNOR-148623 HRAS protein P01112 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 8052307 t lperfetto "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-236443 MAPK14 protein Q16539 UNIPROT USF1 protein P22415 UNIPROT "up-regulates activity" phosphorylation Thr153 EALLGQAtPPGTGQF 9606 19389701 t lperfetto "Following uv irradiation, usf-1 is phosphorylated by the p38 stress-activated kinase on threonine 153 and directly up-regulates expression of the pomc, mc1r, tyr, tyrp-1 and dct genes" SIGNOR-185572 "cyclosporin A" chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates "chemical inhibition" 10116 BTO:0001103 15829723 t apalma "On one hand, inhibition of calcineurin with cyclosporin A (CsA) significantly reduced the growth of both the slow/type I soleus muscle and fast/type II plantaris muscle in normal, ambulatory rats" SIGNOR-255102 RXRA protein P19793 UNIPROT THRB protein P10828 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-81449 DNMT1 protein P26358 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-254027 NEUROG2 protein Q9H2A3 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-265173 "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 TNFAIP3 protein P21580 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity" ubiquitination 9606 15258597 t "The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation." SIGNOR-259978 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 PIEZO1 protein Q92508 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-262571 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 DOCK4 protein Q8N1I0 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0001976 32009906 t miannu "DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. " SIGNOR-266823 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 EIF5B protein O60841 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 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-269121 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 ponatinib chemical CHEBI:78543 ChEBI RIPK1 protein Q13546 UNIPROT "down-regulates activity" "chemical inhibition" 9606 25801024 t Federica "Discovery of ponatinib as the first-in-class dual inhibitor of RIPK1 and RIPK3" SIGNOR-261082 PHA-665752 chemical CHEBI:90197 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-258265 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207830 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 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-250558 SRF protein P11831 UNIPROT PTGS2 protein P35354 UNIPROT up-regulates 9606 22225874 t FFerrentino "Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy." SIGNOR-255965 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 TPH2 protein Q8IWU9 UNIPROT tryptophan smallmolecule CHEBI:27897 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|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-264011 TP53 protein P04637 UNIPROT VCAN protein P13611 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12438652 t miannu "By using in vitro and in vivo assays, we showed CSPG2 to be directly transactivated by p53." SIGNOR-255441 ATM protein Q13315 UNIPROT SP1 protein P08047 UNIPROT unknown phosphorylation Ser101 DLTATQLsQGANGWQ 9606 18619531 t llicata "Thus, phosphorylation of ser-101 on sp1 is a general response to dna damage, dependent on both atm and atr." SIGNOR-179435 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser262 TFRPRSSsNASSVST 10090 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-252862 SRC protein P12931 UNIPROT SPTAN1 protein Q13813 UNIPROT up-regulates phosphorylation Tyr1176 AVQQQEVyGMMPRDE 9606 11971983 t llicata "Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro." SIGNOR-86718 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser293 GSTKRRKsMSGASPK 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-99733 CSNK2A3 protein Q8NEV1 UNIPROT F8 protein P00451 UNIPROT "down-regulates activity" phosphorylation Ser1656 GRTERLCsQNPPVLK -1 8427963 t lperfetto "Our findings suggest that phosphorylation of factors Va and VIIIa by a platelet casein kinase II-like kinase may downregulate the activity of the two cofactors.| Recombinant human factor VIII also showed incorporation of radioactivity in the presence of purified casein kinase II at the acidic NH2-terminal portion of factor VIII light chain (residues 1648 through 1689). Based on all the considerations reported above Se1657 is the most likely candidate within this region capable of incorporation of radioactivity" SIGNOR-263649 CSNK2A1 protein P68400 UNIPROT CAV1 protein Q03135 UNIPROT unknown phosphorylation Ser88 FDGIWKAsFTTFTVT -1 8058322 t llicata "Here, we have identified this serine kinase activity as a casein kinase II-like enzyme, since the phosphorylation of caveolin-rich membrane domains is stimulated and inhibited by known effectors of casein kinase II (poly-L-lysine, endogenous polyamines, and a casein kinase II inhibitor peptide), but is unaffected by modulators of other known kinases. In support of these observations, caveolin contains a consensus sequence for casein kinase II phosphorylation in its cytoplasmic N-terminal domain (Ser-88)" SIGNOR-250835 IL2RB protein P14784 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica "In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain" SIGNOR-204972 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 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 DPF3 protein Q92784 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-270703 OPTN protein Q96CV9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0005118 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-259876 "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 MAPK3 protein P27361 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 21757713 t lperfetto "The phosphorylation of Raptor on these sites enhances mTORC1 activity, and contributes largely to arsenite-induced mTORC1 activation." SIGNOR-217544 PPP2CA protein P67775 UNIPROT KRT8 protein P05787 UNIPROT unknown dephosphorylation Ser432 SAYGGLTsPGLSYSL 9606 BTO:0000182 16554440 t "K8 Ser431-P is a physiologic substrate to PP2A during hyposmotic conditions and possibly other biologic contexts." SIGNOR-248623 FLNA protein P21333 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "up-regulates quantity by stabilization" binding 9606 11706047 t lperfetto "We conclude that FLNa is essential in cells that express it for stabilizing orthogonal actin networks suitable for locomotion. " SIGNOR-261851 ECM stimulus SIGNOR-ST20 SIGNOR "A4/b1 integrin" complex SIGNOR-C162 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-259045 IL1R1 protein P14778 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto "The Il-1 family of ligands and receptors is primarily associated with acute and chronic inflammation." SIGNOR-171876 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 AMER1 protein Q5JTC6 UNIPROT CSNK1G1 protein Q9HCP0 UNIPROT up-regulates binding 9606 21304492 t gcesareni "Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6." SIGNOR-171889 TP53 protein P04637 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 24212651 f miannu "P53 is a nuclear transcription factor with a pro-apoptotic function" SIGNOR-255678 LCK protein P06239 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" phosphorylation Tyr394 RLIEDNEyTAREGAK 9606 2250907 t lperfetto "They also demonstrate that replacement of the major site of autophosphorylation of p56lck (tyrosine 394) by a phenylalanine residue abolishes the ability to activate p56lck by CD4 cross-linking, implying that this residue is critical for the positive regulation of the Lck tyrosine kinase activity by CD4." SIGNOR-81372 ENOBOSARM chemical CID:11326715 PUBCHEM AR protein P10275 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-195892 AVPR1B protein P47901 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-256934 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 ATF2 protein P15336 UNIPROT IL6 protein P05231 UNIPROT up-regulates "transcriptional regulation" 9606 BTO:0000801 20086235 f "JNK phosphorylates proteins that are part of AP-1, in particular c-Jun and activating transcription factor 2 (ATF-2). With dominant-negative mutants, antisense RNA, inhibitors, and genetic ablation, it has been shown that JNK and c-Jun play a major role in IL-1–induced expression of genes encoding IL-6 and IL-8 and other IL-1–responsive genes" SIGNOR-254512 CHEK2 protein O96017 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates activity" phosphorylation Ser60 DNTAGCTsAGPHFNP 4932 24647101 t "ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes." SIGNOR-262794 POLR3G protein O15318 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-266127 RNF144A protein P50876 UNIPROT PRKDC protein P78527 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 24979766 t miannu "We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation." SIGNOR-272213 PRKACA protein P17612 UNIPROT PLIN1 protein O60240 UNIPROT "down-regulates activity" phosphorylation Ser277 QAVSRRRsEVRVPWL 10090 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-250029 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 SOSTDC1 protein Q6X4U4 UNIPROT BMP7 protein P18075 UNIPROT "down-regulates activity" 10090 18032587 f lperfetto "SOSTDC1 is orthologous to a recently characterized murine antagonist of BMPs-2, -4, and -7" SIGNOR-242752 "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 FGFR1 protein P11362 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-259703 AURKA protein O14965 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser539 TSLSPRSsLSSPSPP 9606 21878642 t llicata "We identified the highly conserved ser(539) as the primary phosphorylation site for aurora kinases." SIGNOR-176359 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 AKT proteinfamily SIGNOR-PF24 SIGNOR USP14 protein P54578 UNIPROT "up-regulates activity" phosphorylation Ser432 THQGRSSsSGHYVSW 9606 BTO:0000007 26523394 t lperfetto "Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system|These results suggested S432 as a major and S143 as a minor phosphorylation site of Akt." SIGNOR-265055 NGLY1 protein Q96IV0 UNIPROT RAD23B protein P54727 UNIPROT "up-regulates activity" binding 9606 16401726 t miannu "The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome." SIGNOR-261061 WNT5A protein P41221 UNIPROT ROR1 protein Q01973 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Ror1 and ror2 bind wnt5a." SIGNOR-199644 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 12612081 t "In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A substrate-trapping mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR beta-subunit in 293 cells.|IR β-subunit phosphorylated on tyrosine and specifically on tyrosines 1162 and 1163 could be coimmunoprecipitated with the TC48-D182A and TC45-D182A mutants but not the wild-type TC48 or TC45 in response to insulin" SIGNOR-248386 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 DIABLO protein Q9NR28 UNIPROT XIAP protein P98170 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000567 11583623 t "Smac/DIABLO released from mitochondria" amattioni "Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity" SIGNOR-110831 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 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 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 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" phosphorylation Ser198 TRKSAPSsPTLDCEK 10090 BTO:0000142 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-250675 PGAM1 protein P18669 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-266514 CHIR-98014 chemical CID:53396311 PUBCHEM GSK3A protein P49840 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190985 SMAD3 protein P84022 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14993291 f gcesareni "Smad3 is required for both tgf-beta-induced repression of c-myc and subsequent growth arrest in keratinocytes" SIGNOR-123087 CYSLTR2 protein Q9NS75 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-256746 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK9 protein P45984 UNIPROT down-regulates binding 9606 10490659 t "JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)" gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70854 MOB1A protein Q9H8S9 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR 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-269866 "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 ZNF804A protein Q7Z570 UNIPROT CLIC2 protein O15247 UNIPROT "down-regulates quantity by repression" "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-269465 FLT3 protein P36888 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15498859 f "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-261519 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 MC4R protein P32245 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-257270 FOXO proteinfamily SIGNOR-PF27 SIGNOR PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 16670091 f lperfetto " FOXO1 coexpression dose-dependently repressed transcription from either the PPARgamma 1 or PPARgamma2 promoter reporter by 65%, whereas insulin (100 nm, 20-24 h) either partially or completely reversed this effect. " SIGNOR-252910 H3C1 protein P68431 UNIPROT Transcritpional_activation phenotype SIGNOR-PH205 SIGNOR "up-regulates activity" 9606 22266761 f Gianni "Widely described to be associated with active chromatin, H3K36 methylation has also been implicated in transcriptional repression, alternative splicing, dosage compensation, DNA replication and repair" SIGNOR-269072 PIM1 protein P11309 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 cellshere 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-164642 RALGAPA2 protein Q2PPJ7 UNIPROT RalGAP2 complex SIGNOR-C469 SIGNOR "form complex" binding 10090 21148297 t miannu "Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA." SIGNOR-269793 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 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNE1 protein P24864 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193543 PIAS1 protein O75925 UNIPROT RPA2 protein P15927 UNIPROT up-regulates sumoylation 9606 20016603 t gcesareni "Pias1 and pias4 promote brca1 accumulation and sumoylation, rpa phosphorylation, and dsb repair" SIGNOR-162153 Ub:E2 complex SIGNOR-C497 SIGNOR HERC2 protein O95714 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-271292 RNF111 protein Q6ZNA4 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates binding 9606 14657019 t gcesareni "Arkadia physically interacts with inhibitory smad, smad7, and induces its poly-ubiquitination and degradation." SIGNOR-119663 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 p38 proteinfamily SIGNOR-PF16 SIGNOR EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation -1 12171600 t "inferred from 70% family members" miannu "Inhibition of eEF2 kinase resulting from phosphorylation of Ser-396 by SAPK2a p38 was approx.25%." SIGNOR-270127 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 HNF4A protein P41235 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-4_ is a necessary factor for the activation of the human DD4 gene. is much higher than that of vHNF-1-C." SIGNOR-240016 STAT6 protein P42226 UNIPROT CHI3L1 protein P36222 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-249537 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 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 FGF2 protein P09038 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 11390973 t lperfetto "we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2).These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity." SIGNOR-86121 SKI protein P12755 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" binding 9606 BTO:0000848 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-236074 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr117 IIRLRNKtLIEDEIA 9606 20086174 t 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-244345 ODC1 protein P11926 UNIPROT spermine smallmolecule CHEBI:15746 ChEBI "up-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-256035 CBLB protein Q13191 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 16503409 t lperfetto "Activated Cbl and Cbl-b interacted with Crk-L, Zap-70, Nck, PLC-gamma" SIGNOR-236054 XL765 chemical CHEBI:71958 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207872 VAV1 protein P15498 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 7809090 t gcesareni "Here we report that both in cell extracts and within intact mammalian cells vav binds to grb2 (sem-5/ash/drk), an adaptor molecule which plays a key role in ras activation." SIGNOR-33840 IFNG protein P01579 UNIPROT HLA-B protein P01889 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 2507660 f Regulation miannu "HLA-B (class I) and C13 gene expression was transcriptionally activated by IFN-gamma and IFN-alpha 2" SIGNOR-251926 IL10 protein P22301 UNIPROT SCN4A protein P35499 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 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-253500 NOTCH1 protein P46531 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001253 12107827 f gcesareni "Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression." SIGNOR-90455 NELF complex SIGNOR-C521 SIGNOR "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "down-regulates activity" 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-271403 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 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 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-257934 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 15851026 t gcesareni "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 signalin." SIGNOR-135692 HPN protein P05981 UNIPROT F7 protein P08709 UNIPROT "up-regulates activity" cleavage Arg212 NASKPQGrIVGGKVC -1 7814421 t lperfetto "Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation|In contrast, an activation cleavage site factor VII mutant, R152E factor VII, was not cleaved by hepsin-transfected cells, suggesting that factor VII and S344A factor VII were activated on these cells by cleavage of the Arg152-Ile153 peptide bond. I" SIGNOR-263638 MAML1 protein Q92585 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11390662 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.Maml1 functions as a transcriptional co-activator for notch signalling." SIGNOR-86117 (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 LCK protein P06239 UNIPROT CD3D protein P04234 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-259929 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 21419176 t gcesareni "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 notch signaling in preadipocytes and mouse embryo fibloblasts." SIGNOR-172864 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 GNB1 protein P62873 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates 9606 23074268 f 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-199129 PPARGC1A protein Q9UBK2 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-254262 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr653 RDIHHIDyYKKTTNG 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-236195 ivacaftor chemical CHEBI:66901 ChEBI CFTR protein P13569 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck;potentiator gcesareni SIGNOR-193495 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 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser280 VDGTGDTsSEEDEDE 9606 11278496 t lperfetto "TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels" SIGNOR-246630 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 FYN protein P06241 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 9741627 t lperfetto "Shc is subsequently phosphorylated at tyrosine 317 and recruits grb2" SIGNOR-60160 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 MRAP protein Q8TCY5 UNIPROT MC3R protein P41968 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-252366 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MKNK2 protein Q9HBH9 UNIPROT up-regulates phosphorylation 9606 9155017 t "inferred from 70% family members" gcesareni "Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity." SIGNOR-270115 PRKAA1 protein Q13131 UNIPROT GLI1 protein P08151 UNIPROT "down-regulates activity" phosphorylation Ser102 LQTVIRTsPSSLVAF 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-259861 AMPK complex SIGNOR-C15 SIGNOR AMOTL1 protein Q8IY63 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser793 SSLRPARsVPSIAAA 9606 BTO:0000007 25373897 t miannu "we show that AMPK directly phosphorylates S793 of AMOTL1. AMPK activation stabilizes and increases AMOTL1 steady-state protein levels, contributing to YAP inhibition." SIGNOR-263105 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193615 Volasertib chemical CID:10461508 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190290 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 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR "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-259241 SRC protein P12931 UNIPROT FLT4 protein P35916 UNIPROT up-regulates phosphorylation Tyr1337 QVFYNSEyGELSEPS 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, demonstrating that integrin-mediated receptor phosphorylation induces a phosphorylation pattern that is distinct from that induced by growth factors. Furthermore, pull-down assays show that integrin-mediated vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk." SIGNOR-165043 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 MC4R protein P32245 UNIPROT "Food intake" phenotype SIGNOR-PH152 SIGNOR down-regulates 9606 BTO:0000614 33094623 f miannu "Enhanced melanocortin signaling in the hypothalamus results in both decreased food intake and increased energy expenditure. Adipose tissue derived hormone leptin induces negative energy balance by stimulating α-MSH and melanocortin-4 receptor (MC4R) (Friedman 1997, Kask et al. 1998). Increased melanocortin signaling in hypotalamus leads not only to decreased food intake but also increases sympathetic nervous system outflow to skeletal muscle, energy expenditure and physical activity" SIGNOR-263504 BNIP2 protein Q12982 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" binding 9606 BTO:0000222 18678706 t lperfetto "Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation." SIGNOR-179861 PRKAA1 protein Q13131 UNIPROT LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 SIGNOR-C15 9636039 t gcesareni "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-58255 HDAC2 protein Q92769 UNIPROT CCND1 protein P24385 UNIPROT up-regulates binding 9606 15713663 t gcesareni "Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5." SIGNOR-134062 RPS6KA1 protein Q15418 UNIPROT 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-123993 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 YY1 protein P25490 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001130 19013255 f miannu "Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative prostate cancers." SIGNOR-254233 RIPK1 protein Q13546 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 18545270 t lperfetto "The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis" SIGNOR-177949 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 ATXN7L3 protein Q14CW9 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-269579 GFPT1 protein Q06210 UNIPROT Hexosamine_biosynthesis phenotype SIGNOR-PH194 SIGNOR up-regulates 9606 21310273 f miannu "GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation." SIGNOR-267819 venetoclax chemical CHEBI:133021 ChEBI BCL2 protein P10415 UNIPROT "down-regulates activity" "chemical inhibition" 9606 23291630 t miannu "Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers." SIGNOR-261938 MAPK8 protein P45983 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT unknown phosphorylation Ser15 GLGGGAAsPPAASPF 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-250123 PRKD1 protein Q15139 UNIPROT KIDINS220 protein Q9ULH0 UNIPROT unknown phosphorylation Ser918 RTITRQMsFDLTKLL 10116 10998417 t lperfetto "Our results provide the first physiological substrate for PKD and indicate that Kidins220 is phosphorylated by PKD at serine 919 in vivo." SIGNOR-249052 CYC-116 chemical CID:6420138 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191224 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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190245 RXRB protein P28702 UNIPROT NR4A2 protein P43354 UNIPROT up-regulates binding 9606 BTO:0000938 9636132 t lperfetto "The recent discovery that the nuclear transcription factor, nurr1, in heterodimeric tandem with rxr, is unequivocally necessary for the expression of dopaminergic neurons" SIGNOR-58309 IL4R protein P24394 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "The type i il-4 receptors result from association of IL-4R With the common ? Chain (?c), which is also a component of the receptors for il-2, il-7, il-9, and il-15." SIGNOR-100765 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 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 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser459 TSSSPPIsPASSDLS 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-251243 WNT5A protein P41221 UNIPROT ROR2 protein Q01974 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-199647 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 DERA protein Q9Y315 UNIPROT "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "up-regulates quantity" "chemical modification" 9606 25229427 t miannu "Deoxyribose-phosphate aldolase (EC 4.1.2.4), which converts 2-deoxy-d-ribose-5-phosphate into glyceraldehyde-3-phosphate and acetaldehyde, belongs to the core metabolism of living organisms. his study provides the first experimental evidence that DERA, which is mainly expressed in lung, liver and colon, is the human deoxyribose phosphate aldolase." SIGNOR-267098 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 IRF8 protein Q02556 UNIPROT CYBB protein P04839 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 11483597 f 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-222710 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 INSR protein P06213 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation Tyr607 NENTEDQySLVEDDE 9534 BTO:0000298 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-252693 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 NSMCE3 protein Q96MG7 UNIPROT NSMCE1 protein Q8WV22 UNIPROT "up-regulates activity" binding -1 20864041 t miannu "MAGE-G1 enhances NSE1 ubiquitin ligase activity in vitro." SIGNOR-265489 WNT11 protein O96014 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-131637 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 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 RUNX1 protein Q01196 UNIPROT hsa-mir-223 mirna URS000037EC34_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 25092144 f miannu "We could show that STAT5 is involved in miR-155 induction. STAT5 knockdown in FLT3-ITD model systems reduced miR-155 expression in vitro and in vivo. In silico analyses predicted an STAT binding site in the miR-155 promoter." SIGNOR-255817 "glutamic acid" smallmolecule CHEBI:18237 ChEBI AMPA proteinfamily SIGNOR-PF58 SIGNOR "up-regulates activity" "chemical activation" 9606 15919192 t 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‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits." SIGNOR-264696 ADSS2 protein P30520 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-267834 GMIP protein Q9P107 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-260506 NOTCH1 protein P46531 UNIPROT FABP7 protein O15540 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16554461 f gcesareni "Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through notch1 and erbb receptors. First, notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (blbp) and erbb2 genes." SIGNOR-145365 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 SPI1 protein P17947 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-222880 regorafenib chemical CHEBI:68647 ChEBI PDGFRB protein P09619 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-259180 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 DLG4 protein P78352 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 19075115 f miannu "Postsynaptic density 95 (PSD-95) is an important regulator of synaptic structure and plasticity." SIGNOR-264053 LMO2 protein P25791 UNIPROT TAL1 protein P17542 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 9020185 t miannu "Transcriptional activity of tal1 in t cell acute lymphoblastic leukemia (t-all) requires rbtn1 or -2" SIGNOR-46161 PRKCD protein Q05655 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser46 AMDDLMLsPDDIEQW 9606 16377624 t llicata "Here, we show that the pro-apoptotic kinase, protein kinase c delta (pkcdelta), is involved in phosphorylation of p53 on ser(46). pkcdelta potentiates p53-dependent apoptosis by ser(46) phosphorylation in response to genotoxic stress." SIGNOR-143382 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-200030 TNF protein P01375 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR "up-regulates activity" 9606 23685857 f "Tumor necrosis factor α (TNF-α, also known as cachectin) is a strong pro-inflammatory cytokine which plays an important role in the immune system during inflammation, cell proliferation, differentiation and apoptosis" SIGNOR-258988 ADCY1 protein Q08828 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI up-regulates "chemical modification" 9606 22863277 t milica "To further explore the role of camp signaling in the hippo pathway, we treated cells with forskolin, an activator of adenylyl cyclase that results in cAMP production." SIGNOR-198486 MRPL11 protein Q9Y3B7 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-262382 UVRAG protein Q9P2Y5 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-260322 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser286 SSMSSCGsSGYFSSS 9606 22017877 t lperfetto "We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1" SIGNOR-176883 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 PRKCA protein P17252 UNIPROT GRIN1 protein Q05586 UNIPROT "up-regulates activity" phosphorylation Ser896 SSFKRRRsSKDTSTG 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-263177 TPR protein P12270 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-262070 acetyl-CoA smallmolecule CHEBI:15351 ChEBI (3S)-3-hydroxy-3-methylglutaryl-CoA(5-) smallmolecule CHEBI:43074 ChEBI "up-regulates quantity" "precursor of" 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-267651 retinal smallmolecule CHEBI:15035 ChEBI "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" "precursor of" 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-265127 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000627 8866550 f "inferred from family member" 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-267798 ABL1 protein P00519 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates activity" phosphorylation Tyr433 KIPQDGDyEFLKSWT 10116 21715626 t Manara "In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1." SIGNOR-260927 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 PTPN2 protein P17706 UNIPROT JAK3 protein P52333 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-133078 ITGB1BP1 protein O14713 UNIPROT "AD/b2 integrin" complex SIGNOR-C172 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-257654 CHUK protein O15111 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 15808510 t gcesareni "Ikkalpha phosphorylates eralpha, aib1/src-3, and histone h3." SIGNOR-135050 PK proteinfamily SIGNOR-PF80 SIGNOR STAT3 protein P40763 UNIPROT up-regulates phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 22306293 t llicata "Pkm2 activates transcription of mek5 by phosphorylating stat3 at y705. pkm2 regulates mek5 transcription via activation of stat3" SIGNOR-268152 EREG protein O14944 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 22891299 t gcesareni "For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4" SIGNOR-191785 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "up-regulates activity" phosphorylation Ser441 GHSPLSLsAQSVMEE 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-204708 MASP1 protein P48740 UNIPROT 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-263432 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BS1 protein P57053 UNIPROT "down-regulates activity" monoubiquitination Lys35 RKRKRSRkESYSVYV 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-271984 MCF2L protein O15068 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-260560 PAICS protein P22234 UNIPROT SAICAR(4-) smallmolecule CHEBI:58443 ChEBI "up-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-267322 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12110166 f fspada "We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-90507 EIF2B3 protein Q9NR50 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-269131 DPF2 protein Q92785 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-270719 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 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 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 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 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser233 VSSQHRYsTPHAFTF 9534 12801936 t miannu "Protein kinase A blocks Raf-1 activity by stimulating 14-3-3 binding and blocking Raf-1 interaction with Ras. Cyclic AMP (cAMP) blocks Raf-1 activation by stimulating its phosphorylation on serine 43 (Ser43), serine 233 (Ser233), and serine 259 (Ser259)." SIGNOR-250040 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 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 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11781324 t lperfetto "Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. 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-113645 FBXW7 protein Q969H0 UNIPROT NOTCH1 protein P46531 UNIPROT "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-130706 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 MED21 protein Q13503 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-266678 FASN protein P49327 UNIPROT "hexadecanoic acid" smallmolecule CHEBI:15756 ChEBI "up-regulates quantity" "chemical modification" 9606 12689621 t "An organizational model for animal FAS was proposed in which the two subunits depicted in domains I, II, and III were arranged in an antiparallel fashion, thereby generating two sites for palmitate synthesis. Initiation of the series of condensation reactions leading to the production of palmitic acid requires the translocation of one acetyl and seven malonyl moieties, from CoA thioester to the phosphopantetheine thiol of the ACP domain." SIGNOR-267373 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 MAPK3 protein P27361 UNIPROT NOS2 protein P35228 UNIPROT up-regulates phosphorylation Ser745 KSRQNLQsPTSSRAT 9606 BTO:0000007 17804409 t esanto "Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist." SIGNOR-157711 PKMYT1 protein Q99640 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 BTO:0000567 9001210 t "Preference on the part of Myt1Hu for the cyclin-bound form of Cdc2" lperfetto "Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory." SIGNOR-45729 CAMK4 protein Q16566 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 7925472 t gcesareni "Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr." SIGNOR-34743 nintedanib chemical CHEBI:85164 ChEBI FGFR4 protein P22455 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-257803 BMP4 protein P12644 UNIPROT BMPR1A/1B/2 complex SIGNOR-C29 SIGNOR "up-regulates activity" binding 9606 8006002 t fspada "BMP-4 bound to ALK-3 and ALK-6 efficiently" SIGNOR-236932 PTGER2 protein P43116 UNIPROT GNAS protein Q5JWF2 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-256756 MAPK1 protein P28482 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser87 AAAGPALsPVPPVVH 9606 BTO:0000567 10669763 t lperfetto "Phosphorylation of the map kinase sites in bcl-2, thr56, thr74, and ser87, is sufficient to inhibit tnf--induced degradation." SIGNOR-74931 WNT7B protein P56706 UNIPROT LRP5 protein O75197 UNIPROT up-regulates binding 9606 15923619 t flangone "These studies point to an important interaction between wnt7b, lrp5, and fzd1 and fzd10." SIGNOR-137937 COL1A1 protein P02452 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 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-272346 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 DCAF15 protein Q66K64 UNIPROT RBM39 protein Q14498 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001109 31819272 t miannu "Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation." SIGNOR-272203 indisulam chemical CHEBI:145431 ChEBI DCAF15 protein Q66K64 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001109 31819272 t miannu "Indisulam promotes an interaction between RBM39 and the DCAF15 E3 ligase substrate receptor, leading to RBM39 ubiquitination and proteasome-mediated degradation." SIGNOR-272204 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1393 GSVPLSSsPPATHFP 9606 7635160 t llicata "We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. phosphopeptide 1 was eliminated by replacement of ser1392" SIGNOR-30256 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 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI PTGER2 protein P43116 UNIPROT up-regulates "chemical activation" 9606 15299086 t gcesareni "Pge2 acts via four ep receptors termed ep1 to ep4." SIGNOR-127735 MTOR protein P42345 UNIPROT Myotube_hypertrophy phenotype SIGNOR-PH20 SIGNOR up-regulates 9606 BTO:0000887;BTO:0001103;BTO:0001760 22179044 f gcesareni "In differentiated myofibres, we observed that wnt7a binding to fzd7 directly activates the akt/mtor growth pathway, thereby inducing myofibre hypertrophy." SIGNOR-191564 GSK3A protein P49840 UNIPROT GSK3A protein P49840 UNIPROT up-regulates phosphorylation Tyr279 RGEPNVSyICSRYYR 9606 BTO:0000527 18701488 t gcesareni "Gsk3a is activated by phosphorylation at tyr-279." SIGNOR-180035 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 POU5F1 protein Q01860 UNIPROT SOX2 protein P48431 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-254942 HNF4G protein Q14541 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-254442 SUZ12/EZH2 complex SIGNOR-C77 SIGNOR SUZ12/EZH2/YY1 complex SIGNOR-C102 SIGNOR "form complex" binding 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-235577 TARS1 protein P26639 UNIPROT threonine smallmolecule CHEBI:26986 ChEBI "down-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-270502 TFIIH complex SIGNOR-C457 SIGNOR E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Thr433 DCDFGDLtPLDF 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-269354 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 SMAD7 protein O15105 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3." SIGNOR-64085 NONO protein Q15233 UNIPROT NONO/SFPQ complex SIGNOR-C62 SIGNOR "form complex" binding 9606 BTO:0000017 9756848 t miannu "We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i" SIGNOR-60475 Scribble_complex_DLG3-LLGL2_variant complex SIGNOR-C504 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-270886 ATF4 protein P18848 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002182 18940792 f miannu "C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." SIGNOR-253838 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser37 YLDSGIHsGATTTAP 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "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-141803 GNG2 protein P59768 UNIPROT GNB1 protein P62873 UNIPROT "up-regulates activity" binding 10696571 t "GNG2 dissociates from the activated receptor, bound with GNB1 as stable dimer." SIGNOR-251106 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT "up-regulates activity" deacetylation Lys215 QENREKMkQKKFDKK 9606 30327428 t miannu "SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR" SIGNOR-258986 EXT1 protein Q16394 UNIPROT WNT8B protein Q93098 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-264020 Ub:E2 complex SIGNOR-C497 SIGNOR NSMCE1 protein Q8WV22 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-270994 EEF1A1P5 protein Q5VTE0 UNIPROT Translational_elongation phenotype SIGNOR-PH210 SIGNOR up-regulates 9606 23699257 f 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-269395 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 DYRK3 protein O43781 UNIPROT AKT1S1 protein Q96B36 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C3 23415227 t lperfetto "When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40" SIGNOR-201002 NUP93 protein Q8N1F7 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-262081 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 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Ser206 ATPPTLSsTVLIVRN 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-249219 RNF185 protein Q96GF1 UNIPROT DVL2 protein O14641 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 10090 BTO:0001957 24727453 t miannu "The E3 ligase RNF185 negatively regulates osteogenic differentiation by targeting Dvl2 for degradation. Overexpression of RNF185 decreases the exogenous and endogenous level of Dvl2, promotes the ubiquitination and degradation of Dvl2" SIGNOR-272173 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 EPB42 protein P16452 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266014 "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 CUDC-907 chemical CID:54575456 PUBCHEM HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191157 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser187 NSHPFPHsPNSSYPN 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-161593 PPP2R1A protein P30153 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-243436 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 IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192880 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 22492984 t lperfetto "Bim, and puma bind with high affinity to all pro-survival proteins" SIGNOR-196935 RTKN protein Q9BST9 UNIPROT SEPTIN9 protein Q9UHD8 UNIPROT down-regulates 9606 16007136 f miannu "We identified rhotekin, a downstream effector for rho, as a candidate regulator organizing septin structures through filament disruption." SIGNOR-138578 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser597 VPMNPNLsSEDPNLF 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-129192 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 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 MAPK1 protein P28482 UNIPROT ZFP36 protein P26651 UNIPROT unknown phosphorylation Ser228 PPGDLPLsPSAFSAA 10090 BTO:0000944 7768935 t lperfetto "By a combination of protease digestion experiments and site-directed mutagenesis strategies, we found that serine 220 was phosphorylated by p42 MAP kinase in vitro. Expression of mutant TTP in fibroblasts confirmed that serine 220 was one of the major, mitogen-stimulated phosphorylation sites on the protein in intact cells. |It is not obvious how phosphorylation of TTP at serine 220 would alter DNA binding, since this residue lies well outside of the putative zinc finger region, which is between amino acids 95 to 159 in the mouse protein" SIGNOR-249456 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 PRKCA protein P17252 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-59229 CNOT2 protein Q9NZN8 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-268306 MYC protein P01106 UNIPROT USP22 protein Q9UPT9 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26049753 f "USP22 expression was regulated by c-MYC and contributed to c-MYC mediated reduction in SIRT1 polyubiquitination and degradation. USP22 directly interacted with and removing polyubiquitin chains from SIRT1 to increase SIRT1 protein stabilization and expression. These results support a role for USP22 in MYC-mediated increase in SIRT1 protein stabilization, and indicate that FLT3-ITD, c-MYC and USP22 form an oncogenic network that enhances SIRT1 expression and activity in leukemic cells." SIGNOR-261560 RBP2 protein P50120 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "up-regulates quantity" relocalization 9606 31963453 t lperfetto "Either acting on the producing cell (autocrine signaling) or the receiving cell (paracrine signaling), RA is transferred into the nucleus by Cellular retinoic acid-binding protein 2 (CRABP2) [18]. Once inside the nucleus, RA binds to specific nuclear transcription factors named Retinoic acid receptors (RARs)" SIGNOR-265130 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 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 20626350 t lperfetto "The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation" SIGNOR-166571 "aspartic acid" smallmolecule CHEBI:22660 ChEBI Asp-tRNA(Asp) smallmolecule CHEBI:29158 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-270378 CCT129202 chemical CID:16202152 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190883 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT up-regulates phosphorylation Ser70 RDPVARTsPLQTPAA 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-179088 COL4A1 protein P02462 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-272353 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 CSNK2B protein P67870 UNIPROT SEC63 protein Q9UGP8 UNIPROT "up-regulates activity" phosphorylation Ser576 VSDKGSDsEEEETNR 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-265268 CDKN1B protein P46527 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 18423396 f fspada "Moreover, expression of p27(kip1), an inhibitor of the cell cycle, was down regulated in an akt1/pkbalpha-specific manner during adipocytedifferentiation." SIGNOR-178278 TBK1 protein Q9UHD2 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 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-178391 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 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 ACSS1 protein Q9NUB1 UNIPROT acetyl-CoA(4-) smallmolecule CHEBI:57288 ChEBI "up-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-271829 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 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 PSMB1 protein P20618 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-263356 TFAP2D protein Q7Z6R9 UNIPROT ST8SIA2 protein Q92186 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9031 24462686 t lperfetto "We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2 and the ST8SIA2 promoter.|We show that ST8SIA2 is induced by AP-2δ overexpression in chick retina. We use chromatin immunoprecipitation and gel shift assays to demonstrate direct interaction between AP-2δ and the ST8SIA2 promoter." SIGNOR-268992 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 10550055 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-72075 TWIST1 protein Q15672 UNIPROT RUNX2 protein Q13950 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003298 21931630 f miannu "Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2." SIGNOR-255593 (S)-verapamil chemical CHEBI:77736 ChEBI ABCC1 protein P33527 UNIPROT "up-regulates activity" "chemical activation" 10036 17646169 t Federica "(S)-Verapamil acts as a “killer” by activation of MRP1-mediated GSH efflux, leading to the death of potentially resistant tumor cells." SIGNOR-261081 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192470 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT "up-regulates activity" phosphorylation Thr125 MIPQKNQtASGDSLD 9606 BTO:0001938 22535524 t lperfetto "We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors." SIGNOR-252049 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Tyr264 FAFSGGLyGGLPPTH -1 11104670 t "Tyrosine phosphorylation of NIPP1 by Lyn was abolished by the Tyr-264 to Asp mutation." SIGNOR-251405 EP300 protein Q09472 UNIPROT MN1 protein Q10571 UNIPROT up-regulates binding 9606 12569362 t miannu "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-97899 PLK1 protein P53350 UNIPROT RIOK2 protein Q9BVS4 UNIPROT "up-regulates activity" phosphorylation Ser548 KSSLEAAsFWGE -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-262939 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 SPI1 protein P17947 UNIPROT NAB2 protein Q15742 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 16923394 f miannu "PU.1 Induces Egr-2 and Nab-2, which Repress Neutrophil Genes during Macrophage Differentiation" SIGNOR-256039 FASN protein P49327 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 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-267211 TP53 protein P04637 UNIPROT RPS6KA1 protein Q15418 UNIPROT up-regulates 9606 15073170 f gcesareni "Rather, p53 expression stimulates the serine/threonine kinase ribosomal s6 kinase 1 (rsk1), which in turn phosphorylates the p65 subunit of nf-kb." SIGNOR-124038 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 NKX3-1 protein Q99801 UNIPROT AR protein P10275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16697957 t miannu "Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events." SIGNOR-251547 MAPK3 protein P27361 UNIPROT KLC1 protein Q07866 UNIPROT down-regulates phosphorylation Ser460 YKACKVDsPTVTTTL 9606 21385839 t 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-172642 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 PRKACA protein P17612 UNIPROT PSEN1 protein P49768 UNIPROT unknown phosphorylation Ser310 PEAQRRVsKNSKYNA -1 14576165 t miannu "PKA-mediated phosphorylation of PS1 is completely inhibited by mutation of Ser310.phosphorylation of Ser310 does not inhibit the caspase-mediated cleavage of PS1, and the biological function of this phosphorylation event remains to be determined in further experiments." SIGNOR-250036 BUB1 protein O43683 UNIPROT BUB3 protein O43684 UNIPROT "up-regulates activity" relocalization 11402067 t lperfetto "Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity" SIGNOR-252019 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 GH1 protein P01241 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 15665309 t Luana "Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells" SIGNOR-261628 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGC5 protein Q9Y5F6 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-265683 DTX1 protein Q86Y01 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" ubiquitination 10090 BTO:0000165 11226752 t gcesareni "Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis" SIGNOR-236870 TAOK2 protein Q9UL54 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" binding -1 10497253 t lperfetto "Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7." SIGNOR-70947 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 CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206130 FOXM1 protein Q08050 UNIPROT SLC27A2 protein O14975 UNIPROT "up-regulates quantity by expression" 9606 31949772 f lperfetto "FOXM1 as a prognostic biomarker promotes endometrial cancer progression via transactivation of SLC27A2 expression." SIGNOR-260414 acyl-CoA smallmolecule CHEBI:17984 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-268106 NPM1 protein P06748 UNIPROT CENPA protein P49450 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19410544 t miannu "Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1." SIGNOR-263708 STOML2 protein Q9UJZ1 UNIPROT MFN2 protein O95140 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20359165 f Giorgia "Of interest, induction of SLP-2 expression also resulted in significant increases in the levels of OPA-1 and mitofusin-2 (P < 0.05), both integral mitochondrial membrane proteins associated with mitochondrial fusion." SIGNOR-260380 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 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 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 9878069 t gcesareni "Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e." SIGNOR-62936 CDK5R1 protein Q15078 UNIPROT CDK5 protein Q00535 UNIPROT up-regulates binding 9606 15013773 t miannu "In brain, p35 or p25 exists with and activates cdk5" SIGNOR-123387 N-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]-6-quinazolinyl]-2-propenamide chemical CHEBI:91467 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189945 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 MET protein P08581 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 22128289 t irozzo "For activation of the mitogen-activated protein kinase (MAPK) cascades, c-MET activation stimulates the activity of the rat sarcoma viral oncogene homolog (RAS) guanine nucleotide exchanger son of sevenless (SOS) via binding with SHC and GRB2 leading to the activation of RAS." SIGNOR-256261 MAX protein P61244 UNIPROT MXI1 protein P50539 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-240314 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 BTO:0000938 10529400 t lperfetto "Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9BAD phosphorylation by Akt is an essential step for growth factor-mediated inhibition of caspase activation" SIGNOR-71480 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 GTF2H4 protein Q92759 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-269315 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 ATR protein Q13535 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-177813 MYCL protein P12524 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0002891 27546534 f irozzo "Our findings demonstrate that stable expression of the L-MYC gene in NSC008 cells promotes their survival and proliferation while preserving their migration and differentiation properties in vitro and in vivo." SIGNOR-259109 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 SMAD3 protein P84022 UNIPROT SMAD3/JUN complex SIGNOR-C86 SIGNOR "form complex" binding 9606 9732876 t gcesareni "These results show a ligand-dependent association of smad3 with c-jun" SIGNOR-59873 SOCS1 protein O15524 UNIPROT IFNG protein P01579 UNIPROT down-regulates 9606 21628332 f lperfetto "SOCS1 inhibits macrophage responses to IFN-g, and SOCS1-deficient mice develop symptoms of severe systemic autoimmune and inflammatory disease." SIGNOR-249571 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI TYRO3 protein Q06418 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190410 ERBB4 protein Q15303 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16829981 t gcesareni "Like erbb1, erbb4 recruits grb2, shc and stat5." SIGNOR-147850 CAMK2A protein Q9UQM7 UNIPROT ANKS1B protein Q7Z6G8 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 27477489 t miannu "CaMKII-mediated displacement of AIDA-1 out of the postsynaptic density core. The present study indicates that CaMKII activation is necessary for the NMDA-induced movement of AIDA-1 out of the PSD core." SIGNOR-264231 PEX12 protein O00623 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" 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-253020 calcium(2+) smallmolecule CHEBI:29108 ChEBI FLNA protein P21333 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000132 27871158 t lperfetto "Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step. Cofilin also binds to actin and contributes to the disassembly of actin filaments and the subsequent release of actin monomers. The actin cross-linking complex, GP1b/IX-filamin, translocates from the plasma membrane to the cytoskeleton during this step." SIGNOR-261845 pentazocine chemical CHEBI:7982 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-258766 AANAT protein Q16613 UNIPROT N-acetylserotonin smallmolecule CHEBI:17697 ChEBI "up-regulates quantity" "chemical modification" -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-265478 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 RNF146 protein Q9NTX7 UNIPROT TNKS2 protein Q9H2K2 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 21799911 t "We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation." SIGNOR-260005 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Ser32 RSEDARSsPSQRRRG 9606 BTO:0000567 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-100881 PRKACA protein P17612 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser579 NVKSKIGsTENLKHQ -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-250008 IL17A protein Q16552 UNIPROT KLF3 protein P57682 UNIPROT up-regulates "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-210114 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 carfilzomib chemical CHEBI:65347 ChEBI PSMB8 protein P28062 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000873 19348473 t Luana "Carfilzomib selectively inhibits the CT-L activity of the 20S proteasome and displays equivalent potency against β5 and LMP7 with minimal cross reactivity to other protease classes." SIGNOR-257819 COPS8 protein Q99627 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-270770 ERBB4 protein Q15303 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146885 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 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM59 protein Q8IWR1 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-271123 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 18498746 t gcesareni "Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf)." SIGNOR-178686 MYO5A protein Q9Y4I1 UNIPROT ACTB protein P60709 UNIPROT "up-regulates activity" binding 9606 21077886 t 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-269280 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 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 PRKACA protein P17612 UNIPROT SNAPIN protein O95295 UNIPROT "up-regulates activity" phosphorylation Ser50 HVHAVREsQVELREQ 11283605 t miannu "PKA-phosphorylation of Snapin significantly increases its binding to synaptosomal-associated protein-25 (SNAP-25). Mutation of Snapin serine 50 to aspartic acid (S50D) mimics this effect of PKA phosphorylation" SIGNOR-250053 CAMK2G protein Q13555 UNIPROT FLNA protein P21333 UNIPROT unknown phosphorylation Ser2523 VTGPRLVsNHSLHET BTO:0001141 11290523 t llicata "Our TER experiments using a CaM peptide, which functions as a specific competitive inhibitor of nonmuscle filamin phosphorylation by CaM kinase II, strongly suggest that filamin phosphorylation is involved in endothelial cell barrier regulation, although the exact mechanism is not clear and consequent signaling events are not well understood. " SIGNOR-250696 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 MAPK6 protein Q16659 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000551 22505454 t gcesareni "Here, we report that erk3 interacted with and phosphorylated steroid receptor coactivator 3 (src-3), an oncogenic protein overexpressed in multiple human cancers at serine 857 (s857)" SIGNOR-196957 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 BKM120 chemical CHEBI:71954 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190389 GSK3B protein P49841 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser33 LPENNVLsPLPSQAM 9606 11483158 t "Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity." SIGNOR-251258 AIMP2 protein Q13155 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-270361 GCGR protein P47871 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 12626323 t "Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA)." SIGNOR-267715 POLR3H protein Q9Y535 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-266126 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 PHF10 protein Q8WUB8 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-270614 MAK protein P20794 UNIPROT MAK protein P20794 UNIPROT "up-regulates activity" phosphorylation Thr157 LRSQPPYtDYVSTRW 9606 21986944 t Manara "We conclude that dual phosphorylation on the TDY motif is crucial for MAK activity, and that the autokinase activity is required for this phosphorylation" SIGNOR-260779 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 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 ZNF148 protein Q9UQR1 UNIPROT SOX18 protein P35713 UNIPROT "down-regulates quantity by repression" "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-254821 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 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 PSMD6 protein Q15008 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-263350 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 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" binding 9606 25520508 t miannu "We show that G3BP1 can activate effectors of the innate immune transcriptional program, culminating in enhanced expression of a set of cytokines. We demonstrate that a subset of PKR is recruited to SGs, that close-proximity interactions between G3BP1 and PKR complexes increase in response to stress and PKR activation, that once activated PKR no longer associates with SGs, and that the PXXP domain of G3BP1 is essential for PKR recruitment to SGs and PKR activation in cells. Together, these findings suggest that G3BP1 plays an important role in the recruitment of PKR to SGs and suggest that activation of PKR can take place at the SG." SIGNOR-260750 MAGED1 protein Q9Y5V3 UNIPROT CDKN1A protein P38936 UNIPROT up-regulates 9606 BTO:0001760 20646279 f gcesareni "By comparing in vitro differentiation of myoblasts derived from wild-type or maged1 knockout mice, we observed that maged1 deficiency results in reduced levels of p21cip1/waf1, defective cell cycle exit and impaired myotube maturation." SIGNOR-166893 AKT proteinfamily SIGNOR-PF24 SIGNOR SLC2A4 protein P14672 UNIPROT up-regulates 9606 9415393 f "Translocation from intracellular compartment to cell surface in muscle and adipose tissue" gcesareni "Akt is not only capable of stimulating the translocation of glut4 to the cell surface. Endogenous akt is likely to play a significant physiological role in insulin-stimulated glucose uptake in insulin targets such as muscle and adipose tissue" SIGNOR-53968 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1193 QPTSKAYsPRYSISD 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." SIGNOR-244747 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 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 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 Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 32979938 t miannu "We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F)." SIGNOR-262512 SCN10A protein Q9Y5Y9 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-253454 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 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 SFXN1 protein Q9H9B4 UNIPROT L-serine chemical CHEBI:17115 ChEBI "up-regulates quantity" relocalization 9606 30442778 t lperfetto "SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism." SIGNOR-268245 CASP7 protein P55210 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-261746 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 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 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 SCAP protein Q12770 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" relocalization 10029 BTO:0000246 12202038 t "SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function" SIGNOR-267501 SMARCA4 protein P51532 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-270738 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 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 SRC protein P12931 UNIPROT ITGB3 protein P05106 UNIPROT "down-regulates activity" phosphorylation Tyr773 DTANNPLyKEATSTF 9606 BTO:0003904 11723131 t lperfetto "The phosphorylation level of beta(3) integrin was modulated using a temperature-sensitive v-Src kinase. Increased beta(3) phosphorylation abolished alpha(v)beta(3)- but not alpha(5)beta(1)-mediated adhesion to fibronectin. Thus, phosphorylation of the cytoplasmic domain of beta(3) is a negative regulator of alpha(v)beta(3)-fibronectin binding strength." SIGNOR-247202 PGD protein P52209 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-267053 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 serotonin smallmolecule CHEBI:28790 ChEBI HTR3C protein Q8WXA8 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-264296 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 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 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3." SIGNOR-26061 DOK7 protein Q18PE1 UNIPROT MUSK protein O15146 UNIPROT up-regulates binding 9606 16794080 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-147323 JAK1 protein P23458 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 9305869 t "Janus kinase-dependent activation of insulin receptor substrate 1" SIGNOR-251343 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 CDH1 protein P12830 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "up-regulates activity" binding 9606 24336504 t miannu "Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm." SIGNOR-265821 GREB1 protein Q4ZG55 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 BTO:0000599 31462641 t miannu "GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Binding of GREB1 to Smad2/3 inhibits transcription" SIGNOR-265885 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser163 KRFSFKKsFKLSGFS -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-248926 HSPB1 protein P04792 UNIPROT GCH1 protein P30793 UNIPROT "up-regulates quantity by stabilization" binding 9606 18241680 t miannu "GTP cyclohydrolase I (GCH), an oligomeric protein composed of 10 identical subunits, is required for the synthesis of neurotransmitters; mutations in GCH are associated with dopa-responsive dystonia (DRD) and hyperphenylalaninemia. Mutated GCH proteins are unstable and prone to dominant-negative effect. We show herein that expression of the GCH mutant GCH-201E or the splicing variant GCH-II caused intracellular inclusion bodies. When Hsp27 was expressed together with the GCH mutants, Hsp27 expression decreased the formation of inclusion bodies by GCH (as assessed by immunofluorescence) and decreased the amount of insoluble GCH mutant proteins (as assessed by Western blot). we demonstrated that Hsp27 increases the expression of the wild-type GCH protein, causes the appearance of the soluble GCH-II protein, and decreases the quantities of insoluble mutated GCH protein. Therefore, it is likely that Hsp27 improves the folding of mutated GCH proteins, so they can stay in free cytosolic compartment." SIGNOR-252222 HK2 protein P52789 UNIPROT Glycolysis phenotype SIGNOR-PH34 SIGNOR "up-regulates activity" 9606 18350175 f "The first step in metabolism of glucose (Glc) is usually phosphorylation, catalyzed by hexokinase." SIGNOR-259980 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Thr357 FELRKTQtSMSLGTT -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-266438 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 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 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 NPM1 protein P06748 UNIPROT HEXIM1 protein O94992 UNIPROT "down-regulates activity" binding 9606 BTO:0001545 18371977 t miannu "We identified NPM as a novel HEXIM1-binding protein. NPM functioned as a negative regulator of HEXIM1. cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction." SIGNOR-260134 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 PRKACA protein P17612 UNIPROT KDELR1 protein P24390 UNIPROT up-regulates phosphorylation Ser209 VLKGKKLsLPA 9606 14517323 t llicata "We conclude that pka phosphorylation of serine 209 is required for the retrograde transport of the kdel receptor from the golgi complex to the er from which the retrieval of proteins bearing the kdel signal depends." SIGNOR-118257 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Ser358 ELRKTQTsMSLGTTR -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-266439 RPS6KA1 protein Q15418 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-203298 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 2-acyl-sn-glycero-3-phospho-D-myo-inositol smallmolecule CHEBI:62746 ChEBI 1-phosphatidyl-1D-myo-inositol smallmolecule CHEBI:16749 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-267245 GRB2 protein P62993 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271;BTO:0000785 24737791 t milica "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-204969 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 dactolisib chemical CHEBI:71952 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000848 21803746 t "ATP-competitive inhibitor of PI3K and mTOR" gcesareni "The dual pi3k and mtorc1/2 inhibitor bez235 was highly specific" SIGNOR-175706 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 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 SMARCE1 protein Q969G3 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-270731 SOCS1 protein O15524 UNIPROT JAK1 protein P23458 UNIPROT down-regulates binding 9606 11133764 t gcesareni "Jab/socs1/ssi-1 is an il-2 induced inhibitor of il-2 signaling that functions by inhibiting jak kinase activity" SIGNOR-85352 AMPK complex SIGNOR-C15 SIGNOR VASP protein P50552 UNIPROT down-regulates phosphorylation Ser322 TTLPRMKsSSSVTTS 9606 21945940 t lperfetto "Here we show that phosphorylation of vasp by ampk occurs at a novel site, serine 322, and that phosphorylation at this site alters actin filament binding. We also show that inhibition of ampk activity results in the accumulation of vasp at cell-cell adhesions and a concomitant increase in cell-cell adhesion." SIGNOR-216568 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 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 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser519 SGYSSPGsPGTPGSR 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-249416 PRKACA protein P17612 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-180780 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM73 protein Q86UV7 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-271187 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 VPS18 protein Q9P253 UNIPROT GGA3 protein Q9NZ52 UNIPROT "down-regulates activity" monoubiquitination Lys258 LFDQCENkRRTLFKL -1 16996030 t miannu "Monoubiquitylation of GGA3 by hVPS18 regulates its ubiquitin-binding ability. By in vitro ubiquitylation assays, we have identified lysine 258 in the GAT domain as a major ubiquitylation site that resides adjacent to the ubiquitin-binding site. Furthermore, the GAT domain ubiquitylated by hVPS18 no longer binds to ubiquitin, indicating that ubiquitylation negatively regulates the ubiquitin-binding ability of the GAT domain. These results suggest that the ubiquitin binding and ubiquitylation of GGA3-GAT domain are mutually inseparable through a ubiquitin ligase activity of hVPS18." SIGNOR-271610 NOTCH proteinfamily SIGNOR-PF30 SIGNOR JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20953350 f 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-254348 MAP3K14 protein Q99558 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser866 TAEVKEDsAYGSQSV 9606 BTO:0000007 11239468 t lperfetto "NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870" SIGNOR-105553 RELA protein Q04206 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates binding 9606 15988006 t gcesareni "P65 and histone deacetylases 4 cooperate to inhibit the ability of mef2 factors to induce the klf2 promoter" SIGNOR-138368 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 HOXA9 protein P31269 UNIPROT PIM1 protein P11309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001412 17327400 t Luana "Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its antiapoptotic and proproliferative effects in early cells. " SIGNOR-261632 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 NDUFS2 protein O75306 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-262176 RAF1 protein P04049 UNIPROT STK3 protein Q13188 UNIPROT down-regulates binding 9606 15618521 t gcesareni "Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2)" SIGNOR-132824 "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 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 NatC complex SIGNOR-C417 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-267236 MYOD1 protein P15172 UNIPROT "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR "form complex" binding 9606 BTO:0001103 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-151682 asparagine smallmolecule CHEBI:22653 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-264753 KLHL17 protein Q6TDP4 UNIPROT GRIK2 protein Q13002 UNIPROT "down-regulates quantity by destabilization" binding 9534 BTO:0000298 17062563 t miannu "Here, we report that actinfilin is able to bind to GluR6, a kainate-type glutamate receptor subunit, and target GluR6 for degradation. Like many members of its protein family, actinfilin acts as a substrate adaptor, binding Cullin 3 (Cul3) and linking GluR6 to the E3 ubiquitin-ligase complex. Together our data demonstrate that actinfilin acts as a scaffold, linking GluR6 to the Cul3 ubiquitin ligase to provide a novel mechanism for kainate receptor degradation." SIGNOR-271612 XRCC6 protein P12956 UNIPROT PRKDC protein P78527 UNIPROT up-regulates relocalization 9606 19133841 t gcesareni "Ku and dna-pkcs only interact in the presence of dna and recruitment of dna-pkcs to sites of dna damage in vivo is ku-dependent. Inward translocation of ku allows dna-pkcs to interact with the extreme termini of the dna, allowing two dna-pkcs molecules to interact across the dsb in a so-called synaptic complex . This interaction stimulates the kinase activity of dna-pkcs, promoting phosphorylation in trans across the dsb (discussed in more detail below). Once assembled at the dna ends, the dna-pkcs-ku-dsb complex serves to tether the ends of the dsb together and protects the dna ends from nuclease attack." SIGNOR-183276 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR PPP2R5B protein Q15173 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23135275 t miannu "Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β." SIGNOR-272019 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 9606 20068231 t Luana "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-260755 PALB2 protein Q86YC2 UNIPROT RAD51 protein Q06609 UNIPROT up-regulates binding 9606 19423707 t miannu "We propose that both palb2 chromatin association and its oligomerization serve to secure the brca2 x rad51 repair machinery at the sites of dna damage." SIGNOR-185656 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT "up-regulates activity" phosphorylation Tyr113 SSFEEDDyESPNDDQ 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-102507 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 TGFBI protein Q15582 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 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-253271 GPR119 protein Q8TDV5 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-257153 "phosphatidylinositol 4-phosphate" smallmolecule CHEBI:37530 ChEBI "Receptor_mediated_ endocytosis" phenotype SIGNOR-PH121 SIGNOR up-regulates 9534 22253445 f lperfetto "Further research suggested that PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment." SIGNOR-260745 HIF1A protein Q16665 UNIPROT KDM2B protein Q8NHM5 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-271567 SND1 protein Q7KZF4 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" binding -1 12234934 t irozzo "STAT6 interacted with p100 in vitro and in vivo. Here, we show that the TAD of STAT6 is interacting with p100. p100 was found to enhance the STAT6-mediated transcription [.]." SIGNOR-259134 PDPK2P protein Q6A1A2 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation 9606 15505410 t gcesareni "Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2." SIGNOR-252628 ENAH protein Q8N8S7 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR up-regulates 9606 18508258 f miannu "Here we review recent findings into Ena/VASP function in neurite initiation, axon outgrowth and guidance." SIGNOR-268389 "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 PD318088 chemical CID:10231331 PUBCHEM MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205740 MAPK14 protein Q16539 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR "down-regulates activity" 9606 BTO:0001255 12839928 f miannu "Activation of p38 MAPK is required for arsenite-induced apoptosis and MEK1,2 dephosphorylation in human skin fibroblasts. Our data suggest the presence of a continuous negative feedback from p38α and p38β to MEK1,2 as simultaneous inhibition of p38α and p38β isoforms in normal quiescent cells resulted in accumulation of phosphorylated MEK1,2 (Fig. 2A) ⇓ . This negative regulation of MEK1,2 in normal cells could be considered a means to control MEK1,2-mediated proliferation and expression of transformation-related genes." SIGNOR-263511 NKX2-5 protein P52952 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21261500 f "Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling." SIGNOR-253656 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 CDK8 protein P49336 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 9606 19914168 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-161626 HDAC1 protein Q13547 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-263851 GABA-A proteinfamily SIGNOR-PF61 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-268610 PI3K complex SIGNOR-C156 SIGNOR PIP3 smallmolecule CHEBI:16618 ChEBI "up-regulates quantity" "chemical modification" 9606 12040186 t lperfetto "The activated PI3K converts the plasma membrane lipid phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] to phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3]." SIGNOR-252713 ANK1 protein P16157 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266013 CDK2 protein P24941 UNIPROT FOXO4 protein P98177 UNIPROT down-regulates phosphorylation 9606 19188143 t gcesareni "Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity" SIGNOR-183655 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 Ub:E2 complex SIGNOR-C497 SIGNOR RBBP6 protein Q7Z6E9 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-271183 SIRT4 protein Q9Y6E7 UNIPROT GLUD1 protein P00367 UNIPROT "down-regulates activity" glycosylation 9606 16959573 t miannu "We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity." SIGNOR-267828 WNT7A protein O00755 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5" SIGNOR-60471 NAB2 protein Q15742 UNIPROT TNFSF10 protein P50591 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000782 22128144 f miannu "In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8(+) T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8(+) T cells. Enforced expression of Nab2 prevents TRAIL induction after restimulation of primary helpless CD8(+) T cells, and expression of a dominant-negative form of Nab2 in helped CD8(+) T cells impairs their secondary proliferative response that is reversible by TRAIL blockade." SIGNOR-253893 BMPR1A protein P36894 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR "up-regulates activity" phosphorylation 9606 "BTO:0000165;BTO:0002974; BTO:0002809" 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-255830 RPS6KA1 protein Q15418 UNIPROT DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser287 SMSSCGSsGYFSSSP 9606 22017877 t lperfetto "We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1" SIGNOR-176887 ERG protein P11308 UNIPROT NKX3-1 protein Q99801 UNIPROT "down-regulates quantity by repression" "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-251556 GLA protein P06280 UNIPROT 1,3-dichloro-7-hydroxy-9,9-dimethyl-9H-acridin-2-one smallmolecule CHEBI:52012 ChEBI "up-regulates quantity by expression" "chemical modification" -1 31996391 t lperfetto "DDAOG is cleaved by -galactosidase ( Lindvall et al., 2009 ) in the Trpv1 cells to produce 7-hydroxy-9H(I,3-dichloro-9,9-dimethylacridin-2-one (DDAO)." SIGNOR-261334 CREB1 protein P16220 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 10090 BTO:0000763 20660310 f Luana "Beta-catenin/CBP-driven transcription is critical for maintenance of an undifferentiated/proliferative state" SIGNOR-261288 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 SIRT5 protein Q9NXA8 UNIPROT SIRT3 protein Q9NTG7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31608237 f Monia "In U2OS cells, SIRT5 silencing resulted in downregulation of SIRT1 and SIRT3 protein levels (Figures 4Ai,ii, compare bars 1 to 5)." SIGNOR-261209 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr93 GHITTTPtPTQFLCP 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170776 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 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 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 SIGNOR up-regulates relocalization 9606 25627476 t lperfetto "One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP. " SIGNOR-267008 D-glucopyranose smallmolecule CHEBI:4167 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-268474 HIF3A protein Q9Y2N7 UNIPROT HIF1A protein Q16665 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-261615 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 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 NFIA protein Q12857 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-268873 CLTC protein Q00610 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-260676 BCHE protein P06276 UNIPROT acetylcholine smallmolecule CHEBI:15355 ChEBI "down-regulates quantity" "chemical modification" 15841900 t "The other subgroup, butyrylcholinesterase (BuChE) (or acyl- choline acyl-hydrolase, EC 3.1.1.8) also known as plasma, serum, benzoyl, false, butyryl, nonspecific, or type II ChE. BuChE exists in plasma and has more than eleven isoenzy- me variants. BuChE is also present in liver, smooth muscle, intestines, pancreas, heart and white matter of brain |It hydrolyzes butyrylcholine 4 times more rapidly than acetylcholine." SIGNOR-253982 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1651 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-203520 SLC36A1 protein Q7Z2H8 UNIPROT alanine smallmolecule CHEBI:16449 ChEBI "up-regulates quantity" relocalization 9606 12748860 t lperfetto "Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut." SIGNOR-264739 RB1 protein P06400 UNIPROT HDAC3 protein O15379 UNIPROT up-regulates 9606 14560017 f gcesareni "We find that active rb mediates histone deacetylation on cyclin a, cdc2, topoisomerase iialfa, and thymidylate synthase promoters. We also demonstrate that this deacetylation is hdac dependent, since the hdac inhibitor trichostatin a (tsa) prevented histone deacetylation at each promoter." SIGNOR-118839 PRKCE protein Q02156 UNIPROT OCLN protein Q16625 UNIPROT up-regulates phosphorylation Thr404 HYETDYTtGGESCDE 9606 BTO:0000195 BTO:0000671 21545357 t lperfetto "Thr403, thr404, thr424 and thr438 in the occludin c-terminal domain are the predominant sites of pkc_-dependent phosphorylation . The present study demonstrates that pkc_ phosphorylates occludin on specific threonine residues and promotes assembly of epithelial tight junctions." SIGNOR-173635 STK24 protein Q9Y6E0 UNIPROT STK24 protein Q9Y6E0 UNIPROT up-regulates phosphorylation Thr190 DTQIKRNtFVGTPFW 9606 BTO:0000671 17046825 t gcesareni "Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (mst3) involves paxillin and protein-tyrosine phosphatase-pest." SIGNOR-150131 XL765 chemical CHEBI:71958 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207881 NFKB1 protein P19838 UNIPROT BIRC3 protein Q13489 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f gcesareni "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59951 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 C5AR1 protein P21730 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-263460 tRNA(Ala) smallmolecule CHEBI:29170 ChEBI Ala-tRNA(Ala) smallmolecule CHEBI:17732 ChEBI "up-regulates quantity" "precursor of" 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-270451 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 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 INSR protein P06213 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" phosphorylation Tyr992 DGPLGPLyASSNPEY -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-106522 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 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" phosphorylation 9606 21232017 t lperfetto "Tak1 become activated and then phosphorilates and activates ikk2 whic in turn now phosphorylates ikba, marking it for k48-ubiquitination and proteasomal degradation." SIGNOR-209759 PDGFRB protein P09619 UNIPROT CRK protein P46108 UNIPROT up-regulates binding 9606 10733900 t amattioni "Crk could bind to both pdgf alpha- and beta-receptors in vivo" SIGNOR-75884 seliciclib chemical CHEBI:45307 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206571 NEK7 protein Q8TDX7 UNIPROT KIF14 protein Q15058 UNIPROT "up-regulates activity" phosphorylation Ser1219 KNLHSSHsSGLMDKS 9606 BTO:0000565 28630147 t miannu "Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C)." SIGNOR-266419 POGLUT1 protein Q8NBL1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates glycosylation 9606 22872643 t O-glycosilation gcesareni "O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus." SIGNOR-254319 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 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT "down-regulates quantity" binding -1 10929711 t amattioni "Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, IAPs, and removing their inhibitory activity. Smac is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis." SIGNOR-80206 ETV3 protein P41162 UNIPROT DDX20 protein Q9UHI6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 22028472 t miannu "ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation." SIGNOR-262779 p38 proteinfamily SIGNOR-PF16 SIGNOR NFATC4 protein Q14934 UNIPROT down-regulates phosphorylation Ser170 GGAFFSPsPGSSSLS 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-87397 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 3142692 t irozzo "The c-Jun and c-fos proto-oncogenes encode proteins that form a complex which regulates transcription from promoters containing AP-1 activation elements. c-Jun has specific DNA binding activity, while c-Fos has homology to the putative DNA binding domain of c-Jun." SIGNOR-256365 KLF1 protein Q13351 UNIPROT KLF8 protein O95600 UNIPROT "up-regulates quantity by expression" "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-266050 NHLRC1 protein Q6VVB1 UNIPROT EPM2A protein O95278 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 15930137 t miannu "Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation. " SIGNOR-271547 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 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR SCAF11 protein Q99590 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-271007 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR UNG protein P13051 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 20870715 t miannu "Using reconstituted CRL4(DCAF1) and CRL4(DCAF1-Vpr) E3 ubiquitin ligases in vitro reveals that UNG2 ubiquitination (ubiquitylation) is facilitated by Vpr. Co-expression of DCAF1 and Vpr causes down-regulation of UNG2 in a proteasome-dependent manner, with Vpr mutants that are defective in UNG2 or DCAF1 binding abrogating this effect." SIGNOR-271905 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 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 6958488 t "nasal polyposys" gcesareni SIGNOR-251688 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 FYN protein P06241 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr323 DEPVADPyDQSFESR 9606 15735648 t fstefani "T cell src family kinases and zap70 activate p38 by phosphorylating tyr323." SIGNOR-134293 MTNR1A protein P48039 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-256985 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser396 NTVDLHIsNSHPLSL -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-178371 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 MSX1 protein P28360 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001103 15192231 f gcesareni "We found that msx1 and h1b bind to a key regulatory element of myod, a central regulator of skeletal muscle differentiation, where they induce repressed chromatin." SIGNOR-125765 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 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val76 LTGKLTTvFLPIVYT -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-263592 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 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 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 "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 "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR NANOS2 protein P60321 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-268349 SMARCE1 protein Q969G3 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-132942 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 AKT1 protein P31749 UNIPROT PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 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-252575 TUBB protein P07437 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates binding 9606 17429065 t lpetrilli "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-154319 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 14963330 t gcesareni "Tp53 directly activated the proapoptotic bcl-2 protein bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program" SIGNOR-121895 CDKN1A protein P38936 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 9606 24470334 f "The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression" SIGNOR-251564 MAPK1 protein P28482 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 17604322 t lperfetto "In colon cancer cells, the Ras/mitogen‐activated protein kinase (MAPK) pathway phosphorylates RXRalpha, which impairs its function as a heterodimeric partner for PPARgamma|A point‐mutated 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-88658 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" 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-252352 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 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 [‚Ķ] 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-267394 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 ATF2 protein P15336 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 22685333 f Luana "ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death." SIGNOR-261324 940929-33-9 chemical CID:49867937 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206724 MAPK3 protein P27361 UNIPROT TFCP2 protein Q12800 UNIPROT down-regulates phosphorylation Ser291 TYVNNSPsPGFNSSH 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-184176 ARHGAP40 protein Q5TG30 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-260497 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 PRKD1 protein Q15139 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-148876 MAPK14 protein Q16539 UNIPROT ELK3 protein P41970 UNIPROT up-regulates phosphorylation Ser357 IHFWSSLsPVAPLSP 9606 9130707 t gcesareni "Tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387. Mutation of these sites to alanine severely reduces c-fos sre-dependent transcription mediated by sap-1a and p38 map kinase." SIGNOR-47681 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 CDC42 protein P60953 UNIPROT PAK2 protein Q13177 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-248253 NFIA protein Q12857 UNIPROT NEUROD4 protein Q9HD90 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-268891 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT "up-regulates activity" phosphorylation Thr183 SDGEFLRtSCGSPNY -1 16054095 t lperfetto "The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase." SIGNOR-139297 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Ser20 KRPQRATsNVFAMFD -1 21457715 t Giulio "Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation." SIGNOR-260307 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 CSNK2A2 protein P19784 UNIPROT EIF2B5 protein Q13144 UNIPROT "up-regulates activity" phosphorylation Ser717 LKEAEEEsSEDD 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-250989 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Inflammation phenotype SIGNOR-PH12 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-260445 edrophonium chemical CHEBI:251408 ChEBI ACHE protein P22303 UNIPROT "down-regulates activity" "chemical inhibition" -1 9301662 t miannu "With the aim of performing a rigorous test of the anti-AChE properties of our compounds, the kinetics of enzyme inhibition were studied in purified enzyme preparations. The inhibition data are shown in Table 1. Additionally, known competitive inhibitors of AChE (procainamide and edrophonium) were included in the study for comparative purposes." SIGNOR-258667 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 SYK protein P43405 UNIPROT SLC4A1 protein P02730 UNIPROT up-regulates phosphorylation Tyr21 ENLEQEEyEDPDIPE 9606 10942405 t llicata "Our findings suggest that, upon phosphorylation by p72syk, y8 and y21 act as docking sites for the sh2 domain of lyn, which subsequently phosphorylates band 3 at additional secondary sites." SIGNOR-80788 VAV2 protein P52735 UNIPROT RAC1 protein P63000 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 10982832 t miannu "Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases." SIGNOR-81645 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser692 GQLMSQPsTASNSLP 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-251280 EDNRB protein P24530 UNIPROT GNAS protein Q5JWF2 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-256781 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 LPAR4 protein Q99677 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-256928 ketoprofen chemical CHEBI:6128 ChEBI PTGS2 protein P35354 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-257811 IL15RA protein Q13261 UNIPROT TYK2 protein P29597 UNIPROT up-regulates 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-256253 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 SIGNOR-C110 23151663 t gcesareni "Beta-catenin phosphorylation in vivo is sequentially carried out by two distinct kinases, ckialfa and gsk-3. Ckialfa phosphorylation of s45 proceeds and is required for subsequent gsk-3 phosphorylation of t41, s37, and s33 one key substrate of gsk3 is the transcriptional co-activator beta catenin, whichis inactivated by gsk3 mediated phosphorylation and targeted for proteasomal degradation in unstimulated cells." SIGNOR-199512 BCL9 protein O00512 UNIPROT PYGO1 protein Q9Y3Y4 UNIPROT up-regulates binding 9606 BTO:0000776 11955446 t miannu "Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin." SIGNOR-116577 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser438 PGLLRRVsSTWTTTT 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-184456 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 MYC protein P01106 UNIPROT CDK6 protein Q00534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "The degradation of c-myc protein decreases the expression of the cell cycle regulators cdk4 and cdk6, which reversibly slows down the cell cycle." SIGNOR-102737 MCF2 protein P10911 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-260557 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 GPR35 protein Q9HC97 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-257204 RELA protein Q04206 UNIPROT CITED1 protein Q99966 UNIPROT up-regulates binding 9606 SIGNOR-C13 9660950 t gcesareni "The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276." SIGNOR-59054 PRKCA protein P17252 UNIPROT THOC5 protein Q13769 UNIPROT up-regulates phosphorylation Ser5 sSKKRKPK 9606 BTO:0000801;BTO:0000876 15221008 t llicata "We conclude m-csf-mediated activation of pkcalpha can potentiate fmip action to initiate survival/differentiation signaling." SIGNOR-126568 FGF11 protein Q92914 UNIPROT SCN1A protein P35498 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-253422 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR EP300 protein Q09472 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-261497 PRKCA protein P17252 UNIPROT PTPN6 protein P29350 UNIPROT down-regulates phosphorylation Ser591 DKEKSKGsLKRK 9606 15269224 t llicata "Protein kinase calpha therefore critically and negatively regulates shp-1 function, forming part of a mechanism to retain shp-1 in a basal active state through interaction with its sh2 domains, and phosphorylating its c-terminal ser591 upon cellular activation" SIGNOR-126876 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT unknown phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t llicata "Atm and dna?PK Phosphorylate rpa32 thr21in vitro and in vivo" SIGNOR-121865 "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 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser434 SFEPKIRsPRRFIGS 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-201534 "Papain-like proteinase" protein P0C6X7-PRO_0000037311 UNIPROT STING1 protein Q86WV6 UNIPROT "down-regulates activity" binding 9606 22312431 t miannu "Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKε, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING" SIGNOR-260247 NFYB protein P25208 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-254431 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 C4A protein P0C0L4 UNIPROT "C3 convertase complex" complex SIGNOR-C310 SIGNOR "form complex" binding -1 cleavage:Arg756;Gly1446 KGQAGLQrALEILQE;TPLQLFEgRRNRRRR 17204478 t "complement C4b fragment: PRO_0000005970" lperfetto "However, following cleavage of C4, C2 binds tightly to C4b to form the C4b2 complex" SIGNOR-263400 IL31RA protein Q8NI17 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 18926762 t gcesareni "Il-31 can activate janus kinase (jak) 1 and jak2 signaling molecules after binding to its receptor complex." SIGNOR-161430 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000675 23616010 lperfetto "The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase C_ (PKC_) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun" SIGNOR-236767 SIRT2 protein Q8IXJ6 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity by stabilization" deacetylation Lys71 GILRRLKkYDNCWLA 9606 BTO:0000007 21726808 t lperfetto "Conversely, SIRT2 deacetylates and stabilizes 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-267601 KDM2B protein Q8NHM5 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. The assembly of Fbxl10-BcoR complex(es), the associations among its various subunits, and its functional significance remain to be characterized but are presently under investigation." SIGNOR-252242 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates 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-120048 ABL1 protein P00519 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9534 BTO:0000298 10896159 t gcesareni "Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity." SIGNOR-245288 GH1 protein P01241 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001939 15665309 t Luana "Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells" SIGNOR-261629 BCS1L protein Q9Y276 UNIPROT LETM1 protein O95202 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 18628306 t lperfetto "LETM1 was co-precipitated with BCS1L and formation of the LETM1 complex depended on BCS1L levels, suggesting that BCS1L stimulates the assembly of the LETM1 complex." SIGNOR-262543 LIF protein P15018 UNIPROT LIFR protein P42702 UNIPROT up-regulates binding 9606 16051226 t gcesareni "Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44)." SIGNOR-139102 CHUK protein O15111 UNIPROT NFKB2 protein Q00653 UNIPROT "up-regulates activity" phosphorylation Ser866 TAEVKEDsAYGSQSV 10090 BTO:0000785 15084608 t lperfetto "Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52." SIGNOR-124226 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 PAM protein P19021 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT "up-regulates activity" cleavage 9606 23084901 t lperfetto "Nevertheless, overall the results of this study show that peptide sequence recognition is an important aspect of the interactions of the prohormone substrates prooxytocin (3d) and procalcitonin (7e) with PAM, which is mirrored in the potency of analogous peptidomimetic glycolate inhibitors of the enzyme." SIGNOR-268551 ERG protein P11308 UNIPROT MYC protein P01106 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-251554 DEPTOR protein Q8TB45 UNIPROT mTORC1 complex SIGNOR-C3 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-205600 FLT3 protein P36888 UNIPROT SIRT3 protein Q9NTG7 UNIPROT "down-regulates activity" phosphorylation Tyr226 KGLLLRLyTQNIDGL -1 34289383 t lperfetto "We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right)." SIGNOR-267631 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR USP37 protein Q86T82 UNIPROT "up-regulates activity" phosphorylation Ser628 MVNSCITsPSTPSKK 9606 BTO:0000007;BTO:0000567 21596315 t lperfetto "There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity" SIGNOR-265053 SYK protein P43405 UNIPROT SNCA protein P37840 UNIPROT down-regulates phosphorylation Tyr125 VDPDNEAyEMPSEEG 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-113061 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 "HIF-1 complex" complex SIGNOR-C418 SIGNOR BNIP3 protein Q12983 UNIPROT "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-267454 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 AKT1 protein P31749 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" phosphorylation Ser262 TFRPRSSsNASSVST 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-252569 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 PCSK5 protein Q92824 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-270334 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 KU-60019 chemical CID:15953870 PUBCHEM ATM protein Q13315 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193597 TGFB1 protein P01137 UNIPROT CCNA2 protein P20248 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 7592630 f gcesareni "Expression of one of these components, cyclin a, is inhibited by tgf-beta treatment. We have identified a 760-base pair fragment of the human cyclin a gene promoter that is sufficient to confer tgf-beta responsiveness." SIGNOR-29516 FGF14 protein Q92915 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-253441 AKT1 protein P31749 UNIPROT MAP3K11 protein Q16584 UNIPROT down-regulates phosphorylation Ser674 PGRERGEsPTTPPTP 9606 BTO:0000938 12458207 t lperfetto "Negative regulation of mixed lineage kinase 3 by protein kinase b/akt leads to cell survivalthe expression of activated akt1 inhibits mlk3-mediated cell death in a manner dependent on serine 674 phosphorylation." SIGNOR-252592 MAP3K7 protein O43318 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" phosphorylation Ser177 AKELDQGsLCTSFVG 9606 SIGNOR-C14 11460167 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-109490 MBTPS2 protein O43462 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" cleavage 10029 BTO:0000246 10419520 t "In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted" SIGNOR-267499 PKC proteinfamily SIGNOR-PF53 SIGNOR ARHGEF6 protein Q15052 UNIPROT "down-regulates activity" phosphorylation Ser640 RKTERKPsEEEYVIR 9606 BTO:0000132 26507661 t lperfetto "ARHGEF6 is a Rho guanine nucleotide exchange factor for Rac1 and constitutively bound to GIT1. NO and PGI2 activate PKG and PKA, respectively and both kinases phosphorylate ARHGEF6 on Ser-684 and possibly on Ser-640. Phosphorylation of ARHGEF6 results in the assembly of a GIT1-ARHGEF6–14-3-3 complex. These changes might contribute to PGI2- and NO-mediated Rac1 inhibition." SIGNOR-272164 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 SUCLG1 protein P53597 UNIPROT "Succinyl-CoA ATP variant" complex SIGNOR-C398 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266261 YY1 protein P25490 UNIPROT ATP2C1 protein P98194 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-255193 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 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 MSX1 protein P28360 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates activity" binding 10090 BTO:0000946 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-240987 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 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 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 IL13RA1 protein P78552 UNIPROT TYK2 protein P29597 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "IL-4R, ?c, and IL-13R1 All contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectivelyil-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells." SIGNOR-100756 PRKACA protein P17612 UNIPROT CSK protein P41240 UNIPROT "up-regulates activity" phosphorylation Ser364 ALREKKFsTKSDVWS 9606 BTO:0000782 11181701 t lperfetto "Activation of the cooh-terminal src kinase (csk) by camp-dependent protein kinase inhibits signaling through the t cell receptor.Pka phosphorylates csk at s364 in vitro and in vivo leading to a two- to fourfold increase in csk activity that is necessary for camp-mediated inhibition of tcr-induced interleukin 2 secretion." SIGNOR-105229 RAP1GDS1 protein P52306 UNIPROT CDC42 protein P60953 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-171412 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 GSK3A protein P49840 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-159377 CEBPB protein P17676 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 11884404 f fferrentino "Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma." SIGNOR-250564 CACNA1B protein Q00975 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" relocalization 9606 20655485 t miannu "The main G b/g-dependent effectors of presynaptic GABAB receptors are P/Q-and N-type voltage-dependent Ca2+ channels. GABAB receptors inhibit these Ca2+ channels at excitatory and inhibitory terminals, thereby restricting neurotransmitter release." SIGNOR-265069 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 CDKN2A protein Q8N726 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates quantity by destabilization" binding 9606 14636574 t gcesareni "The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division" SIGNOR-245077 CDKN1A protein P38936 UNIPROT PCNA protein P12004 UNIPROT down-regulates binding 9606 22911014 t gcesareni "P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna)" SIGNOR-191939 SMAD6 protein O43541 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" binding 9606 9892110 t lperfetto "Smad6 and smad7, can prevent tgfb signaling by interacting either with the receptor or with smad2 and smad3" SIGNOR-64071 CDK2 protein P24941 UNIPROT NPAT protein Q14207 UNIPROT up-regulates phosphorylation Thr1350 ISRTTSAtPLKDNTQ 9606 10995387 t llicata "Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter." SIGNOR-82141 AKT2 protein P31751 UNIPROT RALGAPA2 protein Q2PPJ7 UNIPROT "down-regulates activity" phosphorylation Ser696 TTVGRSFsLSWRSHP 10090 SIGNOR-C469 21148297 t miannu "RGC2 is an endogenous substrate for Akt2 downstream of PI 3-kinase" SIGNOR-269798 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1651 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-248749 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 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 PDPK1 protein O15530 UNIPROT PRKCG protein P05129 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof 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-126072 CDK6 protein Q00534 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser249 DTRQIQPsPPWSYDQ 9606 BTO:0002181 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-138953 PI-103 chemical CHEBI:90524 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-258266 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 clofarabine chemical CHEBI:681569 ChEBI RRM1 protein P23921 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" SIGNOR-258357 PKI-402 chemical CID:44187953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206250 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR PARP1 protein P09874 UNIPROT "down-regulates activity" cleavage 10090 BTO:0000331 11907276 t 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-256465 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 CDK1 protein P06493 UNIPROT BUB1B protein O60566 UNIPROT up-regulates phosphorylation Thr620 RAARFVStPFHEIMS 9606 17785528 t lperfetto "Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions" SIGNOR-157642 BMP4 protein P12644 UNIPROT BMP4 protein P12644 UNIPROT up-regulates binding 9606 11178121 t lperfetto "Bmps are dimeric proteins with a single inter-chain disulfide bond. The dimeric conformation is anabsolute requirement for the biological action and interaction with receptors" SIGNOR-236169 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 TESK2 protein Q96S53 UNIPROT CFL1 protein P23528 UNIPROT "down-regulates activity" phosphorylation Ser3 sGVAVSDG 9606 BTO:0000567 11418599 t lperfetto "Like tesk1, tesk2 phosphorylated cofilin specifically at ser-3 and induced formation of actin stress fibers and focal adhesions." SIGNOR-108753 APPL1 protein Q9UKG1 UNIPROT STK11 protein Q15831 UNIPROT up-regulates binding 9606 BTO:0000887 19520843 t milica "In this study, we identified lkb1 as a new binding partner of appl1 and showed that the bar domain of appl1 is involved in this interaction.Here we show that in muscle cells adiponectin and metformin induce ampk activation by promoting appl1-dependent lkb1 cytosolic translocation. Appl1 mediates adiponectin signaling by directly interacting with adiponectin receptors and enhances lkb1 cytosolic localization by anchoring this kinase in the cytosol." SIGNOR-186065 KAT2B protein Q92831 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-269618 PRKDC protein P78527 UNIPROT HNRNPU protein Q00839 UNIPROT up-regulates phosphorylation Ser59 AMEPGNGsLDLGGDS 9606 19351595 t lperfetto "We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks" SIGNOR-185058 TOR1A protein O14656 UNIPROT SNAPIN protein O95295 UNIPROT "up-regulates activity" binding 9606 BTO:0000793 18167355 t Monia "In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA." SIGNOR-261170 NR3C1 protein P04150 UNIPROT CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000746 27777311 f "We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα." SIGNOR-256117 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 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 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 MAPK8 protein P45983 UNIPROT NR4A1 protein P22736 UNIPROT down-regulates phosphorylation Ser95 TSSSSATsPASASFK 9606 17023523 t llicata "We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity." SIGNOR-149998 SOX2/POU5F1 complex SIGNOR-C73 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-269238 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 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-236318 AP3B1 protein O00203 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-260681 CHEK1 protein O14757 UNIPROT MDM4 protein O15151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto "The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes." SIGNOR-178067 CRBN protein Q96SW2 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "form complex" binding 9606 22649780 t gcesareni "The CUL4 family employs the structurally distinct triple WD40 ²-propeller domain-containing DDB1 adaptor to recruit members of the DDB1€“CUL4 associated factors (DCAF) family of substrate receptors" SIGNOR-234805 L-thyroxine smallmolecule CHEBI:18332 ChEBI iodide smallmolecule CHEBI:16382 ChEBI "up-regulates quantity" "precursor of" 9606 12746313 t scontino "Human type III iodothyronine deiodinase (D3) catalyzes the conversion of T(4) to rT(3) and of T(3) to 3, 3'-diiodothyronine (T2) by inner-ring deiodination. Like types I and II iodothyronine deiodinases, D3 protein contains selenocysteine (SeC) in the highly conserved core catalytic center at amino acid position 144." SIGNOR-266946 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 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCE protein Q02156 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190353 FZD4 protein Q9ULV1 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 12958364 t amattioni "Endocytosis of frizzled 4 (fz4) in human embryonic kidney 293 cells was dependent on added wnt5a protein and was accomplished by the multifunctional adaptor protein beta-arrestin 2 (betaarr2), which was recruited to fz4 by binding to phosphorylated dvl2." SIGNOR-100274 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 MAP4K3 protein Q8IVH8 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation Thr538 LGDAKTNtFCGTPDY 9606 BTO:0000782 21983831 t llicata "We report that the kinase glk (map4k3) directly activated pkc-? During tcr signaling." SIGNOR-176744 BRF2 protein Q9HAW0 UNIPROT TFIIIB complex SIGNOR-C393 SIGNOR "form complex" binding 29378333 t lperfetto "Both in yeast and mammalian cells, TFIIIB consists of three subunits: TFIIB-related Brf1, TATA-box binding protein (TBP), common also for the other two RNA polymerases, and Pol III-specific subunit, Bdp1 (Table 1)." SIGNOR-266191 MAPK1 protein P28482 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Ser387 PATVEPAsPTPAHSL 9606 17311928 t 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-153379 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0000938 12040039 t lperfetto "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-236130 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 NEDD4L protein Q96PU5 UNIPROT SCN3A protein Q9NY46 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-253464 SIRT2 protein Q8IXJ6 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 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; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254481 PRKCD protein Q05655 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates activity" phosphorylation Ser40 SREVFDFsQRRKEYE -1 12198130 t lperfetto "Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription." SIGNOR-249161 CDC42BPA protein Q5VT25 UNIPROT LIMK1 protein P53667 UNIPROT "up-regulates activity" phosphorylation Thr508 PDRKKRYtVVGNPYW BTO:0000567 11340065 t llicata "Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment." SIGNOR-250721 GTF2H1 protein P32780 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser403 PEEFISLsPPHEALD -1 10428966 t "TFIIH-mediated phosphorylation of E2F-1 plays a role in triggering E2F-1 degradation during S phase. E2F-1 activation domain interacts with a kinase activity which phosphorylates two sites, Ser403 and Thr433, within the activation domain. We demonstrate that TFIIH is responsible for the E2F-1 phosphorylation observed in cell extracts and that endogenous E2F-1 interacts in vivo with p62, a component of TFIIH, during S phase." SIGNOR-251259 TGFB2 protein P61812 UNIPROT TGFBR1 protein P36897 UNIPROT up-regulates binding 9606 22326956 t miannu "Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family." SIGNOR-196025 BRCA1 protein P38398 UNIPROT CTSD protein P07339 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 11244506 f miannu "BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D." SIGNOR-253759 BRCA2 protein P51587 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-263256 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 MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001271 21697284 t gcesareni "Cocrystallization of the met kinase domain in complex with nvp-bvu972 revealed a key role for y1230 in binding of nvp-bvu972, as previously reported for multiple other selective met inhibitors." SIGNOR-174555 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser348 SDLSIASsEEDKLSQ 9606 16837460 t gcesareni "Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity." SIGNOR-147883 "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 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-266477 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 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" relocalization 9606 20515759 t lperfetto "Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor." SIGNOR-59145 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 CHUK protein O15111 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 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-124203 tolbutamide chemical CHEBI:27999 ChEBI CFTR protein P13569 UNIPROT "down-regulates activity" "chemical inhibition" 10090 1281220 t miannu "The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively." SIGNOR-258345 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 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 "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 PSMA5 protein P28066 UNIPROT XBP1 protein P17861 UNIPROT "down-regulates quantity by destabilization" binding -1 19941857 t 1 miannu "We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination." SIGNOR-239213 CDK1 protein P06493 UNIPROT KHDRBS1 protein Q07666 UNIPROT unknown phosphorylation Thr317 RGALVRGtPVRGAIT 9606 9315091 t lperfetto "Phosphorylation of sam68 by purified cdc2." SIGNOR-51275 PTGER1 protein P34995 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000586 17251915 t gcesareni "Ep1 is a galfaq-coupled receptor that promotes calcium mobilization and pkc activation, whereas ep2 and ep4, which have a more prominent role in colon cancer, are coupled to galfas and stimulate camp accumulation" SIGNOR-152802 ATM protein Q13315 UNIPROT RRM2B protein Q7LG56 UNIPROT up-regulates phosphorylation Ser72 TAEEVDLsKDLPHWN 9606 19015526 t lperfetto "Atm-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53r2 protein against mdm2 to dna damage" SIGNOR-182423 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 BTO:0001412 11283671 t irozzo "AML1–ETO inhibits CEBPA autoregulation in myeloid cells.[…]It was also demonstrated that AML1–ETO and C/EBPα physically interact in vivo." SIGNOR-255700 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 LRRK2 protein Q5S007 UNIPROT AKT1 protein P31749 UNIPROT 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-252598 PTK2 protein Q05397 UNIPROT BCAR1 protein P56945 UNIPROT unknown phosphorylation Tyr664 EGGWMEDyDYVHLQG 11604500 t lperfetto "FAK phosphorylates CAS-SBD tyrosines 668 and/or 670, driving an SH2-mediated recruitment of Src which then phosphorylates CAS-SD." SIGNOR-249111 MAP3K7 protein O43318 UNIPROT NLK protein Q9UBE8 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 12482967 t gcesareni "The tak1-nlk-mapk-related pathway antagonizes signalling between beta-catenin and transcription factor tcf." SIGNOR-96425 tamsulosin chemical CHEBI:9398 ChEBI ADRA1B protein P35368 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-258470 TAF12 protein Q16514 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-263924 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 18423396 t lperfetto "Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export ofFoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-252851 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 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 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 FLCN protein Q8NFG4 UNIPROT RRAGD protein Q9NQL2 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-256504 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Thr502 TPGTGLGtSPALAGD -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-250906 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 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 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 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-258244 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation 9606 19282669 t lperfetto "Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3." SIGNOR-244699 SMARCC2 protein Q8TAQ2 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-269823 ZNF304 protein Q9HCX3 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000391 24623306 t Luana "Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells." SIGNOR-266098 PAK1 protein Q13153 UNIPROT LIMK1 protein P53667 UNIPROT "up-regulates activity" phosphorylation Thr508 PDRKKRYtVVGNPYW 9606 10559936 t lperfetto "Activation of lim-kinase by pak1 couplesp21-activated kinase (pak1) phosphorylates lim-kinase at threonine residue 508 within lim-kinase's activation loop" SIGNOR-72142 KIT protein P10721 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr703 DHAEAALyKNLLHSK 10377264 t gcesareni "We furthermore demonstrate that the adapter protein Grb2 is a specific binding partner for both phosphorylated Tyr-703 and phosphorylated Tyr-936, whereas the adapter protein Grb7 binds selectively to phosphorylated Tyr-936." SIGNOR-248283 purmorphamine chemical CHEBI:63053 ChEBI SMO protein Q99835 UNIPROT up-regulates "chemical activation" 9606 17419683 t gcesareni "The activity of smo toward gi was stimulated severalfold with the synthetic agonist purmorphamine and inhibited almost completely by cyclopamine and other antagonists of shh." SIGNOR-154282 isoprenaline chemical CHEBI:64317 ChEBI ADRB3 protein P13945 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-258577 CSNK2A2 protein P19784 UNIPROT PPP1R2 protein P41236 UNIPROT "up-regulates activity" phosphorylation Ser87 GDDEDACsDTEATEA -1 8288648 t llicata "Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action." SIGNOR-251022 SRC protein P12931 UNIPROT 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-271701 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 PCDHA9 protein Q9Y5H5 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates activity" binding 9606 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-265662 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -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-250907 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 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 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-187578 SMURF2 protein Q9HAU4 UNIPROT SMAD7 protein O15105 UNIPROT "down-regulates activity" ubiquitination 9606 18448069 t lperfetto "The association of Smurf2 with Smad7 and its ubiquitination were inhibited by AIMP1, thereby protecting its autocatalytic degradation stimulated by Smad7." SIGNOR-178501 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 NUAK1 protein O60285 UNIPROT PPP1R12A protein O14974 UNIPROT down-regulates phosphorylation Ser910 SLLGRSGsYSYLEER 9606 20354225 t gcesareni "Phosphorylation of ser(445), ser(472), and ser(910) of mypt1 by nuak1 promoted the interaction of mypt1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity." SIGNOR-22572 DAB2IP protein Q5VWQ8 UNIPROT Cell_migration phenotype SIGNOR-PH38 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-254778 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser249 DTRQIQPsPPWSYDQ 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-138928 PIM proteinfamily SIGNOR-PF34 SIGNOR RPS19 protein P39019 UNIPROT up-regulates phosphorylation 9606 BTO:0000007 16266891 t gcesareni "The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay." SIGNOR-259412 PTPN2 protein P17706 UNIPROT WASL protein O00401 UNIPROT down-regulates dephosphorylation Tyr256 RETSKVIyDFIEKTG 9606 16293614 t gcesareni "Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42" SIGNOR-141652 LRP6 protein O75581 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates activity" relocalization 9606 18632848 t amattioni "The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism." SIGNOR-179469 MAPK8 protein P45983 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni "Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells." SIGNOR-178930 PKN1 protein Q16512 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser339 PRGQRDSsYYWEIEA 9606 15849194 t llicata "P21-activated kinase 1 (pak1)-dependent phosphorylation of raf-1 regulates its mitochondrial localization, phosphorylation of bad, and bcl-2 association. moreover, the mitochondrial translocation of raf-1 and the interaction between raf-1 and bcl-2 are regulated by raf-1 phosphorylation at ser-338/ser-339." SIGNOR-135679 SMAD7 protein O15105 UNIPROT BMPR1B protein O00238 UNIPROT down-regulates 10090 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-236864 DYRK1B protein Q9Y463 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser279 KVAERRSsPLLRRKD 10090 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 mannermirk phosphorylates hdac5 at ser-279" SIGNOR-235809 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 flumazenil chemical CHEBI:5103 ChEBI "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0000227 18790874 t brain lperfetto "Receptors containing the alpha4 or alpha6 subunits, together with beta and gamma2, do not bind the traditional BZ agonists, including zolpidem, but demonstrate high affinity for some ligands, notably the imidazobenzodiazepines such as flumazenil and Ro15-4513, or bretazenil" SIGNOR-263806 RPS6KA5 protein O75582 UNIPROT RPS6KA5 protein O75582 UNIPROT "up-regulates activity" phosphorylation Ser381 GYSFVAPsILFKRNA 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-131395 ITGB1 protein P05556 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-253188 CDK2 protein P24941 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-138936 CDK2 protein P24941 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 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-138940 CHUK protein O15111 UNIPROT CCND1 protein P24385 UNIPROT down-regulates phosphorylation Thr286 EEVDLACtPTDVRDV 9606 16103118 t gcesareni "Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286." SIGNOR-139570 TAOK1 protein Q7L7X3 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "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-201321 CXCL12 protein P48061 UNIPROT CXCR4 protein P61073 UNIPROT up-regulates binding 9606 11859124 t gcesareni "To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells." SIGNOR-115029 DNMT3B protein Q9UBC3 UNIPROT GSTM2 protein P28161 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 21246532 f lperfetto "Knockdown of Sp1 in normal lung cells reduced GST-M2 expression, and silencing of DNMT-3b increased GST-M2 expression in lung cancer cells." SIGNOR-271687 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys64 RAGCCLGkAVRGAKG 9606 12408818 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-95165 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 BMP2 protein P12643 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates 9606 22298955 f "inferred from 70% of family members" lperfetto "Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation." SIGNOR-269848 CSNK2A2 protein P19784 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-250986 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 phosphatidylethanolamine chemical CHEBI:16038 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass" SIGNOR-267002 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 22021368 f apalma "Once genetic mutation of AML1 occurs in hematopoietic cells, aberrant activation of NF-κB signaling exerts antiapoptotic and proliferation-promoting effects via activation of BCL-XL or JUNB." SIGNOR-256654 AMPK complex SIGNOR-C15 SIGNOR RBBP7 protein Q16576 UNIPROT "up-regulates activity" phosphorylation Ser314 LKLHTFEsHKDEIFQ -1 28143904 t lperfetto "AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314| interaction between RBBP7 and HAT1 is required for acetyltransferase activity" SIGNOR-264789 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244595 ITCH protein Q96J02 UNIPROT DTX1 protein Q86Y01 UNIPROT down-regulates ubiquitination 9606 17028573 t gcesareni "Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains." SIGNOR-150002 SDC3 protein O75056 UNIPROT NOTCH1 protein P46531 UNIPROT "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-244072 TAB2 protein Q9NYJ8 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-205446 CDKN1A protein P38936 UNIPROT CDK1 protein P06493 UNIPROT down-regulates binding 9606 15340381 t gcesareni "P21 and p27 are key inhibitors of both cdk1 and cdk2." SIGNOR-128442 GSK3B protein P49841 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 14563837 t gcesareni "Conversely, overexpression of gsk-3 alpha or gsk-3 beta enhances thr-58 phosphorylation and ubiquitination of c-myc" SIGNOR-118844 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 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Thr387 HKKLMFKtEGPDSD 9606 BTO:0001321 15659650 t lperfetto "Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-217861 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 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 IFNG protein P01579 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "down-regulates activity" 10090 23667107 f "Early inhibition of IL-1β expression by IFN-γ is mediated by impaired binding of NF-κB to the IL-1β promoter but is independent of nitric oxide." SIGNOR-255937 MAPK1 protein P28482 UNIPROT DUSP6 protein Q16828 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser197 SATDSDGsPLSNSQP 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-132971 EDN1 protein P05305 UNIPROT MC1R protein Q01726 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-252386 NEDD4L protein Q96PU5 UNIPROT SCN10A protein Q9Y5Y9 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-253463 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 lenalidomide chemical CHEBI:63791 ChEBI CRBN protein Q96SW2 UNIPROT "down-regulates activity" "chemical inhibition" 9606 22552008 t miannu "Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide." SIGNOR-259284 CD19 protein P15391 UNIPROT MAPK1 protein P28482 UNIPROT "up-regulates activity" 9606 10706702 f lperfetto "CD19 is a coreceptor on B cells that enhances the increase in cytoplasmic calcium and ERK2 activation when coligated with the B cell Ag receptor." SIGNOR-249609 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 BTO:0000007 21059642 t "The effect has been demonstrated using Q01196-8" lperfetto "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-216916 RPS6KA3 protein P51812 UNIPROT HMGN2 protein P05204 UNIPROT "down-regulates activity" phosphorylation Ser29 QRRSARLsAKPAPPK 9606 BTO:0000567 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-249103 CAPN3 protein P20807 UNIPROT GSK3A protein P49840 UNIPROT "up-regulates activity" cleavage 9606 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-251606 CPSF2 protein Q9P2I0 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-268335 motesanib chemical CHEBI:51098 ChEBI RET protein P07949 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194572 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22578813 t miannu "We identified the KLHL25-CUL3 complex as the E3 ubiquitin ligase, which targets hypophosphorylated 4E-BP1. Thus, the activity of eIF4E is under homeostatic control via the regulation of the levels of its repressor protein 4E-BP1 through ubiquitination." SIGNOR-272051 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 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR DCTN1 protein Q14203 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 17532294 t miannu "FBXL5 binds to p150(Glued)in vitro and in vivo. FBXL5 and p150(Glued) co-localize primarily in the cytoplasm with peri-nuclear enrichment in HeLa cells. Overexpression of FBXL5 promotes poly-ubiquitination of p150(Glued) and protein turnover of p150(Glued). Our findings provide a potential mechanism by which p150(Glued) protein function is regulated by SCFs." SIGNOR-271653 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 22926518 t miannu "The activated TGFβ type I receptor kinase propagates the signal within the cell through phosphorylation of the receptor-regulated (R-)Smad proteins Smad2 and Smad3 at their extreme carboxyl-terminal serine residues.1, 2 The activated R-Smads then form heteromeric complexes with the common-partner (Co-)Smad, Smad4, and accumulate in the nucleus, where they can bind DNA and regulate gene expression. The Smads control gene expression in a cell type-specific manner by interacting with other proteins, such as AP-1, AP-2 and Ets transcription factors and specific co-activators and co-repressors." SIGNOR-256181 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 "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR "form complex" binding 9606 BTO:0000007 14636569 t lperfetto "These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer" SIGNOR-263208 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 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 FADS3 protein Q9Y5Q0 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-267909 KCNJ5 protein P48544 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-196205 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 MAPK14 protein Q16539 UNIPROT PTPN7 protein P35236 UNIPROT "down-regulates activity" phosphorylation Ser93 ALQRQPPsPKQLEEE -1 10206983 t miannu "The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP." SIGNOR-250109 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 DAB2IP protein Q5VWQ8 UNIPROT ERN1 protein O75460 UNIPROT "up-regulates activity" binding 9606 BTO:0001176 27858941 t miannu "DAB2IP binds IRE1α, and was shown to be required for activation of this signaling cascade in endothelial cells. IRE1α can trigger pro-apoptotic JNK signaling through recruitment of the TRAF2–ASK1 complex. DAB2IP facilitates IRE1α activation, and participates in a signaling complex required to induce TRAF2-dependent ASK1 activation and JNK phosphorylation." SIGNOR-254749 PDX1 protein P52945 UNIPROT SLC2A2 protein P11168 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-255540 TFIIH complex SIGNOR-C457 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 30860024 f lperfetto "Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair." SIGNOR-269323 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr1175 AQQDGKDyIVLPISE 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-157089 PIM1 protein P11309 UNIPROT 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-187905 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 GABA-A proteinfamily SIGNOR-PF61 SIGNOR chloride smallmolecule CHEBI:17996 ChEBI "up-regulates quantity" relocalization 9606 18790874 t 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-264988 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 SNRPD3 protein P62318 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-270686 CSNK2A1 protein P68400 UNIPROT SPIB protein Q01892 UNIPROT down-regulates phosphorylation Ser129 PYPSPVLsEEEDLPL 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-73879 WNT9B protein O14905 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 20093360 t gcesareni "We find that wnt9b binds to a different part of the lrp6 extracellular domain" SIGNOR-163552 "HIF-1 complex" complex SIGNOR-C418 SIGNOR LDHB protein P07195 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 7673128 t lperfetto "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-267653 PAFAH1B2 protein P68402 UNIPROT APP protein P05067 UNIPROT up-regulates 9606 23238734 f miannu "We provide evidence that the loss of pafah1b2 potently reduces a_ by promoting the degradation of its immediate precursor, the _ctf." SIGNOR-200188 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Tyr632 GRKGSGDyMPMSPKS 9606 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118877 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 12676795 f Luana "Activation of the Ras-MAPK/Erk signaling cascade is essential for neurotrophin-promoted differentiation of neurons and PC12 cells." SIGNOR-264978 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1109 FDEIELAyRRRPPRS -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-251171 AKT proteinfamily SIGNOR-PF24 SIGNOR STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t 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-244349 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 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 SGK1 protein O00141 UNIPROT NDRG2 protein Q9UN36 UNIPROT up-regulates phosphorylation Thr330 TRLSRSRtASLTSAA 9606 BTO:0000567 BTO:0000887;BTO:0001103;BTO:0000763 15461589 t llicata "Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344" SIGNOR-129676 HOXB3 protein P14651 UNIPROT OTX2 protein P32243 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000946 9556594 t Luana "Transactivation of the mouse OTX2 Luc constructs by the human HOXB1, HOXB2, and HOXB3 proteins. | Likewise, the construct pOTX2LucΔ−710 showed an 8-, 12-, and 6-fold increase in transcriptional activity if co-transfected with pSG-HOXB1, -HOXB2, and -HOXB3, respectively" SIGNOR-261635 DUSP1 protein P28562 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 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-248465 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 PLK3 protein Q9H4B4 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser73 VGLLKLAsPELERLI 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-179555 "26S Proteasome" complex SIGNOR-C307 SIGNOR Ubiquitinated-Viral_Protein complex SIGNOR-C427 SIGNOR "down-regulates quantity" cleavage 9606 15571818 t scontino "The proteasome system is the central proteolytic system of the eukaryotic cell [1] and plays an important role in the generation of MHC-class I peptides. The enzyme complex responsible for the selectivity of intracellular protein degradation is the 26S proteasome that degrades poly-ubiquitinated substrates." SIGNOR-267769 GFs stimulus SIGNOR-ST12 SIGNOR AKT2 protein P31751 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-245405 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMBRA1 protein Q9C0C7 UNIPROT "up-regulates activity" phosphorylation Thr1238 ASWDQPGtPGREPTQ 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-272967 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 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 FBXW8 protein Q8N3Y1 UNIPROT "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR "up-regulates activity" binding 9606 BTO:0001109 17205132 t miannu "FBXW8 associates with CUL1 or CUL7 and forms a complex with SKP1 and RBX1. We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8." SIGNOR-271631 KIT protein P10721 UNIPROT JAK2 protein O60674 UNIPROT "up-regulates activity" binding 9606 BTO:0000830 15526160 t mainnu "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 PLEKHF2 protein Q9H8W4 UNIPROT EEA1 protein Q15075 UNIPROT "up-regulates activity" binding -1 22816767 t Giulio "In yeast two-hybrid analysis we identified Phafin2 as a novel interactor of the endosomal-tethering protein EEA1, and Phafin2 colocalized strongly with EEA1 in microdomains of the endosome membrane. Our results suggest that Phafin2 controls receptor trafficking and fluid-phase transport through early endosomes by facilitating endosome fusion in concert with EEA1." SIGNOR-261276 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 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 "SAGA complex" complex SIGNOR-C465 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR down-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-269569 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 CDK5 protein Q00535 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-198111 LAMTOR3 protein Q9UHA4 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates binding 9606 15547943 t lperfetto "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-244874 KRAS protein P01116 UNIPROT MAP4K5 protein Q9Y4K4 UNIPROT up-regulates 9606 BTO:0001271 9949177 f fstefani "Bcr-abl_mediated ras activation is crucial for the ability of bcr-abl to activate gckr and is consistent with the previously known requirement for ras in bcr-abl_induced sapk activation how ras activates gckr remains enigmatic." SIGNOR-64262 LYN protein P07948 UNIPROT CASP8 protein Q14790 UNIPROT "down-regulates activity" phosphorylation Tyr448 TILTEVNyEVSNKDD 18086677 t lperfetto "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." SIGNOR-272980 MARCHF5 protein Q9NX47 UNIPROT SOD1 protein P00441 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0004055 19741096 t lperfetto "Mitochondrial ubiquitin ligase MITOL ubiquitinates mutant SOD1 and attenuates mutant SOD1-induced reactive oxygen species generation" SIGNOR-272982 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1675 SPSYSPTsPSYSPTS -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-248773 GSK3B protein P49841 UNIPROT CDX2 protein Q99626 UNIPROT unknown phosphorylation Ser291 PVSSLQAsVPGSVPG -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-251229 PRKCA protein P17252 UNIPROT RPL10 protein P27635 UNIPROT unknown phosphorylation Ser168 GRQKIHIsKKWGFTK -1 9016777 t lperfetto "Moreover, 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-248958 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 "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 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 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 RAC1 protein P63000 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 21712438 f gcesareni "Hypertonicity activates p38 via a rac1-osm-mekk3-mkk3-p38 pathway." SIGNOR-174602 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH11 protein P55287 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-265829 AUTS2 protein Q8WXX7 UNIPROT PREX1 protein Q8TCU6 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-266817 CD19 protein P15391 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 10090 BTO:0000776 25673924 f lperfetto "CD19 is a crucial regulator of B cell activation." SIGNOR-242888 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation -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-251036 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 PLK3 protein Q9H4B4 UNIPROT CASP8 protein Q14790 UNIPROT "up-regulates activity" phosphorylation Thr273 DAGALTTtFEELHFE 27325299 t lperfetto "Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function." SIGNOR-272995 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 PIK3R1 protein P27986 UNIPROT PIK3CA protein P42336 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-242637 EFNA1 protein P20827 UNIPROT EPHA7 protein Q15375 UNIPROT up-regulates binding 9606 9576626 t gcesareni "The best known function is their role in the guidance of migration of axons and cells in the nervous system through repulsive interactions" SIGNOR-56965 "CCT365623 (hydrochloride)" chemical CID:139266765 PUBCHEM LOX protein P28300 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000195 31070916 t "Simone Vumbaca" "Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy." SIGNOR-261121 Gbeta proteinfamily SIGNOR-PF4 SIGNOR MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation -1 32482868 t "inferred from 70% family members" lperfetto "ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation" SIGNOR-270030 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 PDE3A protein Q14432 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates activity" binding 9606 BTO:0000199 25593322 t lperfetto "Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2.|PDE3A co-localized with PLB, SERCA2, and an AKAP18 variant|our studies show that PDE3-selective inhibition (but not PDE4 inhibition) potentiates the phosphorylation of PLB by endogenous PKA and stimulation of SERCA2 activity and Ca2+ uptake in SR-enriched vesicles prepared from human myocardium." SIGNOR-262051 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-269362 CyclinY/CDK14 complex SIGNOR-C541 SIGNOR 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-273010 MRTFA protein Q969V6 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni "Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf." SIGNOR-174264 PPM1A protein P35813 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-248493 FOXO proteinfamily SIGNOR-PF27 SIGNOR FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15109499 t "Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers" SIGNOR-252929 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 Ethylketocyclazocine chemical CHEBI:4901 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-258799 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 MAPKAPK2 protein P49137 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser54 GGFPRRHsVTLPSSK 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-161274 hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "carbamoyl phosphate(2-)" smallmolecule CHEBI:58228 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-267417 JAK1 protein P23458 UNIPROT STAT1 protein P42224 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 9020188 t lperfetto "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-236239 PRKCD protein Q05655 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 16418226 t gcesareni "Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation." SIGNOR-143828 TNF protein P01375 UNIPROT TNFRSF21 protein O75509 UNIPROT up-regulates binding 9606 BTO:0000142 9714541 t gcesareni "We report the identification and initial characterization of dr6, a new member of the tnf receptor family possessing a cytoplasmic death domain." SIGNOR-59745 ponatinib chemical CHEBI:78543 ChEBI KDR protein P35968 UNIPROT "down-regulates activity" "chemical inhibition" -1 23430109 t lperfetto "AP24534 also inhibited SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases (Table 1 and Table S1)" SIGNOR-261984 CREB1 protein P16220 UNIPROT MITF protein O75030 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10841026 t lperfetto "Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription." SIGNOR-249619 GPR119 protein Q8TDV5 UNIPROT GNAS protein Q5JWF2 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-256768 PTGIR protein P43119 UNIPROT GNAS protein Q5JWF2 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-256806 GSK3A protein P49840 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" 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-159381 UNC13B protein O14795 UNIPROT Synaptic_vesicle_exocytosis phenotype SIGNOR-PH160 SIGNOR up-regulates 9606 BTO:0000938 31679900 f 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. MUNC13 is proposed to tether synaptic vesicles by bridging between vesicle and plasma membrane via its C2C-domain and C1/C2B-domains" SIGNOR-264386 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr247 VKGKSDPyHATSGAL 9606 16916748 t lperfetto "The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites." SIGNOR-148913 IL1B protein P01584 UNIPROT KRT1 protein P04264 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17982242 f "Regulation of expression" miannu "IL-1β alone decreased the expression of E-cadherin and cytokeratin" SIGNOR-251883 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 AKT proteinfamily SIGNOR-PF24 SIGNOR MST1R protein Q04912 UNIPROT up-regulates phosphorylation Ser1394 VRRPRPLsEPPRPT 9606 14505491 t lperfetto "Akt/pkb phosphorylates ron ser-1394, thus providing a docking site for 14-3-3based on these results, we propose a mechanism based on msp-ron-dependent phosphorylation and 14-3-3 association, whereby the function of alpha6beta4 switches from a mechanical adhesive device into a signaling component, and might be critically involved in human epidermal wound healing" SIGNOR-118053 PPP2CA protein P67775 UNIPROT TRAF2 protein Q12933 UNIPROT "down-regulates activity" dephosphorylation Thr117 DGCTWKGtLKEYESC 10090 17188031 t "We show that the Thr117 residue in TRAF2 is phosphorylated following TNFalpha stimulation. This phosphorylation process is modulated by PP2A and is required for TRAF2 functional activity." SIGNOR-248640 PRKAA1 protein Q13131 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 SIGNOR-C15 11069105 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-84061 MAPK1 protein P28482 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-269087 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 JAK2 protein O60674 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Tyr693 TERGDKGyVPSVFIP 9606 BTO:0000782 16324152 t gcesareni "Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity" SIGNOR-142736 NUMB protein P49757 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 12682059 t lperfetto "Mammalian numb proteins promote notch1 receptor ubiquitination and degradation of the notch1 intracellular domain" SIGNOR-99762 "Rix1 complex" complex SIGNOR-C373 SIGNOR "Ribosome biogenesis" phenotype SIGNOR-PH164 SIGNOR up-regulates 9606 BTO:0000007 22190736 f miannu "In this study, we show that LAS1L forms a protein complex with PELP1, TEX10, NOL9, SENP3, and WDR18. Our data demonstrate that all the components of the LAS1L complex cosediment with the pre-60S ribosomal particle and are required for proper processing of the 32S rRNA intermediate.These findings demonstrate that the LAS1L complex is critical for ribosome biogenesis and cell proliferation and provide additional evidence that multiple protein complexes have distinct functions in the synthesis of eukaryotic ribosomes." SIGNOR-265473 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RARB protein P10826 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-256195 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 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 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-249398 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 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Thr28 PTMPPPEtPSEGRQP 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124313 STK11 protein Q15831 UNIPROT PRKAA1 protein Q13131 UNIPROT "up-regulates activity" phosphorylation Thr183 SDGEFLRtSCGSPNY -1 14976552 t lperfetto "We 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)." SIGNOR-122721 STAT5A protein P42229 UNIPROT FOXP3 protein Q9BZS1 UNIPROT up-regulates 9606 18270368 t "We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cell" SIGNOR-254301 JUN protein P05412 UNIPROT STAR protein P49675 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-254875 IRF2 protein P14316 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." SIGNOR-254530 PPP2CA protein P67775 UNIPROT EEF2 protein P13639 UNIPROT up-regulates dephosphorylation Thr57 RAGETRFtDTRKDEQ 9606 phosphorylation:Thr57 RAGETRFtDTRKDEQ 8386634 t gcesareni "Protein phosphatases-2a and -2c (pp-2a and pp-2c) can each efficiently dephosphorylate phosphorylated eef-2" SIGNOR-38561 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr771 IGTAEPDyGALYEGR 9606 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-20984 "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 gefitinib chemical CHEBI:49668 ChEBI EGFR protein P00533 UNIPROT "down-regulates activity" "chemical inhibition" 9606 15284455 t SimoneGraziosi "Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. " SIGNOR-269264 GNA13 protein Q14344 UNIPROT ARHGEF1 protein Q92888 UNIPROT "up-regulates activity" binding 9606 14607242 t "It turned out that RGS domain of p115RhoGEF is specific for Gα12 and Gα13, and does not bind Gαi, Gαs and Gαq (Kozasa et al., 1998). The binding of Gα13 but not Gα12 stimulated GEF activity for Rho" SIGNOR-256521 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 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 RBX1 protein P62877 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 11295495 t gcesareni "The scf-betatrcp complex is responsible for the ubiquitination of p100 and p105 following their phosphorylation by ikk." SIGNOR-106781 SPI1 protein P17947 UNIPROT miR-34 mirna URS000033F823_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 10090 21986534 f "We revealed that TNFα treatment results in the up-regulation of miR-155 through the NFκB pathway in 3T3-L1 cells." SIGNOR-255935 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 BID protein P55957 UNIPROT CYCS protein P99999 UNIPROT "up-regulates activity" 9606 9727492 f "Translocation from Mitochondria to Cytosol" lperfetto "TBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c." SIGNOR-59224 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT down-regulates dephosphorylation 9606 15821101 t gcesareni "Ptp1b has been shown to regulate the activation of cytokine receptors through the dephosphorylation of specific members of the jak family, namely jak2 and tyk2" SIGNOR-135207 GAB2 protein Q9UQC2 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 t gcesareni "Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2we propose that gab1 and gab2 in cooperation with other adapter molecules might regulate the cellular localization of gc-gap under specific stimuli." SIGNOR-102628 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 methyltestosterone chemical CHEBI:27436 ChEBI AR protein P10275 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 17202804 t miannu "GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5" SIGNOR-259266 IRS2 protein Q9Y4H2 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 22810696 t lperfetto "These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients." SIGNOR-251492 CSNK1E protein P49674 UNIPROT APC protein P25054 UNIPROT "up-regulates activity" phosphorylation Ser1279 SRCSSLSsLSSAEDE 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-109660 MAPK7 protein Q13164 UNIPROT KLF2 protein Q9Y5W3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0005787 BTO:0001103 23612709 f miannu "The MEK5-dependent activation of ERK5 promotes binding of the transcription factor SP1 to the promoter of the genes encoding the transcription factors Klf2 and Klf4, leading to their increased abundance. Subsequently, Klf2 and Klf4 bind to the Npnt promoter and induce the production of nephronectin during myoblast fusion" SIGNOR-255454 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1102 MLEERKTyVNTTLYE 10090 BTO:0000944 12082108 t lperfetto "Recently, insights into Tie2 activation were provided by a solution of the Tie2 crystal structure (12). This structural analysis revealed several novel features, including two potential autoinhibitory mechanismsIn the unphosphorylated state, the hydroxyl groups of two important tyrosine residues, Tyr1101 and Tyr1112 (murine residue numbers), are hydrogen-bonded to surrounding residues, which may stabilize the C tail in this inhibitory conformationDeletion of the Tie2 C Tail Enhances Autophosphorylation and Kinase Activity in VitroDeletion of the C tail dramatically enhanced Tie2 autophosphorylation, despite the removal of Tyr1112, which was previously shown to be an important autophosphorylation site" SIGNOR-246657 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 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 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR DFFB protein O76075 UNIPROT up-regulates cleavage 9606 9108473 t gcesareni "Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation" SIGNOR-256463 AP2A2 protein O94973 UNIPROT "AP-2 complex" complex SIGNOR-C245 SIGNOR "form complex" binding 31671891 t lperfetto "The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit" SIGNOR-260423 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 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 PPP1R15A protein O75807 UNIPROT PPP1CC protein P36873 UNIPROT up-regulates relocalization 9606 14718519 t lpetrilli "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI." SIGNOR-120734 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 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 FBXO3 protein Q9UK99 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0004573 18809579 t miannu "O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. " SIGNOR-271743 (-)-anisomycin chemical CHEBI:338412 ChEBI JUN protein P05412 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189632 ATOH1 protein Q92858 UNIPROT MUC2 protein Q02817 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17000673 f miannu "This study confirms the importance of HATH1 for the development of intestinal secretory cells. The results further suggest that HATH1 is an important factor in the up-regulation of MUC2 expression that occurs in mucinous cancers and signet ring carcinomas." SIGNOR-253755 AKT1 protein P31749 UNIPROT PHB2 protein Q99623 UNIPROT down-regulates binding 10090 15173318 t lperfetto "Akt binds prohibitin 2 and relieves its repression of myod and muscle differentiation" SIGNOR-252541 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity" acetylation 9606 22298955 t gcesareni "Bmp-induced non-smad erk signaling pathway cooperatively regulates osteoblast differentiation, in part, through increasing the stability and transcriptional activity of runx2 or increasing runx2 acetylation by p300." SIGNOR-195579 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 RNF111 protein Q6ZNA4 UNIPROT SKI protein P12755 UNIPROT down-regulates ubiquitination 9606 BTO:0000150;BTO:0000551 18451154 t gcesareni "On tgf-beta treatment, the e3 ubiquitin ligase arkadia mediates degradation of ski in a smad-dependent manner" SIGNOR-178598 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 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 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 PAK5 protein Q9P286 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser75 EIRSRHSsYPAGTED 9534 BTO:0000298 12897128 t miannu "P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112" SIGNOR-250247 abiraterone chemical CHEBI:68642 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-204810 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 PPP2CA protein P67775 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates dephosphorylation Thr32 QSRPRSCtWPLQRPE 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-163684 MAP4K1 protein Q92918 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly," SIGNOR-43996 TRAPPC9 protein Q96Q05 UNIPROT IKBKB protein O14920 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15951441 t miannu "We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates." SIGNOR-269673 FOXO3 protein O43524 UNIPROT 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-236551 STK38 protein Q15208 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr74 SAHARKEtEFLRLKR 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-96687 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 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 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 BTO:0000567 21658950 t miannu "Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis." SIGNOR-263138 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT "down-regulates activity" dephosphorylation Thr423 PEQSKRStMVGTPYW 10116 11864573 t "The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family|POPX Can Dephosphorylate and Downregulate PAK| To confirm that POPX2 acts on αPAK phospho-Thr422, a key regulator of activity in the kinase activation loop [9], we used phospho-specific antibodies against αPAK P-Thr422 (Figure 3B, lower panel), which proved to be an excellent substrate for POPX2. Similarly, complete loss of αPAK P-Ser57 with 0.2 μg POPX2 contrasts with the slight loss observed with 1.5 μg PP1. On the basis of these results, we suggest PAK is a substrate of POPX." SIGNOR-248531 ABL1 protein P00519 UNIPROT VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t gcesareni "Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro." SIGNOR-114091 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM 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-257913 BMPR1B protein O00238 UNIPROT STAMBP protein O95630 UNIPROT "up-regulates activity" phosphorylation Ser243 SLKPGALsNSESIPT 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-250597 RUNX2 protein Q13950 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254552 DUX4 protein Q9UBX2 UNIPROT PITX1 protein P78337 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17984056 t Luana "DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1" SIGNOR-261590 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 RARA protein P10276 UNIPROT RXRG protein P48443 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-16466 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 INSR protein P06213 UNIPROT IRS4 protein O14654 UNIPROT "up-regulates activity" phosphorylation 10090 25905389 t lperfetto "The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok." SIGNOR-217897 RBL2 protein Q08999 UNIPROT Cell_cycle_progress phenotype SIGNOR-PH42 SIGNOR down-regulates 10090 BTO:0000165 10801445 f gcesareni "Although forced expression of either p130 or pRb in mouse C2 myoblasts efficiently blocked cell cycle progression, only p130 inhibited the differentiation program." SIGNOR-241946 PRKAA1 protein Q13131 UNIPROT FOXO1 protein Q12778 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." SIGNOR-157941 GADD45G protein O95257 UNIPROT CDK11A protein Q9UQ88 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 26885618 t lperfetto "Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58." SIGNOR-273025 CyclinD3/CDK6 complex SIGNOR-C234 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Ser21 TPPSTALsPGKMSEA 9606 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-273031 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 CDK13 protein Q14004 UNIPROT 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-273034 MAP3K7 protein O43318 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT "up-regulates activity" 9606 9890973 f lperfetto "These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway." SIGNOR-63979 CCL2 protein P13500 UNIPROT CCR2 protein P41597 UNIPROT "up-regulates activity" binding 9606 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. " SIGNOR-255113 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT down-regulates phosphorylation Tyr360 VSPSPTTyRMFRDKS 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-40619 FOXO3 protein O43524 UNIPROT FBXO32 protein Q969P5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 15109499 f miannu "Constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers" SIGNOR-252070 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 20724475 t lperfetto "ERK activation was sufficient for the SOS1 phosphorylation and resulting inhibition of EGF-induced Ras activation. This result also showed that SOS1 could be phosphorylated by ERK in the absence of association with EGFR at the plasma membrane, which is a phosphotyrosine-dependent process." SIGNOR-244743 BDKRB2 protein P30411 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-257344 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation Ser118 DKSTQTPsPPCQAFN 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-98388 "enalaprilat (anhydrous)" chemical CHEBI:4786 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-258429 CDK13 protein Q14004 UNIPROT 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-273045 SRGAP1 protein Q7Z6B7 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-260515 PLAUR protein Q03405 UNIPROT ITGB3 protein P05106 UNIPROT "up-regulates activity" binding 9606 27383564 t "Recent evidence suggests that the activation of b3 integrin in podocytes mediates uPAR-induced cellular events leading to proteinuria" SIGNOR-253333 NRF1 protein Q16656 UNIPROT SLC46A1 protein Q96NT5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20724482 f miannu "Overexpression of NRF-1 or a constitutively active NRF-1 VP-16 construct resulted in increased reporter activity and PCFT mRNA levels. These novel findings identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression." SIGNOR-254884 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 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 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 BTO:0000007 28195531 t "While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion. The latter phenotype involved association of SMCR8 with the ULK1 gene locus." SIGNOR-252030 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 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-138585 ACTB protein P60709 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-270717 APBA1 protein Q02410 UNIPROT STXBP1 protein P61764 UNIPROT "up-regulates activity" binding 10116 9395480 t miannu "Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1." SIGNOR-264035 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 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 PPP1CA protein P62136 UNIPROT BRCA1 protein P38398 UNIPROT "down-regulates activity" dephosphorylation Ser1524 LQNRNYPsQEELIKV 9606 BTO:0000007 17603999 t "Protein kinases involved in the DNA damage checkpoint control, such as ATM, ATR, and hCds1/Chk2, have been shown to phosphorylate and activate BRCA1 upon DNA damage. |Altogether, these results indicate that PP1α specifically dephosphorylates BRCA1 at multiple serine sites, including S988 [12], S1423, and S1524." SIGNOR-248562 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 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 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 ASNS protein P08243 UNIPROT "L-asparagine zwitterion" smallmolecule CHEBI:58048 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-267533 F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR "down-regulates activity" relocalization 9606 27871158 t lperfetto "Integrin αIIbβ3 is retained by the actin cytoskeleton in resting platelets but is released to the cell surface during platelet activation. " SIGNOR-261864 POU2F1 protein P14859 UNIPROT HOXD11 protein P31277 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25301728 f miannu "Knockdown of pou2f1 significantly reduced expression of hoxd10 and d11" SIGNOR-205564 GSK690693 chemical CHEBI:90677 ChEBI AKT1 protein P31749 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252462 CDK13 protein Q14004 UNIPROT 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-273058 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 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-252813 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 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 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 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "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-252454 DIO2 protein Q92813 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-266953 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT unknown phosphorylation Ser413 VRYIKENsPCVTPVS 9606 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-104675 SST protein P61278 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 10433861 t gcesareni "The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity." SIGNOR-82496 TG101209 chemical CHEBI:90304 ChEBI RET protein P07949 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207269 ERBB3 protein P21860 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146870 DTNB protein O60941 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-255990 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21357467 f gcesareni "The nfkb p65/p50 heterodimer increases sod2, and p50/p50 suppresses it nf-kb p65/p50 binds to the enhancer and is important for cytokine-induced sod2" SIGNOR-172392 PRKCD protein Q05655 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser64 PRGRPKGsKNKGAAK 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-73610 TEAD1 protein P28347 UNIPROT FOXM1 protein Q08050 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22286761 f gcesareni "Yap directly induced the transcription of ccnd1 and foxm1, in cooperation with tead transcription factor." SIGNOR-194371 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 GSK3B protein P49841 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser366 GCSSQSIsPMRSISE -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-264869 ESRRA protein P11474 UNIPROT NR2F1 protein P10589 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000155 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-253795 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 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates activity" phosphorylation Tyr842 DIMSDSNyVVRGNAR 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-271925 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "Av/b2 integrin" complex SIGNOR-C176 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-259027 mTORC2 complex SIGNOR-C2 SIGNOR AMOTL2 protein Q9Y2J4 UNIPROT "down-regulates activity" phosphorylation Ser759 SSSQRAAsLDSVATS 25998128 t lperfetto "AMOTL2 is phosphorylated at serine 760 by mTORC2. Mutation of AMOTL2 mimicking constitutive Ser(760) phosphorylation blocks its ability to bind and repress YAP leading to increased relative expression of known YAP gene targets." SIGNOR-272085 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 NR3C1 protein P04150 UNIPROT PER1 protein O15534 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19805059 t miannu "GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription" SIGNOR-268050 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-201695 CRX protein O43186 UNIPROT RS1 protein O15537 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18927113 f miannu "Our in vitro and in vivo results indicate that two CRE sites in the minimal RS1 promoter region control retinal RS1 expression and establish CRX as a key factor driving this expression." SIGNOR-253822 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 PLEKHG4 protein Q58EX7 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-260564 nisoxetine chemical CHEBI:73410 ChEBI SLC6A2 protein P23975 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-257797 Corticotropin protein P01189-PRO_0000024969 UNIPROT HSD3B1 protein P14060 UNIPROT "up-regulates quantity" 9606 24631756 f lperfetto "CTH signaling promotes the single steroidogenic rate limiting step, which is the conversion of cholesterol to pregnenolone by Cholesterol Side-Chain Cleavage Enzyme (P450scc), encoded in the CYP11A1 gene. This is conferred by a direct stimulating effect of ACTH on the promoter of CYP11A1 (Chung et al., 1997, Liu and Simpson, 1997, Hu et al., 2001). Further, it stimulates conversion of pregnenolone to 17-hydroxypregnenolone by upregulating the expression of 3β hydroxysteroid dehydrogenase enzyme (3β-HSD)" SIGNOR-268720 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 PTMS protein P20962 UNIPROT EP300 protein Q09472 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-268461 CDK1 protein P06493 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1189 QKGELSRsPSPFTHT 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-187595 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 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 TP63 protein Q9H3D4 UNIPROT PERP protein Q96FX8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21965674 f miannu "SATB2 attenuates p63-mediated gene expression of perp (p53 apoptosis effector related to PMP-22), a critical downstream target gene during development, and specifically decreases p63 perp promoter binding." SIGNOR-255136 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 PTPRZ1 protein P23471 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-157227 MAPK8 protein P45983 UNIPROT YWHAZ protein P63104 UNIPROT down-regulates phosphorylation Ser184 FYYEILNsPEKACSL 9606 15071501 t "JNK1 and JNK2 are required for apoptosis of thymocites,Ser residues in the reagion between alpha-helices 7 and 8." gcesareni "Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax" SIGNOR-124020 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 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 NRXN2 protein P58401 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626545 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites" SIGNOR-265455 "Food intake" phenotype SIGNOR-PH152 SIGNOR "vitamin K" smallmolecule CHEBI:28384 ChEBI "up-regulates quantity" 31226734 f lperfetto "Vitamin K obtained from the diet is considered to reach the target tissues via lipid absorption and the transport system " SIGNOR-265899 PDPK1 protein O15530 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 t gcesareni "Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency" SIGNOR-243519 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 PTGER3 protein P43115 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-regulates binding 9606 BTO:0000938 12038972 t gcesareni "Ep3 receptor signals are primarily involved in adenylyl cyclase via g(i) activation, and in ca(2+)-mobilization through g(beta)(gamma) from g(i)" SIGNOR-88195 RNF31 protein Q96EP0 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 24469399 t miannu "Involvement of Gln271 and Asp275 of NEMO in LUBAC-mediated linear polyubiquitination.vHOIP NZF1 also recognizes NEMO, and this recognition is involved in linear polyubiquitination of NEMO. Linear chains conjugated to NEMO are recognized by NEMO in trans on another IKK complex, thereby inducing multimerization of the IKK complex and trans autophosphorylation of IKK2." SIGNOR-272052 NUP43 protein Q8NFH3 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-262087 "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 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Ser374 GLYSRSGsLSGRSSL -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-249021 NLGN1 protein Q8N2Q7 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-264191 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 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-164651 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr337 LPAQIIEyYNPSGPP 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262301 WNT5A protein P41221 UNIPROT RYK protein P34925 UNIPROT up-regulates binding 9606 22773843 t areggio "Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells." SIGNOR-258970 TTC5 protein Q8N0Z6 UNIPROT EP300 protein Q09472 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 15448695 t miannu "DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY" SIGNOR-262646 RPS6KB1 protein P23443 UNIPROT CCT2 protein P78371 UNIPROT unknown phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 19332537 t llicata "Mass spectrometry and mutagenesis analysis revealed that rsk and s6k1 phosphorylate cct_ ser-260 in vitro and in intact cells" SIGNOR-184926 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI Citric_Acid_Cycle phenotype SIGNOR-PH191 SIGNOR up-regulates 9606 15953811 f miannu "A branch-point metabolite α-ketoglutarate is generated in the TCA cycle during the oxidation of carbohydrates and fatty acids and by glutamate dehydrogenase during the oxidative deamination of glutamate. The enzymes that form the mitochondrial α-ketoglutarate– dehydrogenase complex (KGDHC), a key and arguably rate-limiting enzyme system of the tricarboxylic acid cycle, might mediate the interaction of these processes." SIGNOR-267821 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 26214522 t Luana "In this study, we have demonstrated that the PTPN1 gene, which encodes PTP1B, was a direct target of MECP2 and that PTP1B protein levels were dramatically increased in Mecp2-mutant mice and in fibroblasts derived from patients with RTT." SIGNOR-264546 SFPQ protein P23246 UNIPROT TH protein P07101 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 20938049 t lperfetto "It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter." SIGNOR-271697 GSK3A protein P49840 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser243 PGETPPLsPIDMESQ 9606 1846781 t lperfetto "Phosphorylation of recombinant human c-jun proteins in vitro by gsk-3 decreases their dna-binding activity." SIGNOR-21776 FYN protein P06241 UNIPROT PRKCQ protein Q04759 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 10383400 t miannu "Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn." SIGNOR-68798 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser443 ATGSGIKsHNSALYS 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-131451 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 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-262220 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 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 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 9606 14636580 t lperfetto "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. " SIGNOR-249243 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 TNFRSF1A protein P19438 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 10090 BTO:0000165 17151142 f lperfetto "These results indicate that TNF-alpha regulates myogenesis and muscle regeneration as a key activator of p38." SIGNOR-235370 MAP2K4 protein P45985 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" phosphorylation 9534 BTO:0000298 7839144 t Luana "Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase." SIGNOR-260722 INHA protein P05111 UNIPROT TGFBR3 protein Q03167 UNIPROT down-regulates binding 9606 10746731 t gcesareni "Type iii tgf-beta receptor, betaglycan, can function as an inhibin co-receptor with actrii. Betaglycan binds inhibin with high affinity and enhances binding in cells co-expressing actrii and betaglycan. ability of betaglycan to facilitate inhibin antagonism of activin" SIGNOR-76470 CSNK2A1 protein P68400 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser83 YSGSEGDsESGEEEE -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. We report here that serine 83 appears to be the residue phosphorylated by CKII but that three other serines in this region can also be involved in phosphorylation and the enhancement of DNA-binding activity." SIGNOR-250958 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 FGD3 protein Q5JSP0 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-260553 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr203 SSLATPPtLSSTVLI 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-249220 BMS-754807 chemical CHEBI:88339 ChEBI IGF1R protein P08069 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001802 19996272 t lperfetto "BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR" SIGNOR-262027 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 "SNS-314 Mesylate" chemical CID:24995523 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207105 PDK3 protein Q15120 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t miannu "Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3)" SIGNOR-143974 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 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-183000 CDKN1B protein P46527 UNIPROT CDK2 protein P24941 UNIPROT down-regulates binding 9606 SIGNOR-C16 17409098 t gcesareni "P27, an important cell cycle regulator, blocks the g(1)/s transition in cells by binding and inhibiting cdk2/cyclin a and cdk2/cyclin e complexes (cdk2/e)." SIGNOR-154191 CSNK2A1 protein P68400 UNIPROT VAMP4 protein O75379 UNIPROT up-regulates phosphorylation Ser30 RNLLEDDsDEEEDFF 9606 14608369 t gcesareni "The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway." SIGNOR-119090 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 SCNN1A protein P37088 UNIPROT sodium(1+) chemical CHEBI:29101 ChEBI "up-regulates quantity" relocalization 9606 26772908 t miannu "The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity." SIGNOR-269275 F7 protein P08709 UNIPROT F10 protein P00742 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 SIGNOR-C319 29880919 t lperfetto "TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively." SIGNOR-263545 PTTG1 protein O95997 UNIPROT TIMP2 protein P16035 UNIPROT "down-regulates quantity" 9606 19351864 f miannu "Suppressing PTTG expression by siRNA decreased cell motility in both PTTG-HA/EC9706 and KYSE150 cells. By using mass spectrometric analysis, we identified that PTTG up-regulated S100A4 and galectin-1 secretion and down-regulated tissue inhibitor of metalloproteinase-2 secretion to the culture media." SIGNOR-255069 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 APBA2 protein Q99767 UNIPROT STXBP1 protein P61764 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 9395480 t miannu "Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1." SIGNOR-264037 BCL3 protein P20749 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16713561 t gcesareni "The cyclin d1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of bcl-3-associated nf-kappab p50 and p52." SIGNOR-146768 JNK proteinfamily SIGNOR-PF15 SIGNOR AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" binding 9606 24315690 t miannu "In addition to the possible regulation of the transcription factor c-Jun by phosphorylation via the c-Jun N-terminal kinase (JNK) or the kinases ERK1, ERK2 and GSK3β, further signaling pathways lead to an up-regulation of c-Jun protein and thus AP-1 activity" SIGNOR-253340 NTRK1 protein P04629 UNIPROT SH2B2 protein O14492 UNIPROT up-regulates phosphorylation 9606 BTO:0000938 9856458 t lperfetto "Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons" SIGNOR-62619 GRK5 protein P34947 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Thr55 DDIEQWFtEDPGPDE 9606 20124405 t llicata "Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage." SIGNOR-163707 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT "up-regulates activity" phosphorylation Ser83 QHDDGRVsYPLCFIF -1 9030586 t miannu "Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82." SIGNOR-249983 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 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 KDR protein P35968 UNIPROT KDR protein P35968 UNIPROT up-regulates phosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 10102632 t lperfetto "Autophosphorylation of kdr in the kinase domain is required for maximal vegf-stimulated kinase activity and receptor internalizationthe intensity of vegf-induced autophosphorylation is significantly reduced when using receptor mutated at y996, confirming that this is a major site of autophosphorylation. Second, tyrosines 951 and 996 are the only two tyrosines in the receptor's kinase insert domain, and there is strong evidence from studies using the pdgfr and cfms that autophosphorylation of tyrosines in this domain leads to important signaling events." SIGNOR-66040 TNF protein P01375 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR up-regulates 10090 BTO:0000133 15972951 f lperfetto "Second, LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis was attenuated, but not prevented, by pretreatment with neutralizing anti-TNF-α antibodies." SIGNOR-270588 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Ser5099 DVEFDIKsPKFKAEA 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-262763 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 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 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t "inferred from 70% family members" gcesareni "Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells." SIGNOR-270037 SRC protein P12931 UNIPROT ARAF protein P10398 UNIPROT up-regulates phosphorylation Tyr301 LGYRDSGyYWEVPPS 9534 BTO:0004055 9020159 t lperfetto "A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation. Activation of Raf-1 and A-Raf by Src requires tyrosine phosphorylation at residues 340 and 341 in Raf-1 and 301 and 302 in A-Raf." SIGNOR-236037 PIK3CA protein P42336 UNIPROT RAC1 protein P63000 UNIPROT up-regulates 9606 21779497 f gcesareni "Pi3k can also activate rac, and this activation is involved in cytoskeleton reorganization." SIGNOR-175238 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 PRKACA protein P17612 UNIPROT RET protein P07949 UNIPROT down-regulates phosphorylation Ser696 SSGARRPsLDSMENQ 9606 BTO:0000938 20682772 t llicata "Furthermore, we find that activation of protein kinase a (pka) by forskolin reduces the recruitment of shp2 to ret and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of ser(696), a known pka phosphorylation site in ret, enhances shp2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth." SIGNOR-167349 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BP1 protein Q8IU81 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-271057 LSM-1231 chemical CHEBI:91471 ChEBI NTRK3 protein Q16288 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-258240 regorafenib chemical CHEBI:68647 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206412 FBXO6 protein Q9NRD1 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" 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-271881 GATA2 protein P23769 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 9606 20510530 t fferrentino "GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis" SIGNOR-132949 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Thr302 PEPEVLStQEDLFDQ 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." SIGNOR-197619 "Calprotectin complex" complex SIGNOR-C293 SIGNOR AGER protein Q15109 UNIPROT "up-regulates activity" binding 9606 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-262825 PRKCZ protein Q05513 UNIPROT ATP1A1 protein P05023 UNIPROT "up-regulates activity" phosphorylation Ser16 KYEPAAVsEQGDKKG 9606 BTO:0000018 12671055 t miannu "Na,K-ATPase alpha(1) subunit was phosphorylated by PKC in hypoxia-treated AEC. In AEC treated with a PKC-zeta antagonist peptide or with the Na,K-ATPase alpha(1) subunit lacking the PKC phosphorylation site (Ser-18), hypoxia failed to decrease Na,K-ATPase abundance and function." SIGNOR-263181 BBC3 protein Q9BXH1 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 t gcesareni "Bim, and puma bind with high affinity to all pro-survival proteins" SIGNOR-196929 ARAF protein P10398 UNIPROT MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR up-regulates phosphorylation 9606 21779497 t lperfetto "Active raf phosphorylates mek." SIGNOR-244809 GRK7 protein Q8WTQ7 UNIPROT GRK7 protein Q8WTQ7 UNIPROT unknown phosphorylation Ser490 YAKDIAEiDDFSEVR 9606 15946941 t Manara "In the absence of PKA, GRK1 and GRK7 are autophosphorylated | The mutants, S490A-GRK7 and S490E-GRK7, do not undergo autophosphorylation, indicating that Ser490 is the only autophosphorylation site in GRK7" SIGNOR-260838 CLTB protein P09497 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-260677 CREB1 protein P16220 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates activity" binding 9606 15126506 t lperfetto "We provide evidence that the acetyltransferase creb-binding protein (cbp) binds foxo resulting in acetylation of foxo. This acetylation inhibits foxo transcriptional activity" SIGNOR-124711 PRKCA protein P17252 UNIPROT KIT protein P10721 UNIPROT down-regulates phosphorylation Ser741 TKADKRRsVRIGSYI 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-28601 TUFM protein P49411 UNIPROT ATG5 protein Q9H1Y0 UNIPROT "down-regulates activity" binding 9606 33113344 t miannu "PINK1 interacts with the autophagy effector TUFm and phosphorylates TUFm at Ser222. These results indicated that p222-hTUFm sequestered more monomer Atg5 and reduced the conjugated Atg5-Atg12 complex to subdue mitophagy." SIGNOR-266383 IMPDH2 protein P12268 UNIPROT MKI67 protein P46013 UNIPROT "up-regulates quantity by expression" "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-260958 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 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI PTGER3 protein P43115 UNIPROT up-regulates "chemical activation" 9606 15299086 t gcesareni "Pge2 is the ligand for four ep receptor subtypes termed ep1 to ep4." SIGNOR-127738 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 GSK3B protein P49841 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-249351 RPS6KB1 protein P23443 UNIPROT 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-123997 Ub:E2 complex SIGNOR-C497 SIGNOR NFX1 protein Q12986 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-271015 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 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 "Certolizumab (Cimzia)" antibody DB08904 DRUGBANK TNF protein P01375 UNIPROT "down-regulates activity" binding 9606 32207094 t "Certolizumab pegol (Cimzia®) is a PEGylated, Fab'-only, recombinant humanized antibody against TNF-α. " SIGNOR-272492 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 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 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 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 GSK2126458 chemical CID:25167777 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252645 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 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 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 "5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid" chemical CHEBI:76223 ChEBI PTGS2 protein P35354 UNIPROT "down-regulates activity" "chemical inhibition" -1 22091869 t Luana " Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. " SIGNOR-258324 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser554 RTPPKSPsSAKSRLQ -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250283 GNRH1 protein P01148 UNIPROT EGR1 protein P18146 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-254917 MAP4K1 protein Q92918 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates 9606 10224067 f gcesareni "These studies establish that hpk1 acts as an upstream activator for the tak1-sek-jnk1 module in relaying the tgf-_ signal into the nuclei in 293t cells." SIGNOR-67321 FANCD2 protein Q9BXW9 UNIPROT BRCA2 protein P51587 UNIPROT "up-regulates activity" relocalization 9606 15199141 t lperfetto "FANCD2-Ub then promotes BRCA2 loading into a chromatin complex." SIGNOR-263253 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser359 GTEEKCGsPQVRTLS 9606 BTO:0000887;BTO:0001103 11500363 t lperfetto "Sapk4/p38delta phosphorylated eef2k at ser359 in vitro, causing its inactivation." SIGNOR-109703 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244858 Gbeta proteinfamily SIGNOR-PF4 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-270101 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 "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR FGA protein P02671 UNIPROT "up-regulates activity" binding 9606 BTO:0000132 16418530 t 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-253359 SYNE3 protein Q6ZMZ3 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-263284 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 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 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 SUFU protein Q9UMX1 UNIPROT SAP18 protein O00422 UNIPROT up-regulates binding 9606 11960000 t gcesareni "Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element." SIGNOR-117311 NPTX1 protein Q15818 UNIPROT BAD protein Q92934 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-260410 PPAT protein Q06203 UNIPROT "Purine biosynthesis" phenotype SIGNOR-PH186 SIGNOR "up-regulates activity" 9606 28029518 f "The first reaction in the de novo purine biosynthetic pathway is the conversion of PRPP to 5-phosphoribosylamine (PRA) by PRPP amidotransferase (PPAT) and is presumed to be rate-limiting." SIGNOR-267188 MST1 protein P26927 UNIPROT MST1R protein Q04912 UNIPROT up-regulates binding 9606 8062829 t gcesareni "P185ron is a tyrosine kinase activated by msp" SIGNOR-31107 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 SNRPF protein P62306 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-270682 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190176 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 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-253484 WIF1 protein Q9Y5W5 UNIPROT WNT8A protein Q9H1J5 UNIPROT down-regulates binding 9606 10201374 t gcesareni "Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities." SIGNOR-66892 SELENOS protein Q9BQE4 UNIPROT DERL1 protein Q9BUN8 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15215856 t miannu "VIMP mediates p97 binding to hDerlin-1. these data suggest that Derlin-1 and VIMP form a membrane protein complex that serves as a receptor for p97." SIGNOR-261370 lapatinib chemical CHEBI:49603 ChEBI CSK protein P41240 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-257900 PRKAA2 protein P54646 UNIPROT CRTC2 protein Q53ET0 UNIPROT down-regulates phosphorylation Ser171 SALNRTSsDSALHTS 9606 SIGNOR-C15 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-166365 MAVS protein Q7Z434 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates relocalization 9606 16406812 t gcesareni "Another protein suggested to play a role in caspase-8 translocation to mitochondria is the mitochondrial membrane protein cardif" SIGNOR-143572 Ub:E2 complex SIGNOR-C497 SIGNOR BRCA1 protein P38398 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-271105 TAOK proteinfamily SIGNOR-PF21 SIGNOR STK3/4 proteinfamily SIGNOR-PF41 SIGNOR "up-regulates activity" phosphorylation 9606 23431053 t miannu "The thousand-and-one (TAO) amino acids kinase or TAOK1 – 3 has been shown to directly phosphorylate and activate Hpo or MST1/2." SIGNOR-256182 PDK1 protein Q15118 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni "Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation." SIGNOR-32977 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 CLTA protein P09496 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-260667 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 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr200 SMESIDDyVNVPESG 9606 BTO:0000782 16938345 t gcesareni "Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation." SIGNOR-149182 MYOD1 protein P15172 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001103 18094043 t lperfetto "We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter." SIGNOR-257598 JUN protein P05412 UNIPROT miR-155 mirna URS000062749E_9606 RNAcentral "up-regulates quantity by expression" "transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255767 RFNG protein Q9Y644 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 BTO:0000975 12486116 t gcesareni "We demonstrate that egf 12, a portion of the ligand-binding site, is modified with o-fucose and that this site is evolutionarily conserved. We also show that endogenous fringe proteins in chinese hamster ovary cells (lunatic fringe and radical fringe) as well as exogenous manic fringe modify o-fucose on many but not all egf repeats of mouse notch1." SIGNOR-96561 RARB protein P10826 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-270299 CYP11B1 protein P15538 UNIPROT 11-deoxycorticosterone smallmolecule CHEBI:16973 ChEBI "down-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-268683 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 WASHC1 protein A8K0Z3 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-261020 RPS6K proteinfamily SIGNOR-PF26 SIGNOR H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 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-252806 PDPK1 protein O15530 UNIPROT TSSK3 protein Q96PN8 UNIPROT "up-regulates activity" phosphorylation Thr168 SHRELSQtFCGSTAY -1 16336268 t Manara "We elucidated the mechanism of regulation of TSSK3 activity showing that autophosphorylation and PDK1 phosphorylation in the ‘activation loop’ are necessary for activation." SIGNOR-260786 PRKDC protein P78527 UNIPROT WRN protein Q14191 UNIPROT up-regulates phosphorylation Ser440 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-203737 ADAM10 protein O14672 UNIPROT BTC protein P35070 UNIPROT "up-regulates activity" cleavage 9606 26284334 t miannu "Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin" SIGNOR-259839 NECTIN2 protein Q92692 UNIPROT CD226 protein Q15762 UNIPROT "up-regulates activity" binding 9606 BTO:0000914 15039383 t lperfetto "CD226 (DNAM-1) is an adhesion molecule involved in NK and T cell-mediated cytotoxicity against certain tumors. Here, we have identified the human poliovirus receptor-related (PRR) family members CD155 [poliovirus receptor (PVR)] and CD112 (nectin-2/PRR-2) as the ligands for human CD226." SIGNOR-261426 somatostatin smallmolecule CHEBI:64628 ChEBI SSTR1 protein P30872 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-257581 SMAD6 protein O43541 UNIPROT TAB1 protein Q15750 UNIPROT down-regulates binding 9606 11737269 t lpetrilli "Smad6 interacts with tak1 and tab1, and smad7 with tab1. The interaction of i-smads with tak1 and/or tab1 implies that several mechanisms exist underlying the repression of the tak1-p38 kinase pathway by i-smads." SIGNOR-112642 FUBP1 protein Q96AE4 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19637194 f irozzo "In our analysis of FBP1 shRNA-transduced Hep3B cells, we found that p21 mRNA levels increase following FBP1 knockdown, suggesting that FBP1 functions as a repressor of p21. Our results identify the tumor suppressor p21 as the second direct FBP1 target gene in addition to the proto-oncogene c-myc." SIGNOR-259125 HNF1B protein P35680 UNIPROT UMOD protein P07911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18846391 f miannu "UMOD transcription is activated by the transcription factor HNF1B." SIGNOR-254441 CREBBP protein Q92793 UNIPROT RELA protein Q04206 UNIPROT up-regulates acetylation 9606 SIGNOR-C6 16382138 t gcesareni "Rela is also acetylated at several sites by p300 and cbp" SIGNOR-143396 "SAGA complex" complex SIGNOR-C465 SIGNOR H3C15 protein Q71DI3 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-269643 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 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 CTCF protein P49711 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12032779 f miannu "Several different transcription factors have been implicated in the down-regulation of c-myc expression during differentiation, including C/EBPalpha, CTCF, BLIMP-1, and RFX1." SIGNOR-253827 DNMT1 protein P26358 UNIPROT BAG3 protein O95817 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-254110 miR-155 mirna URS000062749E_9606 RNAcentral SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 22195016 t "Our results elucidate a negative feedback circuit in which IGF-1-stimulated miR-133 in turn represses IGF-1R expression to modulate the IGF-1R signaling pathway during skeletal myogenesis." SIGNOR-255915 SHMT1 protein P34896 UNIPROT 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI "up-regulates quantity" "chemical modification" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269688 MKX protein Q8IYA7 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001592 33115953 t miannu "MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2)." SIGNOR-267215 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Tyr326 EVLEDNDyGRAVDWW 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-166510 RDH5 protein Q92781 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "down-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 DHRS10" SIGNOR-265113 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR RPTOR protein Q8N122 UNIPROT up-regulates phosphorylation Ser719 PCTPRLRsVSSYGNI 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-252772 DICER1 protein Q9UPY3 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR "form complex" binding 9606 23661684 t miannu SIGNOR-143105 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 RBPJ protein Q06330 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 21873209 t gcesareni "When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects." SIGNOR-176200 CDK5 protein Q00535 UNIPROT STXBP2 protein Q15833 UNIPROT down-regulates phosphorylation Thr572 IGSSHILtPTRFLDD 9606 BTO:0000938 17716669 t lperfetto "It was shown that munc18 inhibition of neuronal syntaxin 1 can be overcome by cdk5 phosphorylation, indicating that structural change disrupts the syntaxin-munc18 interaction." SIGNOR-157528 PTPN2 protein P17706 UNIPROT STAT5A protein P42229 UNIPROT "down-regulates activity" dephosphorylation 9606 15780598 t lperfetto "Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5." SIGNOR-133547 AKT1 protein P31749 UNIPROT ZYX protein Q15942 UNIPROT down-regulates phosphorylation Ser142 PQPREKVsSIDLEID 9606 17572661 t llicata "Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation" SIGNOR-156122 ING3 protein Q9NXR8 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-269294 AURKB protein Q96GD4 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT "up-regulates activity" phosphorylation Ser387 ETGLYRIsGCDRTVK 9606 BTO:0000567 12689593 t lperfetto "We also report that aurora b phosphorylates mgcracgap on serine residues and that this modification induces latent gap activity toward rhoa in vitro." SIGNOR-100569 PTPN1 protein P18031 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr534 NFLMDNAyFCEADAK 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-248420 RAGAC complex SIGNOR-C113 SIGNOR MTOR protein P42345 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 SIGNOR-C3 20381137 t lperfetto "The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb" SIGNOR-228657 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Thr180 RHTDDEMtGYVATRW 9606 17126298 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-150875 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 PINK1 protein Q9BXM7 UNIPROT UBC protein P0CG48 UNIPROT "up-regulates activity" phosphorylation Ser65 DYNIQKEsTLHLVLR 9606 BTO:0000938 24784582 t lperfetto "Ubiquitin is phosphorylated by PINK1 to activate parkin|PINK1 phosphorylated ubiquitin at Ser65 both in vitro and in cells" SIGNOR-249691 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR RNF138 protein Q8WVD3 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-271027 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 17827393 t gcesareni "Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K)." SIGNOR-157734 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "precursor of" 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-266282 ANGPT1 protein Q15389 UNIPROT MYOD1 protein P15172 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-241529 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 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-257930 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 PHLPP2 protein Q6ZVD8 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-248730 N-(2-chlorophenyl)-4-[[2-[4-[2-(4-ethyl-1-piperazinyl)-2-oxoethyl]anilino]-5-fluoro-4-pyrimidinyl]amino]benzamide chemical CHEBI:91365 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190029 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR RBPMS protein Q93062 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. The gene for the RNA‐binding protein with multiple splicing (RBPMS) was upregulated in NUP98‐HOXA9–transduced cord blood CD34+ cells and also in the transcriptosomes of normal CD34+ and CD133+ cells." SIGNOR-261503 ELK1 protein P19419 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-256336 CFD protein P00746 UNIPROT CFB protein P00751 UNIPROT "up-regulates activity" cleavage Thr25 LLSGGVTtTPWSLAR 9606 BTO:0000089 26489954 t lperfetto "The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb" SIGNOR-263488 PTK6 protein Q13882 UNIPROT BCAR1 protein P56945 UNIPROT up-regulates phosphorylation Tyr664 EGGWMEDyDYVHLQG 9606 BTO:0001130 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-177242 JAK1 protein P23458 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation Tyr304 PNEPVSDyINANIIM 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-236282 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 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133849 AMER1 protein Q5JTC6 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "up-regulates activity" relocalization 9606 21304492 t lperfetto "Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6." SIGNOR-227991 DCAF1 protein Q9Y4B6 UNIPROT EDVP complex SIGNOR-C530 SIGNOR "form complex" binding 9606 BTO:0000007 19287380 t miannu "We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex. " SIGNOR-271789 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE -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-250940 PRKCD protein Q05655 UNIPROT PLSCR3 protein Q9NRY6 UNIPROT up-regulates phosphorylation Thr21 PPPPYPVtPGYPEPA 9606 16267027 t gcesareni "Ad198-activated pkc-delta induces phosphorylation of mitochondrial pls3 at thr21;pls3 is a critical downstream effector of pkc-delta in ad198-induced apoptosis." SIGNOR-140759 FANCG protein O15287 UNIPROT SPTAN1 protein Q13813 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000773 19102630 t lperfetto "In FA cells, deficiencies in FA proteins lead to decreased stability of alphaRIISp |These results demonstrate that one of the FA proteins, FANCG, contains a motif that interacts directly with the SH3 domain of alphaIISp. We propose that this binding of FANCG to alphaIISp may be important for the stability of alphaIISp in cells and the role alphaIISp plays in the DNA repair process.|" SIGNOR-263275 FGF13 protein Q92913 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-253439 NPM1 protein P06748 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 30205049 t miannu "In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation." SIGNOR-260138 MAP3K7 protein O43318 UNIPROT KSR1 protein Q8IVT5 UNIPROT down-regulates phosphorylation Ser406 TRLRRTEsVPSDINN 9606 11741534 t gcesareni "C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane" SIGNOR-112779 PIAS3 protein Q9Y6X2 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" binding 9606 14691252 t lperfetto "We have further shown that PIAS3, Smad3, and p300 can form a ternary complex, which is significantly increased by TGF-_ treatment. Taken together, these results suggest that PIAS3 stimulates Smad transcriptional activity through formation of a complex with Smad proteins and p300/CBP." SIGNOR-217725 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 DPYD protein Q12882 UNIPROT thymine smallmolecule CHEBI:17821 ChEBI "down-regulates quantity" "chemical modification" 10499634 t "Dihydropyrimidine dehydrogenase (DPD) is responsible for degradation of the pyrimidines uracil and thymine and the inactivation of the chemotherapeutic agent 5-fluorouracil. DPD activity is highly variable in cancer populations, and this variation may influence the antitumor efficacy of 5-fluorouracil." SIGNOR-253989 ASPA protein P45381 UNIPROT N-acetyl-L-aspartate(2-) smallmolecule CHEBI:16953 ChEBI "down-regulates quantity" "chemical modification" 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-267526 PPP3CA protein Q08209 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-251733 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT "down-regulates activity" phosphorylation Ser363 RVTACTPsDGPGGGA 9606 BTO:0000007 11040053 t gcesareni "Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus." SIGNOR-249660 "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 LPAR1 protein Q92633 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193558 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 KAT2B protein Q92831 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-170276 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 MAP3K14 protein Q99558 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 9020361 f amattioni "Nik stimulates nf-kappab activity" SIGNOR-46212 SPI1 protein P17947 UNIPROT FCRL6 protein Q6DN72 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 12695521 f lperfetto "Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression." SIGNOR-268966 CAMK2A protein Q9UQM7 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser843 DVRLSRGsIDREDGS 9606 15845548 t gcesareni "Furthermore, activated camkii directly phosphorylated the recombinant cooh-terminal region of fak at a residue equivalent to ser-843." SIGNOR-135631 RRAGA protein Q7L523 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-228164 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Thr220 QSNYIPEtPPPGYIS 9606 BTO:0000763 12193595 t lperfetto "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-244731 PRKCG protein P05129 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 8288587 t gcesareni "Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation." SIGNOR-37541 NKX2-1 protein P43699 UNIPROT TPO protein P07202 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001073 27347897 t scontino "TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8." SIGNOR-267278 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SREBF2 protein Q12772 UNIPROT up-regulates phosphorylation 9606 14988395 t "inferred from 70% family members" 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-270141 ITCH protein Q96J02 UNIPROT TNFAIP3 protein P21580 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0001271 18246070 t lperfetto "Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract)" SIGNOR-160621 NLGN4X protein Q8N0W4 UNIPROT NRXN3 protein Q9HDB5 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-264170 "Brivanib alaninate" chemical CID:11154925 PUBCHEM FGFR1 protein P11362 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190717 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 GUCY1B2 protein O75343 UNIPROT GUCY1A3-B2 complex SIGNOR-C139 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-244119 PRKACA protein P17612 UNIPROT GMFB protein P60983 UNIPROT "up-regulates activity" phosphorylation Thr27 KFRFRKEtNNAAIIM -1 9030586 t miannu "Protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. PKA is capable of phosphorylating threonine 26 and serine 82." SIGNOR-249984 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 NLGN2 protein Q8NFZ4 UNIPROT NRXN3 protein Q9HDB5 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-264171 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 CHIR-124 chemical CID:11502647 PUBCHEM FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190976 SRC protein P12931 UNIPROT KCNJ1 protein P48048 UNIPROT down-regulates phosphorylation Tyr337 SKTKEGKyRVDFHNF 9606 12556363 t flangone "Inhibition of c-src with herbimycin a significantly decreased the tyrosine phosphorylation level of romk1... tyrosine dephosphorylation enhances the exocytosis of romk1" SIGNOR-97803 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 maraviroc chemical CHEBI:63608 ChEBI CCR5 protein P51681 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194248 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 STAG2 protein Q8N3U4 UNIPROT RAD21 protein O60216 UNIPROT "up-regulates quantity by stabilization" binding 9606 28430577 t miannu "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-261511 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 BRAF protein P15056 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity" relocalization 9606 19861538 f miannu "The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. BRAF induces TGFβ secretion leading to NIS repression in a MEK-ERK–independent manner but cooperating with the MEK-ERK pathway to induce strong tumor invasion, two major traits acquired during PTC progression." SIGNOR-251987 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 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 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 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 MYCT1 protein Q8N699 UNIPROT CCNE1 protein P24864 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-261732 leucine smallmolecule CHEBI:25017 ChEBI Leu-tRNA(Leu) smallmolecule CHEBI:16624 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-270418 CAMK2A protein Q9UQM7 UNIPROT RCHY1 protein Q96PM5 UNIPROT down-regulates phosphorylation Ser155 CLEDIHTsRVVAHVL 9606 17568776 t lperfetto "Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53" SIGNOR-156064 PPARD protein Q03181 UNIPROT HSD11B2 protein P80365 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001975 15591138 f miannu "Peroxisome proliferator-activated receptor delta suppresses 11beta-hydroxysteroid dehydrogenase type 2 gene expression in human placental trophoblast cells." SIGNOR-255050 MDC1 protein Q14676 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19230643 t gcesareni "Mdc1 also undergoes phosphorylation by ck2 after dna damage to generate a phospho-motif on mdc1, which binds directly to nbs1." SIGNOR-184141 FZD1 protein Q9UP38 UNIPROT PPARG protein P37231 UNIPROT down-regulates 9606 BTO:0000222 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-80598 pictrelisib chemical CHEBI:65326 ChEBI PIK3CD protein O00329 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-176298 PRKDC protein P78527 UNIPROT PNKP protein Q96T60 UNIPROT up-regulates phosphorylation Ser126 PPGTPLVsQDEKRDA 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-176020 AMPK complex SIGNOR-C15 SIGNOR LIPE protein Q05469 UNIPROT down-regulates phosphorylation Ser855 EPMRRSVsEAALAQP 9606 9636039 t lperfetto "Phosphorylation of bovine hormone-sensitive lipase by the amp-activated protein kinase." SIGNOR-216507 CAMK2B protein Q13554 UNIPROT CYLD protein Q9NQC7 UNIPROT up-regulates phosphorylation Ser772 LFKKIFPsLELNITD 9606 24614225 t lperfetto "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-91403 TIMM23 protein O14925 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-267697 GATA1 protein P15976 UNIPROT Megakaryocyte_differentiation phenotype SIGNOR-PH103 SIGNOR "up-regulates activity" 10090 12032775 f "Studies involving point mutants of GATA-1 have shown that a direct physical interaction between GATA-1 and FOG-1 is essential for normal human erythroid and megakaryocyte maturation in vivo." SIGNOR-259961 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 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 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR MAGEA3 protein P43357 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002806 31267705 t miannu " The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6" SIGNOR-272265 PTGS2 protein P35354 UNIPROT IL4 protein P05112 UNIPROT up-regulates 9606 22225874 t FFerrentino "Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression" SIGNOR-255967 CUL5 protein Q93034 UNIPROT DAB1 protein O75553 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 24210661 t miannu "SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1." SIGNOR-272140 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 "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 CAMK4 protein Q16566 UNIPROT HNRNPL protein P14866 UNIPROT up-regulates phosphorylation Ser544 GKSERSSsGLLEWES 9606 22570490 t lperfetto "Here we show that the regulation of the stress axis-regulated exon of the slo1 potassium channel transcripts by membrane depolarization requires a highly conserved camkiv target serine (ser-513) of the heterogeneous ribonucleoprotein l. Ser-513 phosphorylation within the rna recognition motif 4 enhanced heterogeneous ribonucleoprotein l interaction with the camkiv-responsive rna element 1 of stress axis-regulated exon and inhibited binding of the large subunit of the u2 auxiliary factor u2af65." SIGNOR-197367 THPO protein P40225 UNIPROT MPL protein P40238 UNIPROT up-regulates binding 9606 11784712 t miannu "Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways." SIGNOR-113955 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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR RBBP8 protein Q99708 UNIPROT "up-regulates activity" phosphorylation Ser327 ELPTRVSsPVFGATS 9606 BTO:0000567 15485915 t lperfetto "Ser327 site is a Ser-Pro site, a preferred phosphorylation site by cyclin-dependent kinases|Unlike wild-type CtIP, the S327A mutant did not bind to BRCA1 BRCT domains in vitro (Fig. ​(Fig.1C)1C) and failed to associate with BRCA1 in vivo (Fig. ​(Fig.1D),1D), suggesting that residue Ser327 of CtIP is critical for the CtIP-BRCA1 interaction." SIGNOR-263227 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 3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N,N-dimethyl-2-oxo-1H-indole-6-carboxamide chemical CHEBI:91423 ChEBI MAP2K5 protein Q13163 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190374 MAPK1 protein P28482 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203286 WEE1 protein P30291 UNIPROT CDK1 protein P06493 UNIPROT down-regulates phosphorylation Tyr15 EKIGEGTyGVVYKGR 9606 16096060 t gcesareni "The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met" SIGNOR-139491 RBX1 protein P62877 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 14676825 t gcesareni "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-120342 FASTKD2 protein Q9NYY8 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-261227 CDK5RAP2 protein Q96SN8 UNIPROT APP protein P05067 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr743 VEVDAAVtPEERHLS 9606 15178331 t Manara "The APPcyt is phosphorylated at Thr668 in vivo specifically in the brain. Cyclin‐dependent kinase 5 (Cdk5), a unique member of the Cdk family that is implicated in central nervous system development, participates in this phosphorylation. | In the present study, we demonstrate that APP phosphorylated at Thr668 is less vulnerable to cytoplasmic cleavage by caspase-3 and caspase-8." SIGNOR-260818 CPT1B protein Q92523 UNIPROT (R)-carnitine smallmolecule CHEBI:16347 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-267121 "1-acyl-sn-glycerol 3-phosphate(2-)" smallmolecule CHEBI:57970 ChEBI "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "up-regulates quantity" "precursor of" 9606 21173190 t lperfetto "The enzyme 1-acylglycerol-3-phosphate-O-acyltransferase (AGPAT) converts lysophosphatidic acid (LPA) to phosphatidic acid (PA).¬†" SIGNOR-267010 anthra[1,9-cd]pyrazol-6(2H)-one chemical CHEBI:90695 ChEBI MAPK8 protein P45983 UNIPROT down-regulates "chemical inhibition" 9606 11717429 t gcesareni "We report the identification of an anthrapyrazolone series with significant jnk1, -2, and -3 (k(i) = 0.19 microm)." SIGNOR-111983 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates binding 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 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-87433 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 DDHD1 protein Q8NEL9 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-269656 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-251483 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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190281 GSK3B protein P49841 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0001103 15829723 f apalma "GSK-3beta is a serine/threonine kinase that can block translation that is initiated by eukaryotic initiation factor-2B (24) and may thereby reduce protein synthesis." SIGNOR-255110 SUN3 protein Q8TAQ9 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-263291 MRPL46 protein Q9H2W6 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-262350 CTTN protein Q14247 UNIPROT ARP2/3 complex SIGNOR-C146 SIGNOR "up-regulates activity" binding 9606 11231575 t "Cortactin binds directly to the Arp2/3 complex and activates it to promote nucleation of actin filaments." SIGNOR-251519 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 MAPK3 protein P27361 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation 9606 BTO:0000567 19777442 t gcesareni "Erk-1 map kinase prevents tnf-induced apoptosis through bad phosphorylation and inhibition of bax translocation in hela cells." SIGNOR-188172 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 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 XL765 chemical CHEBI:71958 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252660 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206361 ABL1 protein P00519 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 BTO:0001271 23399893 t gcesareni "We show that the grb2-related adapter protein, gads, also associates with bcr-abl, specifically through y177 and demonstrate that bcr-abl-driven lymphoid disease requires gads" SIGNOR-200871 PRKCA protein P17252 UNIPROT GRIA4 protein P48058 UNIPROT up-regulates phosphorylation Ser862 IRNKARLsITGSVGE 9606 12536214 t gcesareni "Receptor internalization, altered;intracellular localization" SIGNOR-97554 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252380 ITK protein Q08881 UNIPROT CD28 protein P10747 UNIPROT up-regulates phosphorylation Tyr209 TRKHYQPyAPPRDFA 9606 BTO:0000661 22936936 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-198751 TBK1 protein Q9UHD2 UNIPROT IKBKE protein Q14164 UNIPROT "up-regulates activity" binding 9606 18353649 t lperfetto "Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction" SIGNOR-178053 PHLPP1 protein O60346 UNIPROT STK4 protein Q13043 UNIPROT up-regulates binding 9606 23431053 t gcesareni "Here, we report that phlpp1 is a binding protein for mst1 and it modulates the hippo pathway by dephosphorylating mst1 at the inhibitory thr(387) of mst1." SIGNOR-201262 HCRT protein O43612 UNIPROT HCRTR1 protein O43613 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9491897 t gcesareni "Identification and initial biological characterization of two orexins as well as their two receptors" SIGNOR-53667 AKT proteinfamily SIGNOR-PF24 SIGNOR HNRNPA1 protein P09651 UNIPROT down-regulates phosphorylation Ser199 SQRGRSGsGNFGGGR 9606 18562319 t gcesareni "Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199." SIGNOR-179059 "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 31810556 f scontino "High-affinity peptide/MHC class I complexes that successfully pass the aforementioned “quality controls” will be transported through the Golgi apparatus to the cell membrane to elicit antigen-specific CD8+ T cell responses." SIGNOR-267775 BCL2 protein P10415 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni "Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)" SIGNOR-55546 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 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK1 protein P23458 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191244 RELA protein Q04206 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9733516 f lperfetto "Thus, our data indicate that nf-kb controls the expression of traf1 and traf2 and c-iap1 and c-iap2" SIGNOR-59960 Temsirolimus chemical CHEBI:79699 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 21081844 t gcesareni "Temsirolimus, an inhibitor of mammalian target of rapamycin (mtor) complex 1, is approved for the treatment of metastatic renal cell carcinoma (rcc)." SIGNOR-169712 MAP4K4 protein O95819 UNIPROT MAP3K1 protein Q13233 UNIPROT up-regulates phosphorylation 9606 8824585 t gcesareni "Hpk1 binds and phosphorylates mekk1 directly" SIGNOR-44040 ANK3 protein Q12955 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-266715 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM35 protein Q9UPQ4 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-270974 LPAR3 protein Q9UBY5 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 12531543 t gcesareni "Lpa3couples to gq" SIGNOR-97400 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates activity" phosphorylation Tyr171 NNANYTEyVATRWYR -1 16935860 t miannu "Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif." SIGNOR-245876 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 MAPK1 protein P28482 UNIPROT RPS6KA1 protein Q15418 UNIPROT "up-regulates activity" phosphorylation 9606 12832467 t lperfetto "Efficient rsk activation by erk requires its interaction through a docking site located near the c terminus of rsk" SIGNOR-102645 N-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide chemical CHEBI:94063 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-257929 nintedanib chemical CHEBI:85164 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190305 Telatinib chemical CID:9808844 PUBCHEM KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207227 PRKCA protein P17252 UNIPROT VCL protein P18206 UNIPROT unknown phosphorylation Ser1101 NAQNLMQsVKETVRE -1 11741957 t lperfetto "PKC Phosphorylates Serines 1033 and 1045 in Helix H5" SIGNOR-249128 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 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0000938 BTO:0000142 11160424 t lperfetto "The mek1/2 inhibitors pd98059, sl327, and u0126 have been extensively used to implicate erk1/2 in neuroplasticity." SIGNOR-244930 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 ITCH protein Q96J02 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates ubiquitination 9606 BTO:0001253 10940313 t gcesareni "Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain." SIGNOR-80702 N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)-4-pyrimidinyl]amino]methyl]-2-pyridinyl]methanesulfonamide chemical CHEBI:91370 ChEBI PTK2 protein Q05397 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206067 PTK2 protein Q05397 UNIPROT ATP2B4 protein P23634-6 UNIPROT "up-regulates activity" phosphorylation Tyr1176 LDGEVTPyANTNNNA 9606 12540962 t miannu "Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif." SIGNOR-263194 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROD4 protein Q9HD90 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-254631 LCK protein P06239 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates 9606 17998336 f gcesareni "The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1." SIGNOR-159164 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 TNFRSF17 protein Q02223 UNIPROT MAPK11 protein Q15759 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79495 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 CDK5RAP2 protein Q96SN8 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19282672 t Giulio "These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter" SIGNOR-260313 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 "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 SAFB protein Q15424 UNIPROT FUS protein P35637 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 27731383 t "P35637:p.Pro525Leu (mutation disrupting interaction)" "SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription| In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif." SIGNOR-262821 FYN protein P06241 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-249340 PRKACA protein P17612 UNIPROT GLIS2 protein Q9BZE0 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000938 16537363 t lperfetto "Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity" SIGNOR-145131 MUTYH protein Q9UIF7 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates binding 9606 BTO:0000007 21615992 t miannu "Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis." SIGNOR-173972 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 22798428 t gcesareni "Akt negatively regulates the raf and gsk-3 kinases and the cell cycle regulatory transcription factor fkhr." SIGNOR-252531 HRK protein O00198 UNIPROT BCL2 protein P10415 UNIPROT down-regulates binding 9606 9130713 t gcesareni "Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1." SIGNOR-47794 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 RUNX1 protein Q01196 UNIPROT "Core Binding Factor complex" complex SIGNOR-C214 SIGNOR "form complex" binding 9606 12495904 t irozzo "The core binding factor (CBF) transcription complex, consisting of the interacting proteins RUNX1 and CBFβ, is essential for normal hematopoiesis" SIGNOR-255710 SPX protein Q9BT56 UNIPROT GALR2 protein O43603 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24517231 t lperfetto "Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III." SIGNOR-268574 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR ASB2 protein Q96Q27 UNIPROT "up-regulates activity" phosphorylation Ser371 RIRRSGVsPLHLAAE 24044920 t lperfetto "Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation." SIGNOR-272239 EIF1 protein P41567 UNIPROT 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-269161 doramapimod chemical CHEBI:40953 ChEBI TNF protein P01375 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190335 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 EXTL1 protein Q92935 UNIPROT SHH protein Q15465 UNIPROT down-regulates binding 9606 BTO:0000142 15614771 t gcesareni "A study in mice suggests that ext1 proteins might negatively regulate shh signaling by synthesizing hspgs, which sequester the ligand" SIGNOR-132606 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 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 GSK690693 chemical CHEBI:90677 ChEBI AKT3 protein Q9Y243 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193006 SP1 protein P08047 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10669635 f lperfetto "These results suggest that PMA stimulates transcription of the Mn-SOD gene through an increase in Sp1 expression and thus implicate Sp1 as an effector mediating the PKC-signaling pathway elicited by extracellular signals." SIGNOR-271693 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 FASN protein P49327 UNIPROT WNT1 protein P04628 UNIPROT "up-regulates activity" 9606 18838960 f lperfetto "Overexpression of fatty acid synthase is associated with palmitoylation of Wnt1 and cytoplasmic stabilization of beta-catenin in prostate cancer" SIGNOR-242881 N-(cyanomethyl)-4-[2-[4-(4-morpholinyl)anilino]-4-pyrimidinyl]benzamide chemical CHEBI:91407 ChEBI JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191247 PTPRF protein P10586 UNIPROT FYN protein P06241 UNIPROT down-regulates dephosphorylation Tyr420 RLIEDNEyTARQGAK 9606 12496362 t lperfetto "Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule." SIGNOR-96768 SIRT1 protein Q96EB6 UNIPROT XPA protein P23025 UNIPROT "up-regulates activity" deacetylation Lys67 ANVKAAPkIIDTGGG 9606 BTO:0002806 30327428 t miannu "SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR" SIGNOR-262294 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 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 CEP43 protein O95684 UNIPROT MAPRE1 protein Q15691 UNIPROT up-regulates relocalization 9606 16314388 t miannu "Fop also binds to eb1 and is required for localizing eb1 to the centrosome" SIGNOR-142400 NGFR protein P08138 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14699954 f amattioni "Neurotrophin binding to p75ntr has also been shown to induce apoptosis" SIGNOR-256655 MAPK1 protein P28482 UNIPROT LIFR protein P42702 UNIPROT down-regulates phosphorylation Ser1044 WNLVSPDsPRSIDSN 9606 7777512 t gcesareni "Indeed, phosphorylation of the cytoplasmic domain of the low-affinity lif receptor alpha-subunit (lifr) in mono q-fractionated, lif-stimulated 3t3-l1 extracts occurred only in those fractions containing activated mapk;ser-1044 served as the major phosphorylation site in the human lifr for mapk both in agonist-stimulated 3t3-l1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro" SIGNOR-32753 "glutamic acid" smallmolecule CHEBI:18237 ChEBI MGluR proteinfamily SIGNOR-PF55 SIGNOR "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-264688 TP53 protein P04637 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 15077116 t gcesareni "P53 interacts with the pro-apoptotic mitochondrial membrane protein bak" SIGNOR-124122 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 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 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 PIP3 smallmolecule CHEBI:16618 ChEBI PDPK1 protein O15530 UNIPROT "up-regulates activity" "chemical activation" -1 9094314 t gcesareni "We tested the kinase in the presence of several inositol phospholipids and found that only low micromolar concentrations of the D enantiomers of either phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) or PtdIns(3,4)P2 were effective in potently activating the kinase, which has been named PtdIns(3,4,5)P3-dependent protein kinase-1 (PDK1)" SIGNOR-243274 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 5-Fluoro-8-hydroxy-2-(dipropylamino)tetralin chemical CID:122187 PUBCHEM 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-258865 LYN protein P07948 UNIPROT SLAMF1 protein Q13291 UNIPROT unknown phosphorylation Tyr327 ETNSITVyASVTLPE 9606 15315965 t llicata "Cd150-mediated akt phosphorylation required syk and sh2d1a, was negatively regulated by lyn and btk, but was ship independent. Lyn directly phosphorylated y327 in cd150, but the akt pathway did not depend on cd150 tyrosine phosphorylation and cd150-shp-2 association." SIGNOR-127997 UCHL5 protein Q9Y5K5 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" deubiquitination 9606 16027725 t lperfetto "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases" SIGNOR-232101 MAPK3 protein P27361 UNIPROT PLA2G4A protein P47712 UNIPROT up-regulates phosphorylation Ser505 LNTSYPLsPLSDFAT 9606 8381049 t 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-38434 RET protein P07949 UNIPROT MAPK1 protein P28482 UNIPROT up-regulates phosphorylation Tyr187 HTGFLTEyVATRWYR 9606 16153436 t gcesareni "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-140294 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 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 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 FBXL18 protein Q96ME1 UNIPROT FBXL7 protein Q9UJT9 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002268 25654763 t miannu "F-box protein Fbxl18 mediates polyubiquitylation and proteasomal degradation of the pro-apoptotic SCF subunit Fbxl7.. Here, we identified that an orphan F-box protein, Fbxl18, targets Fbxl7 for its polyubiquitylation and proteasomal degradation. Lys 109 within Fbxl7 is an essential acceptor site for ubiquitin conjugation by Fbxl18." SIGNOR-272448 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 SOX17 protein Q9H6I2 UNIPROT GLI2 protein P10070 UNIPROT up-regulates 10090 33083751 f SimoneGraziosi "Sox17 ablation lowered endogenous Gli2 and Olig2+ cells" SIGNOR-269218 PBX2 protein P40425 UNIPROT EMX2 protein Q04743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15494461 f miannu "EMSA demonstrated HOXA10-Pbx2 binding as a heterodimer to an enhancer of the EMX2 gene, a known target of HOXA10 regulation." SIGNOR-254466 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 PPP2CA protein P67775 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" dephosphorylation Thr308 KDGATMKtFCGTPEY 10090 BTO:0000944 15367694 t "Protein phosphatase 2A negatively regulates insulin's metabolic signaling pathway by inhibiting Akt (protein kinase B) activity in 3T3-L1 adipocytes" SIGNOR-248629 F2 protein P00734 UNIPROT LRP1 protein Q07954 UNIPROT up-regulates binding 9606 8626456 t gcesareni "In vitro binding studies revealed that antithrombin iii (atiii)thrombin, heparin cofactor ii (hcii)thrombin, and ?1-antitrypsin (?1AT)trypsin bound to purified lrp" SIGNOR-41090 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9534 12387817 t lperfetto "Thus, it was suggested that NHERF2 mediates the activation and phosphorylation of SGK1 by PDK1 through its first PDZ domain and PIF motif, as a novel SGK1 activation mechanism." SIGNOR-236800 STAT5A protein P42229 UNIPROT SOCS2 protein O14508 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12468433 t "We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling" SIGNOR-261547 canertinib chemical CHEBI:61399 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191012 FOXO3 protein O43524 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-256645 NOTCH proteinfamily SIGNOR-PF30 SIGNOR RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding BTO:0001103 22045613 t svumbaca "NICD is translocated to the nucleus where it binds recombining binding protein-Jj (RBP-Jj)" SIGNOR-255364 SLC9A4 protein Q6AI14 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-265594 BCL2L11 protein O43521 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 22492984 t gcesareni "Bim, and puma bind with high affinity to all pro-survival proteins" SIGNOR-196932 SLC9A7 protein Q96T83 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-265606 DCAF12 protein Q5T6F0 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0002806 31267705 t miannu " The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6" SIGNOR-272264 Ub:E2 complex SIGNOR-C497 SIGNOR LNX2 protein Q8N448 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-271195 EGFR protein P00533 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000093 BTO:0000150 26918608 t lperfetto "p85alpha promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation." SIGNOR-33633 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000165 10066785 t lperfetto "Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis" SIGNOR-219359 RET protein P07949 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates phosphorylation Tyr182 TDDEMTGyVATRWYR 9606 7535770 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-28063 NHLRC1 protein Q6VVB1 UNIPROT AGL protein P35573 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 17908927 t miannu "The E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL." SIGNOR-271669 "Caspase 8 complex" complex SIGNOR-C231 SIGNOR Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 14585074 f amattioni "Downstream of caspase-8 activation, apoptosis induction takes place" SIGNOR-256641 ADAM10 protein O14672 UNIPROT NOTCH1 protein P46531 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000782 28624438 t miannu "ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development" SIGNOR-259838 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 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 HUWE1 protein Q7Z6Z7 UNIPROT MCL1 protein Q07820 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000093 28939105 t miannu "Mule was identified as Mcl-1 ubiquitin ligase E3 to promote Mcl-1 degradation via the proteasomal pathway [46]. We found that knockdown of Mule (Fig. 4C) but not β-TRCP or FBXW7 (data not shown) prevented Mcl-1 downregulation caused by PKCη depletion." SIGNOR-261909 MED14 protein O60244 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-266676 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 CALM3 protein P0DP25 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-266337 GTF3C3 protein Q9Y5Q9 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR "form complex" binding 9606 29378333 t lperfetto "Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains" SIGNOR-266186 JAK1 protein P23458 UNIPROT JAK3 protein P52333 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-152914 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 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 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-147199 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 "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 CAPN2 protein P17655 UNIPROT GSK3A protein P49840 UNIPROT "up-regulates activity" cleavage 9606 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-251612 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 SDCBP protein O00560 UNIPROT p38 proteinfamily SIGNOR-PF16 SIGNOR "up-regulates activity" 9534 BTO:0001444 25122212 f Luana "Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation." SIGNOR-260753 WNK3 protein Q9BYP7 UNIPROT WNK1 protein Q9H4A3 UNIPROT "up-regulates activity" phosphorylation Ser382 KRASFAKsVIGTPEF 9606 22032326 t Manara "We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro." SIGNOR-260789 FLT3 protein P36888 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates activity" phosphorylation Tyr969 VSECPHTyQNRRPFS 9606 31395582 t lperfetto "A mutation at tyrosine 969, which inhibits activation of downstream signaling by FLT3-ITD." SIGNOR-271919 CDKN1A protein P38936 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 24470334 f "The cell cycle regulator p21 is induced early in myoblast differentiation and functions to block cell cycle progression" SIGNOR-267286 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 ATP(4-) smallmolecule CHEBI:30616 ChEBI ADP(3-) smallmolecule CHEBI:456216 ChEBI "up-regulates quantity" "precursor of" 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-269098 "AL/b2 integrin" complex SIGNOR-C169 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-269018 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 MAPK9 protein P45984 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 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-250136 PFKM protein P08237 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "down-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-266467 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 SUCLG1 protein P53597 UNIPROT "Succinyl-CoA GTP variant" complex SIGNOR-C399 SIGNOR "form complex" binding 9606 32627745 t miannu "Succinyl-CoA synthetase (SCS) catalyzes the only substrate-level phosphorylation in the tricarboxylic acid cycle.  In mammals, SCS is a mitochondrial enzyme and is an α,β-heterodimer with different isoforms: ATP-specific SCS (ATPSCS) and GTP-specific SCS (GTPSCS)." SIGNOR-266263 tri-mu-sulfido-mu3-sulfido-triiron chemical CHEBI:21137 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-267734 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 CDKL5 protein O76039 UNIPROT CDKL5 protein O76039 UNIPROT "up-regulates activity" phosphorylation Thr169 EGNNANYtEYVATRW -1 16935860 t gcesareni "Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif." SIGNOR-262289 IGF2 protein P01344 UNIPROT INSR protein P06213 UNIPROT up-regulates binding 9606 9281335 t fspada "Therefore, these results provide genetic evidence that the growth-promoting function of igf-ii during mouse embryogenesis is mediated in part by signaling through the insulin receptor." SIGNOR-50719 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 14699505 t gcesareni "Pias1 inhibits binding of stat1 dimers to the response elements in the promoters of target genes" SIGNOR-120548 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 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 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Gln) smallmolecule CHEBI:29168 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-269485 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 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 NTS protein P30990 UNIPROT NTSR2 protein O95665 UNIPROT down-regulates binding 9606 BTO:0000975 9851594 t gcesareni "Neurotensin binding to recombinant neurotensin nt2 receptor expressed in cho cells does not elicit a biological response as determined by second messenger measurements." SIGNOR-62519 UBASH3B protein Q8TF42 UNIPROT CBL protein P22681 UNIPROT down-regulates binding 9606 15159412 t gcesareni "Sts-1 and sts-2 contain sh3 domains that interacted with cbl, ub-associated domains, which bound directly to mono-ub or to the egfr/ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of sts-1/2. Ligand-induced recruitment of sts-1/sts-2 into activated egfr complexes led to inhibition of receptor internalization, reduction in the number of egfr-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways." SIGNOR-124897 SH3GLB1 protein Q9Y371 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 11894095 t gcesareni "Cbl rapidly recruits cin85 (cbl-interacting protein of 85k;ref. 6) and endophilins (regulatory components of clathrin-coated vesicles) to form a complex with activated egf receptors, thus controlling receptor internalization." SIGNOR-115826 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Ser360 TEMDPTYsPAALPQS 9606 18267068 t lperfetto "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-249572 ENMD-2076 chemical CID:16041424 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191466 PHA-680632 chemical CID:11249084 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206103 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 PIAS1 protein O75925 UNIPROT PRDM1 protein O75626 UNIPROT up-regulates sumoylation Lys816 PLVPVKVkQETVEPM 9606 22555612 t miannu "Blimp_1 is subjected to pias1_mediated sumoylation at lysine 816 / it appears that sumo_modified blimp_1 is a more potent transcriptional repressor." SIGNOR-197265 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 CSNK1D protein P48730 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT up-regulates phosphorylation Ser601 SDKESKEsSVEGAEN 9606 BTO:0000150 19339517 t lperfetto "In this study, we show that both eralpha and aib1 are substrates for ck1delta in vitro, and identify a novel aib1 phosphorylation site (s601) targeted by ck1delta, significant for the co-activator function of aib1." SIGNOR-184946 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 20463034 t Gianni "We show that loss of suppressor of fused (Sufu; an inhibitory effector for Gli proteins) results in destabilization of Gli2 and Gli3 full-length activators but not of their C-terminally processed repressors, whereas overexpression of Sufu stabilizes them." SIGNOR-268867 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 SUFU protein Q9UMX1 UNIPROT GLI2 protein P10070 UNIPROT "down-regulates activity" relocalization 10090 16316410 t lperfetto "We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms" SIGNOR-129065 CHEK2 protein O96017 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr288 SPDCDVKtDDSVVPC 9606 19151762 t llicata "Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir" SIGNOR-242665 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 DDX20 protein Q9UHI6 UNIPROT FOXL2 protein P58012 UNIPROT up-regulates binding 9606 BTO:0000975 16153597 t miannu "Dp103 further increased the cell killing effect induced by foxl2 probably due to the direct association of dp103 with foxl2 protein." SIGNOR-140388 sapitinib chemical CHEBI:132986 ChEBI ERBB3 protein P21860 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190155 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 PRKCA protein P17252 UNIPROT MET protein P08581 UNIPROT down-regulates phosphorylation Ser985 PHLDRLVsARSVSPT 9606 8294430 t fstefani "These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor." SIGNOR-37718 PPM1F protein P49593 UNIPROT PAK1 protein Q13153 UNIPROT down-regulates dephosphorylation 9606 20016286 t gcesareni "Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity." SIGNOR-162146 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 "PH 797804" chemical CHEBI:82715 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206079 "2-[[(1R)-1-[7-methyl-2-(4-morpholinyl)-4-oxo-9-pyrido[1,2-a]pyrimidinyl]ethyl]amino]benzoic acid" chemical CHEBI:91359 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190200 SP2 protein Q02086 UNIPROT IRF1 protein P10914 UNIPROT "up-regulates activity" binding 9606 BTO:0000552 19482358 t miannu "Sp2 could be also able to interact with IRF-1 and this interaction is also observed on DNA indicating that by this way Sp2 is able to modulate IRF-1 transcriptional activity." SIGNOR-226478 PTPN6 protein P29350 UNIPROT JAK3 protein P52333 UNIPROT up-regulates dephosphorylation 9606 11021818 t gcesareni "The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase." SIGNOR-82764 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser262 TFRPRSSsNASSVST 10090 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-252839 sunitinib chemical CHEBI:38940 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 21423276 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-172908 AKT1 protein P31749 UNIPROT BRAF protein P15056 UNIPROT "down-regulates activity" phosphorylation Ser365 GQRDRSSsAPNVHIN 9606 10869359 t "Akt phosphorylates both S364 and S428. Akt downregulates B-Raf activity in vivo" SIGNOR-251471 EGFR protein P00533 UNIPROT NCK1 protein P16333 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 1333047 t "We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues" SIGNOR-252089 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 TNFRSF17 protein Q02223 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79498 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 NCKIPSD protein Q9NZQ3 UNIPROT NCK1 protein P16333 UNIPROT unknown binding 9606 14559906 t gcesareni "Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck" SIGNOR-118750 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser181 YQPRRRKsVKNGQAE 9606 15889150 t llicata "We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta." SIGNOR-137085 CAMTA1 protein Q9Y6Y1 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0005397 21385898 f irozzo "Our findings define properties of CAMTA1 in growth suppression and neuronal differentiation that support its assignment as a 1p36 tumor suppressor gene in neuroblastoma." SIGNOR-259099 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 KLHL7 protein Q8IXQ5 UNIPROT TUT1 protein Q9H6E5 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000675 29032201 t miannu "Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity." SIGNOR-272318 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 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 12789342 t gcesareni "Ikk-alpha interacts with creb-binding protein and in conjunction with rel a is recruited to nf-kappab-responsive promoters and mediates the cytokine-induced phosphorylation and subsequent acetylation of specific residues in histone h3." SIGNOR-101539 SP1 protein P08047 UNIPROT NDUFV1 protein P49821 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000931 17786189 f miannu "Sp1 role in the regulation of complex I subunits, was demonstrated by the ability of the Sp1/DNA binding inhibitor, mithramycin, to inhibit the transcription of NDUFV1 and NDUFV2, in neuroblastoma cells. In addition, Sp1 activated NDUFV2 promoter by binding to its three GC-boxes. Both activation and binding were inhibited by mithramycin." SIGNOR-255206 SH3GL1 protein Q99961 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-263885 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 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 tetrabenazine chemical CHEBI:9467 ChEBI SLC18A2 protein Q05940 UNIPROT "down-regulates activity" "chemical inhibition" 9606 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-258491 YAP1 protein P46937 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-199217 KAT8 protein Q9H7Z6 UNIPROT FASN protein P49327 UNIPROT "down-regulates quantity by destabilization" acetylation 9606 BTO:0000007 27758890 t "Overexpression of Myc-KAT8 increased the acetylation level of endogenous FASN by 2.2-fold (Fig. 3C). In contrast, knockdown of KAT8 decreased endogenous FASN acetylation by as much as 55%" SIGNOR-267366 AKT1 protein P31749 UNIPROT ATXN1 protein P54253 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser775 ATRKRRWsAPESRKL 9606 BTO:0000567 12757707 t "Interaction of Ataxin-1 and 14-3-3 Requires Akt Phosphorylation at S776. 14-3-3 protein, a multifunctional regulatory molecule, mediates the neurotoxicity of ataxin-1 by binding to and stabilizing ataxin-1, thereby slowing its normal degradation." SIGNOR-252561 RPS6K proteinfamily SIGNOR-PF26 SIGNOR MTOR protein P42345 UNIPROT "down-regulates activity" phosphorylation Ser2448 RSRTRTDsYSAGQSV 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-137251 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 PRKCD protein Q05655 UNIPROT DAB2 protein P98082 UNIPROT down-regulates phosphorylation Ser24 QAAPKAPsKKEKKKG 9606 10542228 t gcesareni "Mutational analysis revealed that a dab2 ser(24) phosphorylation mutant (s24a) abrogated the inhibitory function of dab2." SIGNOR-71764 GMPS protein P49915 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 24462112 t miannu "In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex." SIGNOR-204409 ADAM17 protein P78536 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 20626350 f gcesareni "Such phosphorylation is required for tace mediated ectodomain shedding of tgfalfa family ligands, which results in the activation of egfr and cell proliferation." SIGNOR-166568 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 AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192814 FLT3 protein P36888 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 10090 18192505 f "Inhibition of FLT3/ITD leads to a small decrease in RAC1 activity" SIGNOR-261536 Macrophage_activation phenotype SIGNOR-PH126 SIGNOR IL18 protein Q14116 UNIPROT "up-regulates quantity" 9606 BTO:0000801 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. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR engagement." SIGNOR-260964 GADD45GIP1 protein Q8TAE8 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-262385 haloperidol chemical CHEBI:5613 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-258521 PRKCA protein P17252 UNIPROT NR1H4 protein Q96RI1 UNIPROT up-regulates phosphorylation Ser164 CKGFFRRsITKNAVY 9606 18755856 t llicata "Phosphorylation of farnesoid x receptor by protein kinase c promotes its transcriptional activity. pkcalpha phosphorylates in vitro fxr in its dna-binding domain on s135 and s154." SIGNOR-180541 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 lysine smallmolecule CHEBI:25094 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-264755 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 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 CAMK2D protein Q13557 UNIPROT CAMK2D protein Q13557 UNIPROT up-regulates phosphorylation 9606 19725819 t areggio "Upon binding of the Ca2+/calmodulin complex to the binding domain of CaMKII, it is activated via autophosphorylation, then remaining active independent of of Ca2+ levels." SIGNOR-255954 ZDHHC2 protein Q9UIJ5 UNIPROT AKAP5 protein P24588 UNIPROT "up-regulates activity" palmitoylation Cys129 KSRLKIPcIKFPRGP 10116 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-261289 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 NDUFA11 protein Q86Y39 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)" SIGNOR-262142 TNFSF15 protein O95150 UNIPROT TNFRSF25 protein Q93038 UNIPROT up-regulates binding 9606 14585074 t amattioni "The ligand of dr3 is tl1a" SIGNOR-103078 RXRA protein P19793 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-81446 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 ACTR3 protein P61158 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-251513 estramustine chemical CHEBI:4868 ChEBI ESR2 protein Q92731 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-259299 "Vincristine sulfate" chemical CHEBI:79401 ChEBI TUBB4A protein P04350 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-259250 RET protein P07949 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 16153436 t "inferred from 70% of family members" gcesareni "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-269894 TNKS2 protein Q9H2K2 UNIPROT AXIN2 protein Q9Y2T1 UNIPROT "down-regulates quantity by destabilization" ADP-ribosylation 9606 BTO:0000007 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-263380 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 MT-CYB protein P00156 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-262193 SMAD3 protein P84022 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16766264 f irozzo "This protection is conferred by Smad3’s ability to promote apoptosis by repressing Bcl-2 transcription in vivo through a GC-rich element in the Bcl-2 promoter." SIGNOR-256294 UNC5D protein Q6UXZ4 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-268167 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 SYN1 protein P17600 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-264105 ACD protein Q96AP0 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-263329 MMP2 protein P08253 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-272387 "Raf265 derivative" chemical CID:23654923 PUBCHEM RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206394 PKC proteinfamily SIGNOR-PF53 SIGNOR PPP1R14B protein Q96C90 UNIPROT "up-regulates activity" phosphorylation Thr57 VRRQGKVtVKYDRKE 10606530 t lperfetto "Recombinant tagged PHI-1 was phosphorylated by protein kinase C at two sites, one a Ser and one a Thr; phosphorylation enhanced inhibitory potency 50-fold." SIGNOR-265740 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 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 WNK3 protein Q9BYP7 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT "down-regulates activity" phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 24043619 t Manara "WNK3, which inhibits the activity of KCC3, promoted phosphorylation of Ser-96 as well as Thr-991 and Thr-1048. " SIGNOR-260910 BTRC protein Q9Y297 UNIPROT CDC25A protein P30304 UNIPROT up-regulates ubiquitination 9606 SIGNOR-C5 15340381 t gcesareni "Scfb-trcp has recently been shown to degrade phosphorylated cdc25a in the s and g2 phases." SIGNOR-128436 SLC9A6 protein Q92581 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-265605 AKT1 protein P31749 UNIPROT FSTL1 protein Q12841 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18718903 f miannu "Akt1 Overexpression in Skeletal Muscle Increases Capillary Vessel Formation and Up-regulates Fstl1 Expression" SIGNOR-266605 MMP20 protein O60882 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-272388 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 CENPE protein Q02224 UNIPROT Spindle_assembly phenotype SIGNOR-PH60 SIGNOR up-regulates 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-252013 LIPH protein Q8WWY8 UNIPROT LPAR2 protein Q9HBW0 UNIPROT up-regulates binding 9606 BTO:0000661 9525886 t gcesareni "When overexpressed in jurkat t cells, the edg4 protein mediated lpa-induced activation of a serum response element reporter gene with lpa concentration dependence (ec50 of 10 nm) and specificity." SIGNOR-56093 FOXE1 protein O00358 UNIPROT TPO protein P07202 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001073 27347897 t scontino "TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8" SIGNOR-267279 MAPK6 protein Q16659 UNIPROT MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser189 YSHKGHLsEGLVTKW 9606 8621539 t lperfetto "Ser189 of erk3, which corresponds to thr183, one of the activating phosphorylation sites of erk2, is autophosphorylated in vitro and phosphorylated in vivo." SIGNOR-40097 XIAP protein P98170 UNIPROT CASP9 protein P55211 UNIPROT "down-regulates quantity by destabilization" binding 9606 11242052 t lperfetto "A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis" SIGNOR-105702 PRKAA1 protein Q13131 UNIPROT CRTC1 protein Q6UUV9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21331044 t gcesareni "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-172136 UBE2O protein Q9C0C9 UNIPROT SMAD6 protein O43541 UNIPROT down-regulates ubiquitination Lys173 LLLEQELkTVTYSLL 9606 23455153 t gcesareni "We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174" SIGNOR-192255 "hydrogen peroxide" smallmolecule CHEBI:16240 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto "The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment." SIGNOR-272278 BMP2 protein P12643 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates 9606 22298955 f lperfetto "Neogenin, a transmembranous protein, was reported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation." SIGNOR-195561 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 methionine smallmolecule CHEBI:16811 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-264750 olaparib chemical CHEBI:83766 ChEBI PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195016 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 ATP5F1D protein P30049 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-261402 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 USP36 protein Q9P275 UNIPROT FBL protein P22087 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 19208757 t lperfetto "USP36 deubiquitylated the nucleolar proteins nucleophosmin/B23 and fibrillarin, and stabilized them by counteracting ubiquitylation-mediated proteasomal degradation. " SIGNOR-272291 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 SKA1 protein Q96BD8 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-265197 KLHL25 protein Q9H0H3 UNIPROT ACLY protein P53396 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0002552 27664236 t miannu "Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. " SIGNOR-272333 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 PPARG protein P37231 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 BTO:0002572;BTO:0000011;BTO:0005065 16431920 f "Dislodging hdac1 from the promoter" lperfetto "These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome" SIGNOR-235358 belinostat chemical CHEBI:61076 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-257746 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 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 ULK1 protein O75385 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation 9606 SIGNOR-C15 21460634 t lperfetto "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity." SIGNOR-173047 PPARGC1A protein Q9UBK2 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887;BTO:0001103 17609368 f lperfetto "Furthermore, ampk directly phosphorylates pgc-1?, And this phosphorylation mediates an increase in pgc-1? Protein action on the pgc-1? Promoter." SIGNOR-156783 CSNK1E protein P49674 UNIPROT ROR2 protein Q01974 UNIPROT up-regulates phosphorylation 9606 15375164 t gcesareni "We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues." SIGNOR-129117 AKT1 protein P31749 UNIPROT ZFP36L1 protein Q07352 UNIPROT down-regulates phosphorylation Ser92 RFRDRSFsEGGERLL 9606 15538381 t llicata "Here we report that protein kinase b (pkb/akt) stabilizes are transcripts by phosphorylating brf1 at serine 92 (s92). Recombinant brf1 promoted in vitro decay of are-containing mrna (are-mrna), yet phosphorylation by pkb impaired this activity." SIGNOR-130376 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 U0126.EtOH chemical CHEBI:90692 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244961 SMURF2 protein Q9HAU4 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-153423 valine smallmolecule CHEBI:27266 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-264747 PTPN12 protein Q05209 UNIPROT BCAR1 protein P56945 UNIPROT down-regulates dephosphorylation 9606 BTO:0000782 11432829 t gcesareni "Ptp-pest is an efficient negative regulator of lymphocyte activation. This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway." SIGNOR-109032 HECTD3 protein Q5T447 UNIPROT CASP8 protein Q14790 UNIPROT "down-regulates activity" polyubiquitination Lys231 KVYQMKSkPRGYCLI 9606 BTO:0000007 24287696 t miannu "HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 ubiquitinates caspase-8 with K63-linked polyubiquitin chains at K215." SIGNOR-272077 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 ODC1 protein P11926 UNIPROT putrescine smallmolecule CHEBI:17148 ChEBI "up-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-256034 PMP22 protein Q01453 UNIPROT MPZ protein P25189 UNIPROT "up-regulates activity" binding 9606 10212299 t miannu "Our data provide the first direct evidence for the formation of P0–PMP22 complexes at the plasma membrane. These protein interactions probably participate in holding adjacent Schwann cell membranes together and in stabilizing myelin compaction." SIGNOR-251898 sunitinib chemical CHEBI:38940 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-258290 "Membrane attack complex" complex SIGNOR-C313 SIGNOR Cell_killing phenotype SIGNOR-PH149 SIGNOR up-regulates -1 30552328 f lperfetto "Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions." SIGNOR-263454 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 (~{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 miR-155 mirna URS000062749E_9606 RNAcentral INPP5D protein Q92835 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 24708856 t miannu "We found overexpression of miR-155 led to increase in cJUN, FOS and TRIB2, and decrease in MEIS1, GFI1, cMYC and JARID2." SIGNOR-255764 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 RIMS1 protein Q86UR5 UNIPROT UNC13B protein O14795 UNIPROT "up-regulates activity" relocalization 9606 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-264385 EEF1A2 protein Q05639 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-269533 MMP21 protein Q8N119 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-272389 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 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI ADRA1D protein P25100 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190642 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 MECP2 protein P51608 UNIPROT Neuron_maturation phenotype SIGNOR-PH169 SIGNOR up-regulates 10090 BTO:0000601 17532643 f Luana "Our studies suggest that MeCP2 plays a central role in neuronal maturation, which might be mediated through epigenetic control of expression pathways that are instrumental in both dendritic development and synaptogenesis." SIGNOR-264968 GSK3B protein P49841 UNIPROT CTNND1 protein O60716 UNIPROT unknown phosphorylation Ser252 MEGYRAPsRQDVYGP -1 12885254 t "GSK3beta selectively phosphorylates p120 on S252 and T310 in Vitro" SIGNOR-251234 CDK2 protein P24941 UNIPROT ZC3HC1 protein Q86WB0 UNIPROT down-regulates phosphorylation Ser395 PGLEVPSsPLRKAKR 9606 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-154051 SMAD3/SMAD4 complex SIGNOR-C9 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-242052 MMP24 protein Q9Y5R2 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-272391 MMP25 protein Q9NPA2 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-272392 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A1 protein P30531 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206960 SP1 protein P08047 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-255199 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 ERN1 protein O75460 UNIPROT OS9 protein Q13438 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18417469 f miannu "Here we characterize the function in ER quality control of two proteins derived from alternative splicing of the OS-9 gene. OS-9.1 and OS-9.2 are ubiquitously expressed in human tissues and are amplified in tumors. They are transcriptionally induced upon activation of the Ire1/Xbp1 ER-stress pathway." SIGNOR-261063 MMP26 protein Q9NRE1 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-272393 MMP27 protein Q9H306 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-272394 "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 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCB protein P05771 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191493 HMGCS2 protein P54868 UNIPROT acetyl-CoA smallmolecule CHEBI:15351 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-267658 TNFRSF17 protein Q02223 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates the p38 mapk" SIGNOR-79504 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 MMP3 protein P08254 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-272396 SMC3 protein Q9UQE7 UNIPROT MXD4 protein Q14582 UNIPROT "down-regulates activity" binding 9534 BTO:0000318 9528857 t 2 miannu "We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e€ects of Mad proteins on c-myc functions." SIGNOR-241284 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" phosphorylation Ser207 ISGYLVDsVAKTIDA 9606 BTO:0000007 11279118 t lperfetto "Suggesting that tao2 selectively activates mek3 and mek6 of the p38 pathway in intact cells" SIGNOR-106465 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 "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 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1616 TPQSPSYsPTSPSYS -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-248803 MMP7 protein P09237 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-272397 MMP8 protein P22894 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-272398 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 DDR1 protein Q08345 UNIPROT TM4SF1 protein P30408 UNIPROT "up-regulates activity" binding 30187813 t lperfetto "Gao et al have demonstrated that in metastatic breast cancer cell, DDR1 interacts with cell surface Transmembrane 4 L Six Family Member 1 (TM4SF1) and regulates tumor dormancy and reactivation [3]. The interaction between DDR1 and TM4SF1 is collagen dependent and control Protein Kinase C Alpha (PKCa) mediated downstream JAK-STAT signaling pathway [3] (Figure 3). Interestingly the data also showed that TM4SF1 failed to interact with DDR2. " SIGNOR-272400 TM4SF1 protein P30408 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 33015133 t lperfetto "TM4SF1 is a partner of DVL2 and positively modulates Wnt/beta-catenin signaling by enhancing DVL2-Axin interaction." SIGNOR-272402 DDR1 protein Q08345 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" relocalization 9615 BTO:0000837 16611743 t lperfetto "Overexpression of DDR1a/b increased the interaction of DDR1 with SHP-2 and up-regulated the tyrosine phosphatase activity of SHP-2." SIGNOR-272403 PTPN11 protein Q06124 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9615 BTO:0000837 16611743 t lperfetto "In addition, SHP-2 dephosphorylates tyrosine-phosphorylated Stat1/3/5A (Ohtani et al., 2000; Wu et al., 2002; Chen et al., 2003), and downregulates Stat3-mediated biological actions (Ohtani et al., 2000).|Inhibition of collagen-induced Stat3 tyrosine-705 (Stat3-p-Tyr)" SIGNOR-272404 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 JAK1 protein P23458 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 SIGNOR "form complex" binding 10090 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-235608 PRKCA protein P17252 UNIPROT GRIA2 protein P42262 UNIPROT unknown phosphorylation Ser683 TKEFFRRsKIAVFDK -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-248954 TARDBP protein Q13148 UNIPROT Protein_aggregates phenotype SIGNOR-PH142 SIGNOR "up-regulates quantity" 9606 BTO:0000312 22051914 f lperfetto "Pathological protein aggregates, identified as compact or skein-like ubiquitinated inclusions, are a cardinal feature of ALS.4–6 The identification of TDP-43 as the major protein constituent of these inclusions initi- ated a major shift in our understanding of the patho- biology of ALS" SIGNOR-262278 "PIK-75 Hydrochloride" chemical CID:45265864 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206211 USP20 protein Q9Y2K6 UNIPROT CLSPN protein Q9HAW4 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 25355518 t miannu "USP20 deubiquitinates and stabilizes Claspin." SIGNOR-272821 UBE2V1 protein Q13404 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 11057907 t lperfetto "We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin" SIGNOR-83603 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 pemetrexed chemical CHEBI:63616 ChEBI TYMS protein P04818 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205933 ATXN2L protein Q8WWM7 UNIPROT DDX6 protein P26196 UNIPROT unknown binding 9606 23209657 t miannu "Ataxin-2-like associates with known interaction partners of ataxin-2, the rna helicase ddx6" SIGNOR-199948 959122-11-3 chemical CID:24768261 PUBCHEM DGAT1 protein O75907 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205695 paroxetine chemical CHEBI:7936 ChEBI SLC6A4 protein P31645 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-257795 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1096 RYPNDSVyANWMLSP 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-121149 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 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR M1_polarization phenotype SIGNOR-PH54 SIGNOR up-regulates 9606 30060484 f miannu "The bacterial endotoxin LPS is a known agonist of TLR2 that activates the expression of proinflammatory cytokines and the phosphorylation of MAPKs and NFκB [49]. In addition, the activation of the MAPK and NFκB signaling cascades drive inflammation and macrophage polarization. " SIGNOR-249519 TRAF6 protein Q9Y4K3 UNIPROT RUSC1 protein Q9BVN2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19365808 t miannu " We demonstrated that NESCA and NEMO interact by their N-terminal region. Beside to NEMO, we revealed that NESCA directly associates to the E3 ubiquitin ligase TRAF6, which in turn catalyzes NESCA polyubiquitination. Finally, we demonstrated that NESCA overexpression strongly inhibits TRAF6-mediated polyubiquitination of NEMO. " SIGNOR-272774 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM50 protein Q86XT4 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-271190 SKP2 protein Q13309 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0003725 11439327 t miannu "We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line." SIGNOR-272575 SP3 protein Q02447 UNIPROT MAOB protein P27338 UNIPROT "down-regulates quantity by repression" "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-253870 STK11 protein Q15831 UNIPROT MARK2 protein Q7KZI7 UNIPROT up-regulates phosphorylation 9606 17573348 t gcesareni "Here we show in vitro that lkb1 phosphorylates and activates mark2" SIGNOR-156126 ATM protein Q13315 UNIPROT RNF40 protein O75150 UNIPROT up-regulates phosphorylation 9606 21763684 t gcesareni "E3 ubiquitin ligase, a heterodimeric complex of the ringfinger rfn20/rfn40 is phosphorylated by atm." SIGNOR-175003 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT up-regulates phosphorylation 9606 12591950 t gcesareni "Jnk phosphorylates two members of the bh3-only sub of bcl2-related proteins (bim and bmf)." SIGNOR-98399 "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 glucose chemical CHEBI:17234 ChEBI AMPK complex SIGNOR-C15 SIGNOR "down-regulates activity" 10090 BTO:0000222 18477450 f "Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK)." SIGNOR-256137 HAUS6 protein Q7Z4H7 UNIPROT NEDD1 protein Q8NHV4 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19029337 t miannu "FAM29A recruits NEDD1 to spindle MTs. Ectopically expressed NEDD1 and FAM29A interact with each other." SIGNOR-261421 RUVBL2 protein Q9Y230 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-269291 LRFN4 protein Q6PJG9 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000938 21736948 f miannu "The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation.SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons." SIGNOR-264092 CLASP1 protein Q7Z460 UNIPROT MAPRE1 protein Q15691 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15631994 t 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-265094 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A11 protein P48066 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206990 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 FAS protein P25445 UNIPROT MAP3K5 protein Q99683 UNIPROT up-regulates binding 9606 11495919 t amattioni "Ask1 binds fas" SIGNOR-109676 DTL protein Q9NZJ0 UNIPROT TDG protein Q13569 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24962565 t miannu "TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner" SIGNOR-272847 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192901 CDK19 protein Q9BWU1 UNIPROT PAK1 protein Q13153 UNIPROT unknown phosphorylation Ser174 TPAVPPVsEDEDDDD 9606 19520772 t llicata "Here, we identified p21 activated kinase 1 (pak1) as a new cdk11(p58) substrate and we mapped a new phosphorylation site of ser174 on pak1" SIGNOR-185000 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Thr387 RTQTVRGtLAYLPEE -1 11960013 t "In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4." SIGNOR-251330 ACLY protein P53396 UNIPROT "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI "down-regulates quantity by destabilization" "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-268081 WNT7B protein P56706 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 22944199 f gcesareni "In explant cultures of mouse paraxial mesoderm, wnt1 induced expression of the mrf myf5, whereas wnt7a or wnt6 preferentially activated the mrf myod." SIGNOR-198925 PKI-587 chemical CID:44516953 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252650 SMO protein Q99835 UNIPROT GNB1 protein P62873 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-199174 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR TDG protein Q13569 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 24962565 t miannu "TDG Is Polyubiquitinated by CRL4Cdt2 E3 Ubiquitin Ligase in a PIP Degron-dependent Manner" SIGNOR-272849 MDM2 protein Q00987 UNIPROT PBXIP1 protein Q96AQ6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000093 24488098 t miannu ". Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. " SIGNOR-272850 NUP54 protein Q7Z3B4 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-262078 "Caspase 6 complex" complex SIGNOR-C228 SIGNOR LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 t amattioni "Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis." SIGNOR-256457 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-267846 MRPL42 protein Q9Y6G3 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-262354 "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 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-263775 PCDHAC2 protein Q9Y5I4 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-269038 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr319 TSVYESPySDPEELK 8798643 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-43659 Ub:E2 complex SIGNOR-C497 SIGNOR RNF217 protein Q8TC41 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-270951 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000007 19609947 t lperfetto "Our data suggest that the stimulation of nfkb by akt is dependent on the phosphorylation of p65 at s534, mediated by ikk (ikb kinase) alfa and beta." SIGNOR-216365 1124329-14-1 chemical CID:56973724 PUBCHEM TTK protein P33981 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190137 Guanabenz chemical CHEBI:5553 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-258909 CREB1 protein P16220 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-253791 FSTL1 protein Q12841 UNIPROT DIP2A protein Q14689 UNIPROT "up-regulates activity" binding 9606 BTO:0005562 20054002 t miannu "We identified DIP2A as a novel FSTL1-binding partner from the membrane fraction of endothelial cells. Co-immunoprecipitation assays revealed a direct physical interaction between FSTL1 and DIP2A. The work in the current study identifies DIP2A as a novel receptor for FSTL1 that mediates Akt activation and cell survival and function in cardiovascular cells in vitro." SIGNOR-266603 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 KREMEN2 protein Q8NCW0 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 12050670 t gcesareni "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. Kremen2 forms a ternary complex with dkk1 and lrp6, and induces rapid endocytosis and removal of the wnt receptor lrp6 from the plasma membrane." SIGNOR-88894 PSMC6 protein P62333 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-263370 SPP1 protein P10451 UNIPROT "A9/b1 integrin" complex SIGNOR-C166 SIGNOR "up-regulates activity" binding 9606 24241034 t lperfetto "Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C." SIGNOR-253311 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 CRP protein P02741 UNIPROT IL10 protein P22301 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 16917108 f Regulation miannu "CRP significantly decreased IL-10 mRNA stability" SIGNOR-251825 SIRT5 protein Q9NXA8 UNIPROT GLS protein O94925 UNIPROT "up-regulates activity" binding 9606 BTO:0006301 30910998 t Monia "Immunoprecipitation assays of interaction between GLS and SIRT5 in HepG2 cells infected with lentivirus containing empty or BAG3 construct. Ectopic BAG3 expression decreases the interaction between GLS and SIRT5. It has been reported that SIRT5 is responsible for desuccinylation of GLS35, immunoprecipitation (IP) was then performed." SIGNOR-261207 MK-2461 chemical CID:44137946 PUBCHEM MST1R protein Q04912 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194387 IFNW1 protein P05000 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 t gcesareni "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-105979 MAPK3 protein P27361 UNIPROT METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser525 YGMIERLsPGTRKIE 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-265947 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PPARG protein P37231 UNIPROT "up-regulates quantity by expression" phosphorylation 10090 BTO:0000011 12270934 t lperfetto "Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression." SIGNOR-235334 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 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation Ser1219 DDTESLHsQGEEEFD 9606 22621922 t gcesareni "Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm." SIGNOR-197611 EP400 protein Q96L91 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-269289 STK3 protein Q13188 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-175801 trametinib chemical CHEBI:75998 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192823 CAD protein P27708 UNIPROT CAD protein P27708 UNIPROT "up-regulates activity" phosphorylation Thr1037 QQCRVLGtSPEAIDS -1 11986331 t llicata "Autophosphorylation resulted in a 2-fold increase in CPSase activity, an increased sensitivity to the feedback inhibitor UTP, and decreased allosteric activation by 5-phosphoribosyl-1-pyrophosphate" SIGNOR-250610 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Thr47 GTESEMEtPSAINGN 9606 10617621 t lperfetto "Sapk phosphorylates bcl-x(l) on threonine 47 (thr-47) and threonine 115 (thr-115) in vitro and in vivo. In contrast to wild-type bcl-x(l), a mutant bcl-x(l) with the two threonines substituted by alanines (ala-47, ala-115) is a more potent inhibitor of ionizing radiation-induced apoptosis" SIGNOR-73642 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 Ub:E2 complex SIGNOR-C497 SIGNOR ARIH1 protein Q9Y4X5 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-271012 PLK3 protein Q9H4B4 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr69 SVIVADQtPTPTRFL 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-170004 ADRB2 protein P07550 UNIPROT GNAS protein Q5JWF2 UNIPROT "up-regulates activity" binding 9606 14500986 t "We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum." SIGNOR-256149 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 12105215 t lperfetto "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-216686 NPM1 protein P06748 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003081;BTO:0000849 30616754 t lperfetto "For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma" SIGNOR-267594 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 SPAG9 protein O60271 UNIPROT MAP3K5 protein Q99683 UNIPROT unknown binding 10090 BTO:0000165;BTO:0000222;BTO:0002181 SIGNOR-C21 22337877 t lperfetto "Cdo and jlp interacted with ask1 or tak1 in 293t cells and c2c12 myoblasts" SIGNOR-235545 S1PR3 protein Q99500 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-70713 GLI1 protein P08151 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23074268 f gcesareni "Canonical hh signaling plays an essential role in cell proliferation throught introduction of the genes encoding cyclin d1 and n-myc" SIGNOR-199126 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 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 AMP smallmolecule CHEBI:456215 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-269468 AKT2 protein P31751 UNIPROT TSC2 protein P49815 UNIPROT down-regulates phosphorylation Thr1462 GLRPRGYtISDSAPS 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-91392 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 HES1 protein Q14469 UNIPROT DTX1 protein Q86Y01 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000970 20208568 f gcesareni "The notch target gene hes1 causes transcriptional inhibition of deltex1 by directly binding to the promoter of deltex1." SIGNOR-164071 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 "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 "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 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 INTS9 protein Q9NV88 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-261471 SMAD7 protein O15105 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates 9606 17438144 f gcesareni "Smad7 repressed smad3/4-, smad2/4-, and smad1/4-enhanced reporter gene expression." SIGNOR-154390 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 HES1 protein Q14469 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 25234168 t "We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity." SIGNOR-261563 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 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 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 "Av/b5 integrin" complex SIGNOR-C178 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-269027 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 PRKCA protein P17252 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Ser48 RQGGRTSsQRQRDPE 9606 BTO:0001130 11980664 t llicata "Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ ." SIGNOR-86723 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 CBX4 protein O00257 UNIPROT ZEB2 protein O60315 UNIPROT "down-regulates quantity by destabilization" sumoylation Lys391 QTGLLKIkTEPLDFN 9534 16061479 t Luisa "Pc2 can act directly as an E3 ligase for SIP1 sumoylation.SIP1 sumoylation having a negative effect on its repression of E-cadherin transcription." SIGNOR-268955 DRD2 protein P14416 UNIPROT GNB5 protein O14775 UNIPROT "up-regulates activity" binding 9606 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-264993 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 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 CD28 protein P10747 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7737275 t fspada "In this study, we demonstrate that the co-stimulatory antigen cd28 binds to grb-2 by means of a cytoplasmic pymnm motif, which is the same motif bound by pi 3-kinase." SIGNOR-32509 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 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 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT "up-regulates activity" binding 9606 16977332 t lperfetto "Apaf-1 exists in an inactive conformation in cells and is activated through binding to cytochrome c and dATP." SIGNOR-149574 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 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-161613 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 SOX9 protein P48436 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15240568 f "SOX9 represses the expression of the CDX2 transcription factor, known to be mostly active in villus cells." SIGNOR-253322 ABL1 protein P00519 UNIPROT UBE3A protein Q05086 UNIPROT "down-regulates activity" phosphorylation Tyr659 GDSHPVLyQSLKDLL 9606 23581475 t Manara "Our results suggest that c-Abl protects p53 from HPV-E6-E6AP complex-mediated degradation by phosphorylating E6AP and impairing its E3 ligase activity" SIGNOR-260930 Laminin-10 complex SIGNOR-C182 SIGNOR Laminin-10 complex SIGNOR-C182 SIGNOR "up-regulates activity" binding 10090 BTO:0001086 18757303 t 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-253277 HK1 protein P19367 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-266445 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 SIRT1 protein Q96EB6 UNIPROT FOXL2 protein P58012 UNIPROT down-regulates deacetylation 9606 19010791 t miannu "We find that foxl2 activity is repressed by the sirt1 deacetylase." SIGNOR-182306 873837-23-1 chemical CID:46930994 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190470 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 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-258268 PTPN11 protein Q06124 UNIPROT GAB1 protein Q13480 UNIPROT down-regulates dephosphorylation Tyr627 KGDKQVEyLDLDLDS 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-236262 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser283 NLQMLPEsEDEESYD 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-40502 YAP1 protein P46937 UNIPROT FBXO32 protein Q969P5 UNIPROT down-regulates 9606 BTO:0000222;BTO:0002314 BTO:0000887;BTO:0001103 23038772 f gcesareni "The downregulation of fbox32 expression by high yap activity in activated satellite cells may contribute to sustaining high levels of myod in activated satellite cells." SIGNOR-199069 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 GNA12 protein Q03113 UNIPROT ARHGEF12 protein Q9NZN5 UNIPROT "up-regulates activity" binding 10090 12024019 t "P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation." SIGNOR-256522 PHF3 protein Q92576 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 34667177 t miannu "PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2" SIGNOR-266964 MYOG protein P15173 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR up-regulates binding 9606 BTO:0001103 17194702 t lperfetto "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-217740 LAMB1 protein P07942 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-253233 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF5 protein O00463 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-271084 TFAP2B protein Q92481 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" binding 9606 21556774 t miannu "These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53." SIGNOR-255422 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 CDK8 protein P49336 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR 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-254312 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Val72 GLTEYRLvSINKSSP -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-263579 ASH1L protein Q9NR48 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000942 27229316 t Gianni "Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning." SIGNOR-269056 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 REST protein Q13127 UNIPROT PENK protein P01210 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21832040 f miannu "HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK)." SIGNOR-255074 PGD protein P52209 UNIPROT 6-phospho-D-gluconate smallmolecule CHEBI:16863 ChEBI "down-regulates quantity" "chemical modification" 9606 34775382 t miannu "6 PG undergoes oxidative decarboxylation by 6-phosphogluconate dehydrogenase (6PGD) producing Ru5P and the second NADPH molecule." SIGNOR-267060 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 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 "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 FOXN3 protein O00409 UNIPROT PIM2 protein Q9P1W9 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002552 24403608 t Luana "CHES1/FOXN3 regulates cell proliferation by repressing PIM2 and protein biosynthesis." SIGNOR-261607 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 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 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 IRS2 protein Q9Y4H2 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0004087 24811175 t lperfetto "Insulin receptor substrate 1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate PI3K, only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells." SIGNOR-252696 HNF1B protein P35680 UNIPROT ALB protein P02768 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1673926 f Regulation miannu "VHNF1 transactivated the albumin promoter in transfection experiments" SIGNOR-251930 ABL1 protein P00519 UNIPROT PLSCR1 protein O15162 UNIPROT unknown phosphorylation Tyr74 PVYNQPVyNQPVGAA 9606 11390389 t Manara "Our data establish that the Abl SH3 domain binds to the N-terminal proline-rich segment of PLSCR1 and that ABL1 phosphorylates Tyr residues of the PLSCR1 polypeptide, most likely Tyr69 and Tyr74 within the tandem repeat sequence" SIGNOR-260808 DDB2 protein Q92466 UNIPROT DDB2/DDB1 complex SIGNOR-C39 SIGNOR "form complex" binding 9606 9418871 t miannu "Ddb was identified as a heterodimeric protein (48 and 127 kda) that binds to uv-damaged dna" SIGNOR-54099 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 IL27 protein Q8NEV9 UNIPROT IL27RA protein Q6UWB1 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0000876 14764690 t gcesareni "Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27." SIGNOR-121799 AGRP protein O00253 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" binding 9606 10318826 t miannu "AGRP is a potent antagonist of the melanocortin-3 receptor and the MC4R and has also been shown to have a lesser degree of inhibitory action at the melanocortin-5 receptor." SIGNOR-252379 TLR4 protein O00206 UNIPROT TLR4 protein O00206 UNIPROT up-regulates binding 9606 24352680 t fstefani "Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain" SIGNOR-203484 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 CD40 protein P25942 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000782;BTO:0000776 19904719 f fstefani "Cd40 has been found to be essential in mediating a broad variety of immune and inflammatory responses including t cell-dependent immunoglobulin class switching, memory b cell development" SIGNOR-189109 PRKACA protein P17612 UNIPROT CACNA1C protein Q13936 UNIPROT "up-regulates activity" phosphorylation Ser1897 LLRKANPsRCHSRES 10090 28119464 t "These findings reveal an essential role for _1C phosphorylation at Ser1928 in stimulating CaV1.2 channel activity and vasoconstriction by AKAP-targeted PKA upon exposure to increased glucose and in diabetes" SIGNOR-251709 SMARCB1 protein Q12824 UNIPROT SMARCA4 protein P51532 UNIPROT "up-regulates activity" 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-65438 CEBPB protein P17676 UNIPROT GOT1 protein P17174 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 8454627 t "In cotransfection experiments, the C/EBP beta protein trans-activated 10-15-fold the cAspAT gene promoter in HepG2 cells. Deletion studies revealed that regions P2 and P4 are critical for promoter activity. In gel retardation experiments, the P4 region bound different C/EBP-related proteins in different tissues" SIGNOR-254051 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 BPTF protein Q12830 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-268817 F2RL1 protein P55085 UNIPROT RARG protein P13631 UNIPROT "down-regulates quantity by repression" "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-254858 GLUL protein P15104 UNIPROT ammonium smallmolecule CHEBI:28938 ChEBI "down-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-267825 RPS29 protein P62273 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-262422 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser645 RPASVPPsPSLSRHS -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-253006 ANK2 protein Q01484 UNIPROT DCTN4 protein Q9UJW0 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-266713 JAK2 protein O60674 UNIPROT ITGAL protein P20701 UNIPROT "up-regulates activity" phosphorylation 9606 25624455 t miannu "PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role." SIGNOR-254739 ACVR1 protein Q04771 UNIPROT SMAD1 protein Q15797 UNIPROT "up-regulates activity" phosphorylation Ser465 HNPISSVs 9534 9748228 t "ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif" SIGNOR-251439 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 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CCNE1 protein P24864 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189978 PCSK7 protein Q16549 UNIPROT KHSRP protein Q92945 UNIPROT down-regulates phosphorylation 9606 BTO:0000222 BTO:0000887 16364914 t gcesareni "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-143167 CEBPA protein P49715 UNIPROT GFI1 protein Q99684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20924107 f irozzo "We show here that C/EBPα interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1." SIGNOR-256068 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates phosphorylation 9606 19620713 t gcesareni "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-187193 MAS1 protein P04201 UNIPROT FLNA protein P21333 UNIPROT "up-regulates activity" binding 9606 26460884 t miannu "We further determined that GPCRs, AT1R, and MAS directly recruited FLNa and promoted its phosphorylation by cellular S/T kinases in an agonist-dependent manner. Our studies thus provide a structural framework for filamin in GPCR signaling, potentially regulating a variety of cellular responses. MAS likely binds filamin constitutively and hence leads to constitutive filamin phosphorylation. These results emphasize that it is the active receptor that mediates filamin phosphorylation by PKA or other cellular S/T kinases" SIGNOR-260627 PTN protein P21246 UNIPROT ALK protein Q9UM73 UNIPROT up-regulates binding 9606 11278720 t gcesareni "We conclude from this series of experiments that ptn specifically binds to the alk orphan receptor as a high affinity ligand at least in part via the putative ligand binding domain described above." SIGNOR-106411 CDK3 protein Q00526 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15084261 t gcesareni "The active form of prb is underphosphorylated. Cdk3/cyclin-c-mediated phosphorylation at ser-807 and ser-811 is required for g0-g1 transition." SIGNOR-124212 RNF6 protein Q9Y252 UNIPROT LIMK1 protein P53667 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 16204183 t miannu "Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons. " SIGNOR-271481 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 DET1 protein Q7L5Y6 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154508 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 PRKACA protein P17612 UNIPROT RAP1A protein P62834 UNIPROT "down-regulates activity" phosphorylation Ser180 KKKPKKKsCLLL 9534 9867809 t miannu "Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells." SIGNOR-250042 CH5132799 chemical CID:49784945 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190937 NCKAP1 protein Q9Y2A7 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-261874 PPP3CA protein Q08209 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR "form complex" binding 9606 14623295 t miannu "Calcineurin is a heterodimer consisting of a catalytic subunit with a molecular mass of about 59 kDa (calcienurin A or CNA) and a regulatory subunit with a molecular mass of 19 kDa (calcineurin B or CNB)." SIGNOR-255291 SLC2A1 protein P11166 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI "up-regulates quantity" relocalization 9606 23506862 t miannu "GLUT1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells." SIGNOR-267458 PPP1CB protein P62140 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 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-248572 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 BTO:0000130 14499342 t lperfetto "Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils." SIGNOR-118036 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 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 3-[8-amino-1-(2-phenyl-7-quinolinyl)-3-imidazo[1,5-a]pyrazinyl]-1-methyl-1-cyclobutanol chemical CHEBI:91402 ChEBI IGF1R protein P08069 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193675 Ub:E2 complex SIGNOR-C497 SIGNOR RNF40 protein O75150 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-271109 YARS1 protein P54577 UNIPROT tyrosine smallmolecule CHEBI:18186 ChEBI "down-regulates quantity" "chemical modification" 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-270518 AKT1 protein P31749 UNIPROT CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 t gcesareni "Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1." SIGNOR-252534 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 PIPP smallmolecule CID:24755493 PUBCHEM 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-180797 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR COIL protein P38432 UNIPROT up-regulates phosphorylation Ser184 NEEAKRKsPKKKEKC 9606 BTO:0000567;BTO:0000938 11102515 t lperfetto "In particular, we have recently found that the cdk2/cyclin e complex can phosphorylate coilin in vitro . there is but a single consensus cdk2/cyclin e phosphorylation site in coilin, located at serine 184. when serine 184 was mutated to an alanine (s184a), mimicking a dephosphorylated state, a nucleolar mislocalization similar to that of gfp-coilin(1__†€ †_248) was observed" SIGNOR-216733 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser68 FLEQPICsVQPIDLN 9606 23166821 t llicata "We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5" SIGNOR-199785 PXDN protein Q92626 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 BTO:0000567 29305973 f miannu "Our findings show that Snai1 mediates repression of PXDN and consolidate a role for this ECM-modifier during EMT." SIGNOR-265253 CASP6 protein P55212 UNIPROT CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 t gcesareni "This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8." SIGNOR-109411 EVX1 protein P49640 UNIPROT GSC protein P56915 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001086 22178155 f miannu "We found that EVX1 repressed GSC expression and promoted formation of posterior streak-like progeny in response to BMP4, and conversely that GSC repressed EVX1 expression and was required for development of anterior streak-like progeny in response to activin." SIGNOR-254139 CDK1 protein P06493 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR "form complex" binding 9606 29870721 t lperfetto "Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis." SIGNOR-267570 MECP2 protein P51608 UNIPROT PTPN1 protein P18031 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000478 26214522 f Luana " We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models." SIGNOR-264552 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-252778 CTNNA3 protein Q9UI47 UNIPROT 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-265493 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DOB protein P13765 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-254000 ERBB4 protein Q15303 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 18793634 t gcesareni "Erbb4 might not be able to directly recruit cbl, and therefore downregulation of this receptor is slow." SIGNOR-180895 ponatinib chemical CHEBI:78543 ChEBI FGFR2 protein P21802 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-259278 F2 protein P00734 UNIPROT F5 protein P12259 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-263530 NKX2-2 protein O95096 UNIPROT ERMN protein Q8TAM6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 21221725 t lperfetto "Further study revealed that Nkx2.2 could bind JN promoter and its overexpression increase the promoter activity of JN." SIGNOR-268965 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 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 "SEC61 complex" complex SIGNOR-C368 SIGNOR SEC63 protein Q9UGP8 UNIPROT "up-regulates activity" binding 33925740 t lperfetto "This is where allosteric effectors of the Sec61 complex (BiP together with Sec62/Sec63 complex or TRAP complex) (Figure 2 and Figure 5) and auxiliary membrane protein insertases (EMC and TMCO1 complex) join the game" SIGNOR-265274 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 MRPS5 protein P82675 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-261441 PPP1CA protein P62136 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates dephosphorylation 9606 20186153 t lperfetto "Several stps have been reported to negatively regulate akt pathway. It has been shown that pp1 dephosphorylates akt and regulates cell survival." SIGNOR-244436 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 ADCY10 protein Q96PN6 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-265008 CBL protein P22681 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 10514377 t miannu "Ubiquitination of the PDGF β-receptor (Rβ) by the c-Cbl RING in an SH2-dependent manner." SIGNOR-272553 EXOC2 protein Q96KP1 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-270785 PHF3 protein Q92576 UNIPROT POLR2A protein P24928 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 phosphorylation:Ser1594 GAMSPSYsPTSPAYE 34667177 t miannu "PHF3 interacts with RNA polymerase II through the SPOC domain. PHF3 negatively regulates mRNA levels. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. PHF3 SPOC preferentially binds RNA Pol II CTD phosphorylated on Serine-2" SIGNOR-266965 TP53 protein P04637 UNIPROT AIFM2 protein Q9BRQ8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12135761 t miannu "The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. these results support the hypothesis that the expression of the PRG3 gene in cells undergoing p53‐dependent apoptosis involves direct activation of its promoter by p53." SIGNOR-261808 BMP4 protein P12644 UNIPROT BMPR1A protein P36894 UNIPROT up-regulates binding 26330344 t fferrentino "BMP interacts with specific receptors on the cell surface, BMP receptor types 1 and 2 (BMPr1 and BMPr2)." SIGNOR-253548 HIPK1 protein Q86Z02 UNIPROT PAGE4 protein O60829 UNIPROT "up-regulates activity" phosphorylation Thr51 PGQEREGtPPIEERK 9606 24559171 t Manara "Here, we have identified homeodomain-interacting protein kinase 1 (HIPK1), also a component of the stress-response pathway, as a kinase that phosphorylates PAGE4 at T51 | We show that phosphorylation of PAGE4 is critical for its transcriptional activity since mutating this T residue abolishes its ability to potentiate c-Jun transactivation." SIGNOR-260929 GLUD2 protein P49448 UNIPROT "glutamic acid" smallmolecule CHEBI:18237 ChEBI "down-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-268558 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 NOTCH proteinfamily SIGNOR-PF30 SIGNOR LFNG protein Q8NES3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22298955 f gcesareni "Notch signal transduction pathway genes, lfng, hey1, and hes1, are differen-tially regulated by bmp-2 and tgf-beta." SIGNOR-254336 "ruxolitinib phosphate" chemical CHEBI:66917 ChEBI JAK1 protein P23458 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-259170 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT "up-regulates activity" phosphorylation Thr526 NGKSYDEtVDIFSFG 9534 BTO:0000298 11018042 t lperfetto "Specific Activation of LIM kinase 2 via Phosphorylation of Threonine 505 by ROCK, a Rho-dependent Protein Kinase" SIGNOR-249053 BMPR2 protein Q13873 UNIPROT BMPR1B protein O00238 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-180548 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 MTF1 protein Q14872 UNIPROT SOD1 protein P00441 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-254601 TAOK2 protein Q9UL54 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR up-regulates phosphorylation 9606 23431053 t "inferred from 70% of family members" gcesareni "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-269939 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 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 USP7 protein Q93009 UNIPROT TP53 protein P04637 UNIPROT up-regulates deubiquitination 9606 16082221 t gcesareni "Hausp counteracts the destabilizing effect of mdm2 by direct deubiquitination of p53." SIGNOR-139456 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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206382 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea chemical CHEBI:91327 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207302 SMAD4 protein Q13485 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR "form complex" binding 9606 9436979 t lperfetto "Bone morphogenetic protein (BMP) receptors signal by phosphorylating Smad1, which then associates with Smad4; this complex moves into the nucleus and activates transcription." SIGNOR-103618 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 celecoxib chemical CHEBI:41423 ChEBI PTGS2 protein P35354 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190928 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 GSK3B protein P49841 UNIPROT DPYSL2 protein Q16555 UNIPROT "down-regulates activity" phosphorylation Thr514 SVTPKTVtPASSAKT 10116 BTO:0000938 15652488 t lperfetto "Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it" SIGNOR-133255 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 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 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 MAP3K5 protein Q99683 UNIPROT MAP2K3 protein P46734 UNIPROT "up-regulates activity" phosphorylation 9534 BTO:0004055 8974401 t lperfetto "ASK1 activated SEK1 and MKK3 up to 7.0- and 11.8-fold, respectively" SIGNOR-226672 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 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 IGF1 protein P05019 UNIPROT PPP3CB protein P16298 UNIPROT 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-235825 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr275 TTGTKSNtPTSSVPS 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134545 CEBPA protein P49715 UNIPROT Basophil_diff phenotype SIGNOR-PH116 SIGNOR "up-regulates activity" 10090 BTO:0000725 23990620 f "Notably, enforced overexpression of C/EBP-α in BMCPs results in exclusive differentiation into basophils, whereas conditional deletion of C/EBP-α in these same cells promotes mast cell differentiation,1 suggesting that C/EBP-α is an essential “switch factor” for basophil lineage choice" SIGNOR-259968 IMMT protein Q16891 UNIPROT PINK1 protein Q9BXM7 UNIPROT "up-regulates activity" binding -1 27153535 t miannu "MIC60 Is Crucial for Parkin Recruitment and Transiently Interacts with PINK1" SIGNOR-266301 FGFR2 protein P21802 UNIPROT PTEN protein P60484 UNIPROT unknown phosphorylation Tyr240 RREDKFMyFEFPQPL 9606 22891331 t llicata "Fgfrs phosphorylate pten at tyrosine 240" SIGNOR-191793 TWIST1 protein Q15672 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20646316 f miannu "Individual genes upregulated by TWIST1 known to promote EMT and/or GBM invasion included SNAI2, MMP2, HGF, FAP and FN1." SIGNOR-255525 6-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthalenecarboxamide chemical CHEBI:94965 ChEBI CYP17A1 protein P05093 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207141 GPR119 protein Q8TDV5 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-257366 PRKCH protein P24723 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation Ser21 SGRARTSsFAEPGGG 9606 11884598 t gcesareni "Furthermore, several pkc isotypes phosphorylate gsk-3 in vitro and in vivo. in the presence of atp, several isoforms (?, ___, _, ?, And of pkc phosphorylated both gsk-3? At ser 21 and gsk-3_ at ser 9" SIGNOR-115730 R547 chemical CID:6918852 PUBCHEM CDK2 protein P24941 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-259793 BLOC1S4 protein Q9NUP1 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "form complex" binding 9606 BTO:0002946 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-265932 CSNK2A1 protein P68400 UNIPROT SLK protein Q9H2G2 UNIPROT down-regulates phosphorylation Ser347 SSDLSIAsSEEDKLS 9606 16837460 t gcesareni "Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity." SIGNOR-147879 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 [4-[2-(1H-indazol-3-yl)ethenyl]phenyl]-(1-piperazinyl)methanone chemical CHEBI:91441 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193612 CLK1 protein P49759 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-70563 SRC protein P12931 UNIPROT EMD protein P50402 UNIPROT down-regulates phosphorylation Tyr59 SSSAASSySFSDLNS 9606 BTO:0000567 BTO:0000887 19789182 t llicata "Src phosphorylated emerin specifically at y59, y74 and y95; interestingly y-to-f substitutions at identified src sites reduced recombinant emerin binding to endogenous baf" SIGNOR-188308 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 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 STK4 protein Q13043 UNIPROT LATS1 protein O95835 UNIPROT up-regulates phosphorylation Thr1079 EHAFYEFtFRRFFDD 9606 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-133555 SLC46A1 protein Q96NT5 UNIPROT dihydrofolate(2-) smallmolecule CHEBI:57451 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000575 17129779 t lperfetto "However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1." SIGNOR-268264 LYN protein P07948 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-249382 ROCK1 protein Q13464 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation 9606 15068801 t gcesareni "Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter." SIGNOR-123717 ABL1 protein P00519 UNIPROT WASL protein O00401 UNIPROT "up-regulates activity" phosphorylation Tyr175 EITTNRFyGPQVNNI -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-251436 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr323 STVSFNPyEPELAPW 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-246605 SEMA4D protein Q92854 UNIPROT PLXNB1 protein O43157 UNIPROT up-regulates binding 9606 12198496 t gcesareni "Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors." SIGNOR-92201 "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 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu69 EETCSYEeAFEALES -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-263682 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione chemical CHEBI:92539 ChEBI HTR1A protein P08908 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190687 PRKACA protein P17612 UNIPROT AKAP12 protein Q02952 UNIPROT "up-regulates activity" phosphorylation Ser627 KKRVRRPsESDKEDE -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-271841 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 LRIG3 protein Q6UXM1 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates 9606 23723069 f miannu "Lrig3 opposes lrig1 negative regulatory activity and stabilizes erbb receptors." SIGNOR-202183 PPP1CC protein P36873 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates dephosphorylation 9606 14718519 t lpetrilli "We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI." SIGNOR-121277 serotonin smallmolecule CHEBI:28790 ChEBI HTR2B protein P41595 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-264286 PTPN1 protein P18031 UNIPROT ABL1 protein P00519 UNIPROT down-regulates dephosphorylation 9606 9566916 t gcesareni "These results illustrate selectivity in the effects of ptps in a cellular context and suggest that ptp1b may function as a specific, negative regulator of p210 bcr-abl signalling in vivo." SIGNOR-56815 ERRFI1 protein Q9UJM3 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" binding -1 18046415 t "The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2" SIGNOR-252076 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation Thr261 LVDSIAKtRDAGCRP 9606 9712898 t lperfetto "The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1" SIGNOR-236380 RARA protein P10276 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates 9606 10607566 f gcesareni "We shown that retinoic acid (ra) decreases the activity of the beta-catenin-lef/tcf signaling pathway" SIGNOR-73274 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI THRA protein P10827 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-267255 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 CDK5RAP2 protein Q96SN8 UNIPROT BUB1B protein O60566 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19282672 t Giulio "These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter" SIGNOR-260312 practolol chemical CHEBI:258351 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-258336 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 10398585 t lperfetto "Serine 32 and serine 36 of IkappaBalpha are directly phosphorylated by protein kinase CKII in vitro|Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation" SIGNOR-249332 halothane chemical CHEBI:5615 ChEBI KCNK3 protein O14649 UNIPROT "up-regulates activity" "chemical activation" 10090 20519544 t Luana "We further demonstrate that TASK channels are required for normal sensitivity to immobilizing effects of halothane and isoflurane and to sedative/hypnotic effects of halothane." SIGNOR-257846 Dinaciclib chemical CID:46926350 PUBCHEM CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191328 AKT proteinfamily SIGNOR-PF24 SIGNOR STK4 protein Q13043 UNIPROT down-regulates phosphorylation Thr120 IIRLRNKtLTEDEIA 9606 19940129 t llicata "Akt interacts with mst1 and phosphorylates a highly conserved residue threonine 120 of mst1, which leads to inhibition of its kinase activity and nuclear translocation as well as the autophosphorylation of thr(183)." SIGNOR-161829 SB-202190 chemical CHEBI:79090 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206697 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR1B protein P28222 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-257517 TNFRSF17 protein Q02223 UNIPROT ELK1 protein P19419 UNIPROT up-regulates 9606 10903733 f miannu "Bcma overexpression activates elk-1 nuclear factor" SIGNOR-79486 "STX11-VAMP8 SNARE complex" complex SIGNOR-C273 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 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-261900 SIRT5 protein Q9NXA8 UNIPROT CPS1 protein P31327 UNIPROT "up-regulates activity" "post translational modification" 9606 BTO:0000567 24703693 t deglutarylation lperfetto "Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal|SIRT5 can catalyze the enzymatic removal of lysine glutarylation" SIGNOR-267643 MAPK3 protein P27361 UNIPROT WWC1 protein Q8IX03 UNIPROT unknown phosphorylation Ser548 SSPSPPCsPLMADPL 9606 BTO:0000149 24269383 t llicata "We demonstrated that erk1/2 phosphorylate kibra at ser(548) in cells as well as in vitro." SIGNOR-203290 ARHGEF6 protein Q15052 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 BTO:0000599 23776207 f lperfetto "Expression of the phospho-mimicking ACAP4 mutant promotes ARF6-dependent cell migration." SIGNOR-272237 MLF1 protein P58340 UNIPROT COPS3 protein Q9UNS2 UNIPROT up-regulates binding 9606 15861129 t 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-135937 6-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-[(1R)-1-phenylethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine chemical CHEBI:40629 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189347 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 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16885213 t gcesareni "In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed 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-148478 "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 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 pazopanib chemical CHEBI:71219 ChEBI CSF1R protein P07333 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-257740 PRKACA protein P17612 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 17419683 t gcesareni "In the absence of hh ligands, cubitus interruptus (in drosophila) and gli2 and gli3 (in vertebrates) are phosphorylated by protein kinase a and glycogen synthase kinase-3beta and are proteolytically processed 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-154273 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 SRC protein P12931 UNIPROT GSN protein P06396 UNIPROT up-regulates phosphorylation Tyr465 VPVDPATyGQFYGGD 9606 10210201 t lperfetto "Identification of tyr438 as the major in vitro c-src phosphorylation site in human gelsolin recently" SIGNOR-67014 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser214 SRSGLYRsPSMPENL 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-216765 "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 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 GNAI3 protein P08754 UNIPROT Adenylate_cyclase proteinfamily SIGNOR-PF92 SIGNOR "down-regulates activity" binding 9606 19703466 t miannu "Adenylate cyclase is regulated by stimulatory hormones through Gs(alpha s beta gamma) and inhibitory hormones through Gi(alpha i beta gamma)" SIGNOR-267851 "TREX complex" complex SIGNOR-C444 SIGNOR mRNA-nucleus_export phenotype SIGNOR-PH127 SIGNOR up-regulates 9606 22928037 f miannu "The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export." SIGNOR-268514 MAPK14 protein Q16539 UNIPROT SMARCD3 protein Q6STE5 UNIPROT "up-regulates activity" phosphorylation 9606 21902831 t lperfetto "P38 phosphorylates the baf60 subunit of the swi-snf chromatin remodelling complex, and p38 recruits this complex to differentiation-specific loci." SIGNOR-176557 DUSP4 protein Q13115 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Thr185 HDHTGFLtEYVATRW 10116 7535768 t "Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185" SIGNOR-248717 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 ChEBI dehydroepiandrosterone chemical CHEBI:28689 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-268647 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 CCL25 protein O15444 UNIPROT ACKR4 protein Q9NPB9 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 23341447 t Luana " In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines." SIGNOR-268418 PYGM protein P11217 UNIPROT 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 [‚Ķ] 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-267389 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 palbociclib chemical CHEBI:85993 ChEBI CCND1 protein P24385 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189693 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 11359934 f gcesareni "The nuclear factor-kappaB (NF-kappaB) family of transcription factors has been shown to regulate proliferation in several cell types." SIGNOR-245043 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 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 "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 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 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 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 MAPK8 protein P45983 UNIPROT IRF3 protein Q14653 UNIPROT up-regulates phosphorylation Ser173 PCPQPLRsPSLDNPT 9606 19153595 t lperfetto "In this study, we show that another kinase, c-jun-nh(2)-terminal kinase (jnk), phosphorylates irf3 on its n-terminal serine 173 residuejnk1 can synergize the action of irf3(5d), but not the s173a-irf3(5d) mutant" SIGNOR-183489 SRC protein P12931 UNIPROT RPS6KB2 protein Q9UBS0 UNIPROT unknown phosphorylation Tyr45 GLEPVGHyEEVELTE 9606 16640565 t llicata "Src kinase phosphorylates s6k in the n-terminus. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vitro. tyrosine y39/45 in s6k1/2 is a substrate for src kinase in vivo." SIGNOR-146292 JAK1 protein P23458 UNIPROT JAK3 protein P52333 UNIPROT up-regulates 9606 10825200 f gcesareni "Syk activation required jak3, probably indirectly via activation of jak1." SIGNOR-77551 CRTC2 protein Q53ET0 UNIPROT TSC22D3 protein Q99576 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 26652733 t "CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells" SIGNOR-256109 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 ADA protein P00813 UNIPROT inosine smallmolecule CHEBI:17596 ChEBI "up-regulates quantity" "chemical modification" -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-269737 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 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 PI-103 chemical CHEBI:90524 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206166 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 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation Thr842 CTETFTGtLQYMAPE 10090 11689443 t llicata "After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845." SIGNOR-248540 Kindlin proteinfamily SIGNOR-PF48 SIGNOR ITGB1 protein P05556 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-258999 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 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF6 protein Q9Y4K3 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-270981 RXRG protein P48443 UNIPROT MBP protein P02686 UNIPROT "up-regulates quantity" "transcriptional regulation" 31390799 f SimoneGraziosi "RXRγ gene silencing reduces the ability of the drugs to promote MBP expression." SIGNOR-269266 BTC protein P35070 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 23382875 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-200813 ABL1 protein P00519 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" phosphorylation Tyr315 ETRICKIyDSPCLPE 10090 BTO:0002883 11684015 t gcesareni "Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance" SIGNOR-247599 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 RNF216 protein Q9NWF9 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16968706 t miannu "Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins." SIGNOR-271609 RUNX3 protein Q13761 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254554 RAPGEF6 protein Q8TEU7 UNIPROT NRAS protein P01111 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-183799 imatinib chemical CHEBI:45783 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;VIRAL ABL" gcesareni SIGNOR-193372 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 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 CALM3 protein P0DP25 UNIPROT Calcineurin complex SIGNOR-C155 SIGNOR 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-266347 PTPN6 protein P29350 UNIPROT KCNH2 protein Q12809 UNIPROT down-regulates dephosphorylation 9606 12361947 t gcesareni "Our results show that erg-1 is a shp-1 substrate constituting the first report that an ion current is regulated by shp-1." SIGNOR-94007 SLBP protein Q14493 UNIPROT H3-2 protein Q5TEC6 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-265415 "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 EGLN3 protein Q9H6Z9 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 23732909 t lperfetto "Here we report that EGLN3, but not EGLN1 or -2, interacts with and inhibits K63-linked ubiquitination of IKKγ. The effect appears to be related to inhibition of IKKγ ubiquitination mediated by cIAP1 rather than to stimulation of IKKγ deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKγ ubiquitination and NF-κB signaling. Instead, interaction with IKKγ is required for the ability of EGLN3 to inhibit IKKγ ubiquitination and IKK-NF-κB signaling." SIGNOR-262005 MARCHF8 protein Q5T0T0 UNIPROT HLA-DRB4 protein P13762 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys254 FIYFRNQkGHSGLQP 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-271407 "Embryonic stem cell-specific SWI/SNF" complex SIGNOR-C484 SIGNOR Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 10090 BTO:0001086 19279220 f miannu "An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency" SIGNOR-270728 VASP protein P50552 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-268393 IL15RA protein Q13261 UNIPROT IL2RB protein P14784 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001103 17709786 t milica "The il-15 receptor comprises a heterotrimeric complex consisting of the common ?cytokine Receptor (?c), the il-2 ? Receptor subunit (il-2r?), And an il-15-specific ? Receptor (il-15r?)" SIGNOR-157418 TICAM2 protein Q86XR7 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 14519765 t lperfetto "Tram binds trif directly and recruits it to tlr4" SIGNOR-118367 α-Catenin proteinfamily SIGNOR-PF72 SIGNOR JUP protein P14923 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-265819 BCL2L1 protein Q07817 UNIPROT BAK1 protein Q16611 UNIPROT down-regulates binding 9606 9463381 t amattioni "Bcl-xl bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)" SIGNOR-55549 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 24692351 f scontino "Skeletal muscle has been recognized as a key TH target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal (237, 238). TH stimulation favors transition to fast-twitch fibers and transition to a faster myosin heavy chain (MHC) form." SIGNOR-267619 betamethasone chemical CHEBI:3077 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 17561562 t dermatitis gcesareni SIGNOR-251686 IL6 protein P05231 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-260256 CCT128930 chemical CID:17751819 PUBCHEM AKT2 protein P31751 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor of Akt2" gcesareni SIGNOR-190868 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 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 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 naloxone chemical CHEBI:7459 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-258941 ARG1 protein P05089 UNIPROT L-ornithine smallmolecule CHEBI:15729 ChEBI "up-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-255545 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr280 HRFHPEPyGLEDDQR -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-246492 Telatinib chemical CID:9808844 PUBCHEM PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207230 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCA protein P17252 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190344 SOSTDC1 protein Q6X4U4 UNIPROT WNT9B protein O14905 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-242739 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDKN1B protein P46527 UNIPROT up-regulates phosphorylation Ser10 NVRVSNGsPSLERMD 9606 10831586 t lperfetto "Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability." SIGNOR-244622 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 ALDH2 protein P05091 UNIPROT HDAC3 protein O15379 UNIPROT "up-regulates activity" binding -1 phosphorylation:Thr429 MQILKFKtIEEVVGR 28056995 t lperfetto "Consistent with previous data, HDAC3 only bound to the ATP6V0E2 promoter in the presence of ALDH2.|Taken together, our data demonstrate that in the macrophages of LDLR-KO or ALDH2 rs671 mutant, AMPK phosphorylates ALDH2 at T356, which enables its nuclear translocation. Once in the nucleus, ALDH2 binds to HDAC3 and suppresses the transcription and protein expression of ATP6V0E2." SIGNOR-271867 EEF1G protein P26641 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-269391 WWP1 protein Q9H0M0 UNIPROT AMOTL2 protein Q9Y2J4 UNIPROT "up-regulates activity" ubiquitination Lys347 EKAGRIEkLESEIQR 9606 BTO:0000007 34404733 t lperfetto "AMOTL2 mono-ubiquitination by WWP1 promotes contact inhibition by facilitating LATS activation|Here, we provide evidence that the E3 ligase WWP1 (WW-domain containing protein 1) mono-ubiquitinates AMOTL2 (angiomotin-like 2) at K347 and K408." SIGNOR-271873 PRL protein P01236 UNIPROT KRT15 protein P19012 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251904 "Lig4-Xrcc4 complex" complex SIGNOR-C354 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates -1 19837014 t miannu "The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals." SIGNOR-264534 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 PTPN1 protein P18031 UNIPROT ACTN1 protein P12814 UNIPROT "down-regulates activity" dephosphorylation Tyr12 DSQQTNDyMQPEEDW 9534 BTO:0000298 16291744 t "down-regulates binding to src" lperfetto "Here we report that protein-tyrosine phosphatase 1B (PTP 1B) is an alpha-actinin phosphatase. PTP 1B-dependent dephosphorylation of alpha-actinin was seen in COS-7 cells|No dephosphorylation was observed in cells coexpressing the alpha-actinin phosphorylation mutant Y12F and PTP 1B. |A reversible interaction between alpha-actinin and Src enables the dephosphorylation of alpha-actinin by PTP 1B, releasing Src" SIGNOR-270539 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI pyruvate smallmolecule CHEBI:15361 ChEBI "up-regulates quantity" "precursor of" 9606 33064660 t miannu "Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP." SIGNOR-267721 FYN protein P06241 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-268210 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 ITGA7 protein Q13683 UNIPROT "a7/b1 integrin" complex SIGNOR-C126 SIGNOR "form complex" binding 9606 BTO:0000222;BTO:0002319 10199978 t lperfetto "The alpha7beta1 integrin is a laminin receptor on the surface of skeletal myoblasts and myofibers. Alternative forms of both the alpha7 and beta1 chains are expressed in a developmentally regulated fashion during myogenesis. These different alpha7beta1 isoforms localize at specific sites on myofibers and appear to have distinct functions in skeletal muscle." SIGNOR-241508 MAPK8IP1 protein Q9UQF2 UNIPROT MAP3K12 protein Q12852 UNIPROT down-regulates binding 9606 11432832 t gcesareni "Jip inhibits dlk dimerization." SIGNOR-109046 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR MMP9 protein P14780 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15536164 f miannu "Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG." SIGNOR-254798 UNC80 protein Q8N2C7 UNIPROT NALCN protein Q8IZF0 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22196327 t miannu "The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80." SIGNOR-265184 DVL2 protein O14641 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" binding 9606 17529994 t amattioni "Dix domain of dvl2 mediates dynamic polymerization, which is essential for the signaling activity of dvl2." SIGNOR-155224 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 12637538 t Manara "We show that Abl directly phosphorylates PKD at Tyr(463) in vitro, and in cells phosphorylation of this site is sufficient to mediate full activation of PKD" SIGNOR-260791 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 "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-267077 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR T-reg_differentiation phenotype SIGNOR-PH91 SIGNOR down-regulates 9606 23620016 f "In the current study, addition of ERK inhibitors suppressed IL-6-induced RORgammat expression and promoted TGF-beta-induced Foxp3 expression." SIGNOR-254686 GPER1 protein Q99527 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 11897506 t gcesareni "Gpcr-mediated transactivation of egfrs by estrogen provides a previously unappreciated mechanism of cross-talk between estrogen and serum growth factors, and explains prior data reporting the egf-like effects of estrogen" SIGNOR-115988 CASP3 protein P42574 UNIPROT 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-57891 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 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 MDM4 protein O15151 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" binding 9606 10218570 t miannu "MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2." SIGNOR-272932 TOP2B protein Q02880 UNIPROT PBX3 protein P40426 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-242308 GSK3A protein P49840 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-264887 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 PROC protein P04070 UNIPROT F7 protein P08709 UNIPROT "down-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Activated protein C (APC), which cleaves and inactivates both FVIIIa and FVa, thereby shutting down both the tenase and prothrombinase complexes" SIGNOR-263527 GSK3A protein P49840 UNIPROT AKT1 protein P31749 UNIPROT "down-regulates activity" phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni "GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function." SIGNOR-252434 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 CDKN1A protein P38936 UNIPROT CDK6 protein Q00534 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-30030 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM54 protein Q9BYV2 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-270967 PP121 chemical CHEBI:50915 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252655 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 FOXO4 protein P98177 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-260091 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR JAK2 protein O60674 UNIPROT "up-regulates activity" phosphorylation Tyr1007 VLPQDKEyYKVKEPG 10090 11593427 t irozzo "In this report, we show that Bcr–Abl forms a complex with Jak2, and induces tyrosine phosphorylation of Jak2; full phosphorylation requires the SH2 domain of Bcr–Abl. We found that Y1007 of Jak2 was phosphorylated in Bcr–Abl positive cells; phosphorylation of Jak2 Y1007 is known to be required for Jak2 kinase activation." SIGNOR-255812 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser171 HLQTCCGsLAYAAPE 9606 16216881 t gcesareni "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." SIGNOR-140958 ITGB1BP1 protein O14713 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-257644 SH3RF1 protein Q7Z6J0 UNIPROT RAC2 protein P15153 UNIPROT up-regulates binding 9606 9482736 t gcesareni "Posh interacts with the gtp form of rac but not the gdp form" SIGNOR-55811 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 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RAR proteinfamily SIGNOR-PF45 SIGNOR "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-256197 NGF protein P01138 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003306 24493753 f miannu "Long-term (more than 24 h) treatment with nerve growth factor (NGF) upregulated Nav1.7 functional expression in the strongly metastatic MAT-LyLu rat PCa cell line; acute application had no effect" SIGNOR-253495 SHANK3 protein Q9BYB0 UNIPROT NMDA proteinfamily SIGNOR-PF56 SIGNOR "up-regulates quantity" 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-264701 sulindac chemical CHEBI:9352 ChEBI RXRA protein P19793 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001109 20541701 t Luana "NSAID Sulindac and Its Analogs Bind RXRα and Inhibit RXRα-dependent AKT Signaling" SIGNOR-257847 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 1038915-60-4 chemical CID:24958200 PUBCHEM PARP1 protein P09874 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194399 EIF2AK2 protein P19525 UNIPROT Immune_response phenotype SIGNOR-PH17 SIGNOR up-regulates 9606 27712625 f miannu "The activated kinases then phosphorylate the signal transducers and transcription factors STAT1 and STAT2, which form a complex with IRF9 (ISGF3) that enters the nucleus to transactivate promoters of an antiviral gene expression program. Genes that are specifically upregulated by IFNs are collectively called ISGs (IFN-stimulated genes). The kinase PKR is an ISG product acting as a signaling PRR on one hand (see earlier), but its main function in antiviral defense is the inhibition of protein synthesis.PKR has a broad antiviral spectrum." SIGNOR-260159 "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR TP53 protein P04637 UNIPROT unknown ubiquitination 9606 BTO:0000007 14636569 t lperfetto "However, since the same domain of p53 is also the target of ubiquitination by MDM2 protein, further in vivo experiments are required to demonstrate the biological relevance of p53 ubiquitination by BRCC.|The Extreme C Terminus of p53 Is Ubiquitinated by BRCC" SIGNOR-263210 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 serotonin smallmolecule CHEBI:28790 ChEBI HTR7 protein P34969 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-264289 GSTA1 protein P08263 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0000018 29928434 f irozzo "In addition, the downregulation of GSTA1 in A549 cells significantly induced cell apoptosis in vitro. In conclusion, GSTA1 plays an important role in regulation of cell proliferation and cell apoptosis in A549 cell line." SIGNOR-256297 PRKAA1 protein Q13131 UNIPROT MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser155 GRLKRERsMSENAVR 9606 26816379 t gcesareni "A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission." SIGNOR-245953 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 HIPK2 protein Q9H2X6 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser257 PGVVMASsPALPTQP 9606 20573984 t lperfetto "Ere we found that homeodomain-interacting protein kinase 2 (hipk2), a dna-damage responsive nuclear kinase, is a new creb kinase for phosphorylation at ser-271 but not ser-133, and activates creb transactivation function" SIGNOR-166338 UMPS protein P11172 UNIPROT UMP smallmolecule CHEBI:16695 ChEBI "up-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-267440 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 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 CDK2 protein P24941 UNIPROT GRK2 protein P25098 UNIPROT down-regulates phosphorylation Ser670 KMKNKPRsPVVELSK 9606 20080565 t gcesareni "We report that grk2 protein levels are transiently down-regulated during the g2/m transition by a mechanism involving cdk2-mediated phosphorylation of grk2 at serine670, which triggers binding to the prolyl-isomerase pin1 and subsequent degradation." SIGNOR-163279 lurasidone chemical CHEBI:70735 ChEBI HTR7 protein P34969 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 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-257840 PRKACA protein P17612 UNIPROT EEF2K protein O00418 UNIPROT "up-regulates activity" phosphorylation Ser500 RLHLPRAsAVALEVQ -1 11171059 t miannu "EEF-2K can be phosphorylated in vitro by cAMP-dependent protein kinase (PKA) and that this induces significant Ca(2+)/calmodulin (CaM)-independent eEF-2K activity. sites of phosphorylation were Ser-365 and Ser-499" SIGNOR-250444 "MLL Fusion" "fusion protein" SIGNOR-FP14 SIGNOR "AEP complex" complex SIGNOR-C117 SIGNOR "up-regulates activity" binding 9606 BTO:0005261 19956800 t miannu "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-260131 CAMK2G protein Q13555 UNIPROT GRIA4 protein P48058 UNIPROT unknown phosphorylation Ser862 IRNKARLsITGSVGE 10366608 t llicata "We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA." SIGNOR-250699 NCSTN protein Q92542 UNIPROT APH1A protein Q96BI3 UNIPROT up-regulates binding 9606 BTO:0000142 12297508 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-93313 CHRM2 protein P08172 UNIPROT GNAO1 protein P09471 UNIPROT up-regulates 9606 BTO:0000007 12665513 f lperfetto "Here we show that m2 muscarinic receptors and go require taos and mek3/6 as the primary intermediates activating p38 mapk in 293 cells" SIGNOR-235536 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 "Nucleosome_H3.3 variant" complex SIGNOR-C339 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 15776021 f 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." SIGNOR-263878 CENPK protein Q9BS16 UNIPROT SOX6 protein P35712 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 10996314 t miannu "Here we report the cloning of a novel cDNA, termed Solt, from a mouse testis cDNA library. Its gene product, Solt, interacts with the leucine zipper region of SoxLZ/Sox6. In transient transfection assays with SoxLZ/Sox6 containing the transactivation domain of herpes simplex virus VP16, the expression of a luciferase reporter gene under the control of a promoter containing a synthetic cis element that is bound by the HMG box of SoxLZ/Sox6 was poorly enhanced in the presence of Solt." SIGNOR-221820 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 PRKCG protein P05129 UNIPROT HSP90AA1 protein P07900 UNIPROT down-regulates phosphorylation Thr603 PCCIVTStYGWTANM 9606 24117238 t lperfetto "Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_, and, more interestingly, this threonine residue set serves as a 'phosphorylation switch' for hsp90_ binding or release of pkc_. Moreover, 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-202820 TGFB1 protein P01137 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" binding 9606 22703233 t lperfetto "TGFbeta signals are transmitted via a cell surface receptor complex consisting of the TGFbeta type I receptor (TbetaRI) and TGFbeta type II receptor (TbetaRII). To initiate signal transduction, TGFbeta binds to TbetaRII, which in turn recruits TbetaRI, leading to the formation of a tetrameric receptor complex." SIGNOR-249548 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 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 BRCA1 protein P38398 UNIPROT TFF1 protein P04155 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000356;BTO:0001033 11244506 f "In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D." SIGNOR-253937 CBX1 protein P83916 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "up-regulates activity" binding 9606 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-265323 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 MLL-AF4 "fusion protein" SIGNOR-FP4 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 21389315 f irozzo "Consequently, cell cycle and apoptosis analyses suggest that MLL-AF4 conveys a selective proliferation coupled to a survival advantage, which correlates with changes in the expression of genes involved in apoptosis, sensing DNA damage and DNA repair." SIGNOR-255872 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser138 MEDLTNVsSLLNMER 9606 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265228 "MLL2 complex" complex SIGNOR-C88 SIGNOR H3-4 protein Q16695 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-268800 Kindlin proteinfamily SIGNOR-PF48 SIGNOR FBLIM1 protein Q8WUP2 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 24165133 t "inferred from 70% family members" 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-269956 TSPAN33 protein Q86UF1 UNIPROT ADAM10 protein O14672 UNIPROT "up-regulates activity" binding 10116 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." SIGNOR-261251 "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 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-263813 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001938 24300895 f "These data indicate that basal NFκB activity at the conserved +26/+34 site of the HES1 gene promotes its expression, and that glucocorticoids can silence HES1 by inhibiting this activity." SIGNOR-253063 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser21 TPPSTALsPGKMSEA 9606 SIGNOR-C17 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-169318 CDK1 protein P06493 UNIPROT UBA1 protein P22314 UNIPROT up-regulates phosphorylation Ser4 sPLSKKRR 9606 9099746 t lperfetto "Ubiquitin-activating enzyme, e1, is phosphorylated in mammalian cells by the protein kinase cdc2. Each serine residue was independently mutated to an alanine and analyzed by two-dimensional electrophoresis;only serine 4 was phosphorylated. Disruption of the basic amino acids within the nls resulted in loss of exclusive nuclear localization and a 90-95% decrease in the phosphorylation of ha1-e1" SIGNOR-47162 NCAPD2 protein Q15021 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-263905 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 GNAI1 protein P63096 UNIPROT "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI down-regulates 9606 23994464 f apalma "The G alpha I subunit inhibits adenylyl cyclase activity and therefore reduces cytoplasmic cAMP levels" SIGNOR-255008 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 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 STAT1 protein P42224 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR down-regulates binding 9606 16481475 t lperfetto "Acetylated stat1 is able to interact with nf-kappab p65. As a consequence, p65 dna binding, nuclear localization, and expression of anti-apoptotic nf-kappab target genes decrease." SIGNOR-217418 BGJ-398 chemical CHEBI:63451 ChEBI FGFR4 protein P22455 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190272 CXCL8 protein P10145 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-261030 CDC14A protein Q9UNH5 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-248830 MAPK14 protein Q16539 UNIPROT EZH2 protein Q15910 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr367 NNSSRPStPTINVLE 10090 BTO:0000165 28067271 t "Here, we show that p38α kinase promotes EZH2 degradation in differentiating muscle cells through phosphorylation of threonine 372" SIGNOR-255663 "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 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 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 RNF146 protein Q9NTX7 UNIPROT AXIN1 protein O15169 UNIPROT "down-regulates quantity" ubiquitination 9606 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-259996 RXRA protein P19793 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-270292 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 15769897 t "we observed constitutive activation of Erk-1 and Erk-2, Akt, and of Shc by both Flt3-ITD and Flt3-D835Y" SIGNOR-261540 SGCG protein Q13326 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-255987 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 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 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 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR CITED1 protein Q99966 UNIPROT up-regulates binding 9606 9660950 t lperfetto "The transcriptional coactivator cpb/p300 associates with nf-kappa b p65 through two sites, an n-terminal domain that interacts with the c-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine 276." SIGNOR-216331 MAPK14 protein Q16539 UNIPROT MEF2A protein Q02078 UNIPROT unknown phosphorylation Ser453 PRQEMGRsPVDSLSS 9606 BTO:0000938 BTO:0000887 12586839 t lperfetto "Thr-312 and thr-319 are known phosphorylation sites important for the increased transcriptional activation of mef2a by p38 mapk. Ser-453 and ser-479 are phosphorylated in vitro but were not important functionally" SIGNOR-98228 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT down-regulates phosphorylation Ser168 SEMKYLGsPITTVPK 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36279 MAP2K7 protein O14733 UNIPROT FADD protein Q13158 UNIPROT "down-regulates activity" phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 15001534 t gcesareni "The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells" SIGNOR-123164 quizartinib chemical CHEBI:90217 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-258270 RNF216 protein Q9NWF9 UNIPROT TIRAP protein P58753 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 16968706 t miannu "Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins." SIGNOR-271607 STAT5A protein P42229 UNIPROT DNMT3A protein Q9Y6K1 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 26059451 t "… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells" SIGNOR-255631 (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 P2RY13 protein Q9BPV8 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-257143 PRKACB protein P22694 UNIPROT PHKA1 protein P46020 UNIPROT "down-regulates activity" phosphorylation 9606 10487978 t "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-267413 MLL-AF4 "fusion protein" SIGNOR-FP4 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-255877 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 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 TLRs proteinfamily SIGNOR-PF20 SIGNOR Interferon_Production phenotype SIGNOR-PH16 SIGNOR up-regulates 9606 20404851 f lperfetto "TLR signaling pathways can be largely classified as either MyD88-dependent pathways, which drive the induction of inflammatory cytokines, or TRIF-dependent pathways, which are responsible for the induction of type I interferon as well as inflammatory cytokines3." SIGNOR-216310 RPS6KA3 protein P51812 UNIPROT TH protein P07101 UNIPROT up-regulates phosphorylation Ser71 RFIGRRQsLIEDARK 9606 12421349 t "The effect has been demonstrated using P07101-3" gcesareni "Mitogen-activated protein-kinase (map) kinase-activated protein kinases 1 and 2 (mapkap kinase-1, mapkap kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylaserecombinant 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" SIGNOR-95487 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation 9606 23422745 t gcesareni "The phosphorylation of atr and atm substrates, chk1, chk2, h2ax, and brca1 was significantly reduced or abrogated in mutant cells." SIGNOR-201050 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 MAPK1 protein P28482 UNIPROT KHDRBS1 protein Q07666 UNIPROT up-regulates phosphorylation Thr84 TVGGPAPtPLLPPSA 9606 12478298 t lperfetto "In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites" SIGNOR-96418 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 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 MTSS1 protein O43312 UNIPROT GLI1 protein P08151 UNIPROT up-regulates binding 9606 BTO:0001253 15545630 t gcesareni "Mim is a shh-responsive gene that can potentiate gli transcriptional activity.MIM Appears to regulate target gene expression through its association with the gli complex" SIGNOR-130542 D-thyroxine smallmolecule CHEBI:30659 ChEBI THR proteinfamily SIGNOR-PF84 SIGNOR "up-regulates activity" "chemical activation" 9606 BTO:0003736 6777394 t "inferred from 70% of family members" 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-269878 "alpha-D-glucose 6-phosphate(2-)" smallmolecule CHEBI:58225 ChEBI "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 ChEBI "up-regulates quantity" "precursor of" 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-267936 MAP2K6 protein P52564 UNIPROT CRK protein P46108 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub-family of the mitogen-activated protein kinase superfamily." SIGNOR-42384 GSK3B protein P49841 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" 10090 24260231 f miannu "Involvement of GSK3 Inhibition by the PI3K/Akt Pathway in Regulation of Etoposide-induced Chk1 Activation. GSK3ß regulates etoposide-induced Chk1 activation. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. Thus, proteasomal degradation of Chk1 as well as GSK3 activation may be involved in negative regulation of etoposide-induced Chk1 by imatinib in these cells." SIGNOR-263050 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 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 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-271314 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 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 PTP4A3 protein O75365 UNIPROT KRT8 protein P05787 UNIPROT "down-regulates activity" dephosphorylation Ser432 SAYGGLTsPGLSYSL 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" SIGNOR-248341 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr387 LPWDLWTtSTDLVQP 9606 BTO:0000567 16945112 t lperfetto "Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin." SIGNOR-149318 CCND1 protein P24385 UNIPROT CDK4 protein P11802 UNIPROT up-regulates binding 9606 BTO:0000150 23562856 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-201666 MAP3K1 protein Q13233 UNIPROT FADD protein Q13158 UNIPROT "down-regulates activity" phosphorylation Ser194 QNRSGAMsPMSWNSD 9606 15001534 t gcesareni "The results clearly show that fadd phosphorylation at ser194 affects functions both upstream and downstream of the mekk1/mkk7/jnk1 pathway and is closely associated with chemosensitivity in prostate cancer cells" SIGNOR-123168 AKT1 protein P31749 UNIPROT 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-252508 5-carboxamidotryptamine chemical CHEBI:48292 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-258888 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 PRKACA protein P17612 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000782 19836308 t lperfetto "Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3alpha or ser9 in gsk3beta. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka)." SIGNOR-188577 raloxifene chemical CHEBI:8772 ChEBI ESR1 protein P03372 UNIPROT "down-regulates activity" "chemical inhibition" -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-258582 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 CTSS protein P25774 UNIPROT "peptide antigen" smallmolecule CHEBI:166824 ChEBI "up-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-267867 nalbuphine chemical CHEBI:7454 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 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-258144 RPA1 protein P27694 UNIPROT BRIP1 protein Q9BX63 UNIPROT "up-regulates activity" binding 9606 17596542 t irozzo "Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ." SIGNOR-259187 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 AKT2 protein P31751 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000782 25336630 t miannu "stimulations were performed in the presence or absence of Akt inhibitor VIII, which selectively inhibits Akt1/Akt2 activity." SIGNOR-262228 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 "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 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 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 DDC protein P20711 UNIPROT L-dopa smallmolecule CHEBI:15765 ChEBI "down-regulates quantity" "chemical modification" 9606 NBK536726 t brain lperfetto "Subsequently, L-DOPA is converted into 3,4-dihydroxyphenethylamine (dopamine) through decarboxylation by the enzyme L-3,4-dihydroxyphenylalanine decarboxylase (DOPA decarboxylase) in the pre-synaptic terminal" SIGNOR-263992 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 PTGER2 protein P43116 UNIPROT EGFR protein P00533 UNIPROT up-regulates 9606 BTO:0000586 17251915 f gcesareni "Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)." SIGNOR-152805 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR B2M protein P61769 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12480693 f miannu "The nuclear factor kappa B (NF-kappa B) subunits p50 and p65 bind to the kappa B box and p65 transactivates beta(2)m." SIGNOR-254658 FGF12 protein P61328 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-253440 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 NOTCH3 protein Q9UM47 UNIPROT HES1 protein Q14469 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-174750 TNF protein P01375 UNIPROT SCN5A protein Q14524 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-253486 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 NEFL protein P07196 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-255272 acetylcholine smallmolecule CHEBI:15355 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-258631 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 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 SRC protein P12931 UNIPROT DNM1 protein Q05193 UNIPROT "up-regulates activity" phosphorylation Tyr231 LLPLRRGyIGVVNRS 9606 BTO:0000007 9880482 t lperfetto "Src-mediated tyrosine phosphorylation of dynamin is required for beta2-adrenergic receptor internalization and mitogen-activated protein kinase signalingHere we demonstrate that activation of beta2-adrenergic receptors (beta2-ARs) leads to c-Src-mediated tyrosine phosphorylation of dynamin, which is required for receptor internalization. Two tyrosine residues, Tyr231 and Tyr597, are identified as the major phosphorylation sites" SIGNOR-247124 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 SGI-1776 chemical CID:24795070 PUBCHEM PIM1 protein P11309 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206859 NUP85 protein Q9BW27 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-262093 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 ALK protein Q9UM73 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation Tyr293 RRPGEKTyTQRCRLF 9606 BTO:0000785 17537995 t lperfetto "Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression." SIGNOR-155298 PRKCD protein Q05655 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 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-251631 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 NCAPG protein Q9BPX3 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-263902 PRKCA protein P17252 UNIPROT PIP5K1B protein O14986 UNIPROT down-regulates phosphorylation Ser413 PSKKRCNsIAALKAT 9606 23909401 t lperfetto "Collaboration of ampk and pkc to induce phosphorylation of ser413 on pip5k1b resulting in decreased kinase activity and reduced ptdins(4,5)p2 synthesis in response to oxidative stress and energy restriction. we demonstrate that pkc can directly phosphorylate ser413 in vitro" SIGNOR-194820 INS protein P01308 UNIPROT FOXO1 protein Q12778 UNIPROT "down-regulates activity" 9606 10358076 f lperfetto "Insulin disrupts irs-dependent transactivation by fkhr, and phosphorylation of ser-256 by pkb is necessary and sufficient to mediate this effect." SIGNOR-68155 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT "down-regulates activity" dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t "PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3." SIGNOR-248427 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 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 "A1/b1 integrin" complex SIGNOR-C159 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-257701 FLT3 protein P36888 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates activity" 9606 BTO:0002144 28194038 f "inferred from family member" "FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity" SIGNOR-270268 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR S100A6 protein P06703 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12859951 f miannu "NF-kappaB transcription factor contributes to the activation of S100A6 gene expression in response to TNFalpha in HepG2 cells." SIGNOR-254803 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "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-245480 JNK proteinfamily SIGNOR-PF15 SIGNOR KIF5C protein O60282 UNIPROT "up-regulates activity" phosphorylation Ser176 CTERFVSsPEEVMDV 9606 BTO:0000142 27013971 t miannu "JNK phosphorylates KIF5C on S176 in the motor domain; a site that we show is phosphorylated in brain. In the peroxisome cargo-bound state, S176 phosphorylated KIF5C(1-560) transports to microtubule plus ends, whereas dephosphorylated KIF5C(1-560) is bound tightly to microtubules resulting in an immobile state. As a consequence, phosphorylation of S176 can facilitate plus-end cargo transport by KIF5C(1-560)." SIGNOR-264063 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 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 MAF1 protein Q9H063 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "down-regulates activity" binding 29378333 t lperfetto "The synthesis of transfer RNA (tRNA) is directed by RNA polymerase III (Pol III) specialized in high-level transcription of short DNA templates. Pol III recruitment to tRNA genes is controlled by two general initiation factors, TFIIIB and TFIIIC. |Under stress conditions, tRNA synthesis is negatively regulated by the MAF1 protein, which interacts directly with Pol III." SIGNOR-266198 E2F1 protein Q01094 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12110166 f fspada "We show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-90459 CNP protein P09543 UNIPROT MBP protein P02686 UNIPROT "down-regulates activity" 28076777 t SimoneGraziosi "We provide evidence that CNP directly associates with and organizes the actin cytoskeleton, thereby providing an intracellular strut that counteracts membrane compaction by myelin basic protein (MBP)." SIGNOR-269269 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 promethazine chemical CHEBI:8461 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-257788 TRIM27 protein P14373 UNIPROT STK38L protein Q9Y2H1 UNIPROT "up-regulates activity" ubiquitination Lys119 TGHIYAMkILRKSDM 10090 35670107 t "K11 corresponds to the 11th Lysine, which is in position 119 in the full length sequence" lperfetto "TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1" SIGNOR-270347 SMO protein Q99835 UNIPROT GATA3 protein P23771 UNIPROT "up-regulates activity" 17139329 t fferrentino "That GATA is a downstream effector of the hedgehog pathway." SIGNOR-253527 MAD2L1BP protein Q15013 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-265979 RBPJ/NOTCH complex SIGNOR-C97 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7566092 t lperfetto "Here we show that activated forms of mNotch associate with the human analogue of Su(H), KBF2/RBP-J kappa (refs 8,9) and act as transcriptional activators through the KBF2-binding sites of the HES-1 promoter." SIGNOR-209590 MAP2K7 protein O14733 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates phosphorylation Tyr185 TSFMMTPyVVTRYYR 9606 9312068 t gcesareni "Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues." SIGNOR-51203 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 ACVR1B protein P36896 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 11389842 t "Indirect_regulation of phosphorylation" miannu "Nodal Induces Smad Phosphorylation through ALK4 in a Cripto-Dependent Manner" SIGNOR-251943 CBL protein P22681 UNIPROT MYCBPAP protein Q8TBZ2 UNIPROT "up-regulates activity" monoubiquitination 9606 BTO:0000007 17255943 t miannu "We moreover found that AMAP1 is monoubiquitinated, rather than polyubiquitinated, by virtue of Cbl and provide evidence that the ability of AMAP1 to be monoubiquitinated is important for its involvement in invasion. " SIGNOR-272627 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49D1 protein C9J1S8 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-271269 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser670 SKVRGPVsGSPDSMN 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-251274 KDM5B protein Q9UGL1 UNIPROT PAX9 protein P55771 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-223875 NME1 protein P15531 UNIPROT MMP2 protein P08253 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-255165 RPS6KA4 protein O75676 UNIPROT ATF1 protein P18846 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1." SIGNOR-166661 TLRs proteinfamily SIGNOR-PF20 SIGNOR TLRs proteinfamily SIGNOR-PF20 SIGNOR "up-regulates activity" binding 9606 24352680 t lperfetto "Upon activation, tlrs hetero- or homodimerize inducing the recruitment of adaptor proteins via the cytoplasmic tir domain" SIGNOR-216301 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation 9606 15743829 t lperfetto "3-phosphoinositide-dependent kinase 1 (PDK1) phosphorylates the activation loop of a number of protein serine/threonine kinases of the AGC kinase superfamily, including protein kinase B (PKB; also called Akt)," SIGNOR-244469 PRKCZ protein Q05513 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-249291 NFKB1 protein P19838 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" binding 9606 9450761 t lperfetto "Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna" SIGNOR-55378 LYST protein Q99698 UNIPROT RAB5C protein P51148 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-266003 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 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 CSNK2A1 protein P68400 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-250923 CSNK2B protein P67870 UNIPROT CDC34 protein P49427 UNIPROT unknown phosphorylation Ser203 APAPDEGsDLFYDDY 9606 BTO:0000567 11546811 t llicata "CDC34 is specifically phosphorylated in vitro by recombinant CK2 and HeLa nuclear extract at five sites within the carboxyl-terminal 36 amino acids of CDC34. | 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-251057 (-)-anisomycin chemical CHEBI:338412 ChEBI PCSK7 protein Q16549 UNIPROT up-regulates "chemical activation" 9606 BTO:0000142 16581040 t gcesareni "These results indicate that activation of p38 mapk by anisomycin induces ltd and subsequently occludes electrically induced ltd" SIGNOR-145496 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 JAK1 protein P23458 UNIPROT IFNGR2 protein P38484 UNIPROT "up-regulates activity" phosphorylation 9606 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-249491 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1166 QKGSHQIsLDNPDYQ 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-250624 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 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 FOXO proteinfamily SIGNOR-PF27 SIGNOR G6PC1 protein P35575 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22521266 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-252920 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 CCP110 protein O43303 UNIPROT CALM2 protein P0DP24 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 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-266332 PPP2CA protein P67775 UNIPROT MKNK1 protein Q9BUB5 UNIPROT down-regulates dephosphorylation Thr250 NSCTPITtPELTTPC 9606 20927323 t gcesareni "Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e." SIGNOR-168310 MAPK3 protein P27361 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates phosphorylation Ser197 SATDSDGsPLSNSQP 9606 15632084 t amattioni "Phosphorylation of serines 159 and 197 by erk1/2 enhances proteasomal degradation of mkp-3" SIGNOR-132979 fluoxetine chemical CHEBI:5118 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-258738 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 RFFL protein Q8WZ73 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 18450452 t miannu "We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation." SIGNOR-271482 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 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT down-regulates phosphorylation Thr1491 DYHFVNAtEESDALA 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. eduction in the gtp-bound form of lrrk2 caused by t1491d mutation might have lowered the kinase activity, implicating the autophosphorylation of the roc domain in a negative feedback regulation of the kinase activity of lrrk2." SIGNOR-188425 "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-266465 fexofenadine chemical CHEBI:5050 ChEBI HRH1 protein P35367 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-257827 CSNK2A2 protein P19784 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser112 KRAGGEEsQFEMDI 9606 BTO:0000007 9806882 t lperfetto "The kinase is quite distinct from casein kinase 2, which also phosphorylates Ser-111 of 4E-BP1. The possible importance of these kinases in the phosphorylation of 4E-BP1 in fat cells is discussed. It is suggested that the phosphorylation of Ser-111 might be a priming event that facilitates the subsequent phosphorylation of Thr-36, Thr-45, Ser-64 and Thr69 by a rapamycin-sensitive process that initiates the dissociation of 4E-BP1 from eIF4E and hence the formation of the eIF4F complex." SIGNOR-249334 DGC complex SIGNOR-C217 SIGNOR "GABA-A (a4-b2-d) receptor" complex SIGNOR-C326 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-265436 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 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 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 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 BRD4 protein O60885 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-261094 SMURF2 protein Q9HAU4 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t 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-193119 MAPK1 protein P28482 UNIPROT RPS6K proteinfamily SIGNOR-PF26 SIGNOR "up-regulates activity" phosphorylation Thr573 AENGLLMtPCYTANF 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-252752 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1920 SPTYSPTsPKYSPTS 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-269366 VPS13B protein Q7Z7G8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 25492866 f miannu "Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. COH1 and RAB6 regulate neurite outgrowth in primary neurons" SIGNOR-266872 FAD smallmolecule CHEBI:16238 ChEBI FADH2 smallmolecule CHEBI:17877 ChEBI "up-regulates quantity" "precursor of" 9606 33450351 t miannu "ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a)." SIGNOR-269456 IL15RA protein Q13261 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" 9606 30029643 f areggio "In addition, level of mRNAs encoding C/EBPa, PPARg and FABP4, the classic adipogenic markers, was significantly lower in samples administrated with IL-15" SIGNOR-256228 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 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 BCL2L1 protein Q07817 UNIPROT VDAC1 protein P21796 UNIPROT "down-regulates activity" binding 10365962 t lperfetto "The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly" SIGNOR-249614 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 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 RRAGC protein Q9HB90 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-162054 RRAGB protein Q5VZM2 UNIPROT RAGBC complex SIGNOR-C115 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-228176 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 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM8 protein O00222 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-264073 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 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI Fatty_Acid_Biosynthesis phenotype SIGNOR-PH190 SIGNOR up-regulates 9606 BTO:0000759 24692351 f scontino "TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores. Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis." SIGNOR-267488 CSNK2A2 protein P19784 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -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-251005 CDK1 protein P06493 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr237 KQEKTPKtPKGPSSV 9606 14670079 t gcesareni "We further demonstrate that phospho-mkk1/mkk2 antibodies recognize npm on the c-terminal region, which is phosphorylated by cdc2 (cell division control kinase-2) during g2/m-phase. biochemical and immunocytochemistry analyses verified that the phospho-mkk1/mkk2 antibodies cross-reacted with npm that was phosphorylated at thr234 and thr237 during g2/m-phase, which are the same sites that are targeted by cdc2 (cell division cycle protein-2) during mitosis." SIGNOR-120334 VPS11 protein Q9H270 UNIPROT EZR protein P15311 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 21148287 t Sara "The interaction between the full-length Vps11 and ezrin was confirmed by immunoprecipitation and GST-pull down. ERM proteins and the HOPS complex are required for the transition from early to late endosomes" SIGNOR-261311 ATF4 protein P18848 UNIPROT WARS1 protein P23381 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-269429 CCL11 protein P51671 UNIPROT CCR3 protein P51677 UNIPROT up-regulates binding 9606 24702154 t "Eotaxin (CCL11) is a specific ligand for CCR3 and serves as a potent chemoattractant for eosinophils" SIGNOR-254356 EFNB2 protein P52799 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Lerk-5 is a ligand for both elk and hek and induces receptor phosphorylation" SIGNOR-52583 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 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1B protein P46527 UNIPROT down-regulates binding 9606 23400686 t gcesareni "Furthermore, akt promotes cell cycle progression through downregulation of the cyclin dependent kinase inhibitor p27kip1." SIGNOR-200875 BANP protein Q8N9N5 UNIPROT KHDRBS1 protein Q07666 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 26080397 t miannu "SMAR1 Interacts with Sam68 in a Signal-Dependent Manner. HDAC6 in complex with SMAR1 deacetylates Sam68. Here, we document that SMAR1, in cooperation with histone deacetylase 6 (HDAC6), interacts with Sam68 and maintains it in a deacetylated state, concomitantly inhibiting the inclusion of CD44 alternate exons." SIGNOR-266201 SMARCE1 protein Q969G3 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-270744 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 RPS6KA1 protein Q15418 UNIPROT FOS protein P01100 UNIPROT "up-regulates activity" phosphorylation Ser362 AAAHRKGsSSNEPSS 9606 8248197 t gcesareni "We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling." SIGNOR-37154 Gbeta proteinfamily SIGNOR-PF4 SIGNOR GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 10090 BTO:0002572 28646232 t "inferred from 70% family members" Gianni "We demonstrate that insulin-mediated activation of ERK1/2 results in phosphorylation of GSK3Œ≤ at S9 independently of Akt/mTORC1 activity in Tsc2 null mouse embryonic fibroblasts. In addition, we show that inhibition of ERK1/2 rescues GSK3Œ≤ activity and restores protein synthesis in Tsc2 ‚àí/‚àí MEFs to normal levels" SIGNOR-270068 ATXN2L protein Q8WWM7 UNIPROT MPL protein P40238 UNIPROT down-regulates binding 9606 11784712 t miannu "A2d binds to cytokine receptors mpl and epo-r. A2d is associated with these unoccupied receptorsin vivo,and stimulation with tpo or epo causes the rapid dissociation of a2d from the activated receptor." SIGNOR-113891 SOX9 protein P48436 UNIPROT COL11A2 protein P13942 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-251758 POLR2J protein P52435 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-266161 KCNQ3 protein O43525 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-265984 MAPK3 protein P27361 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-270301 CSNK1E protein P49674 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-230728 AKT2 protein P31751 UNIPROT GSK3A protein P49840 UNIPROT down-regulates phosphorylation 9606 16023596 t gcesareni "Activated pi3k/akt pathway results in inhibitory phosphorylation of gsk3" SIGNOR-138179 TDGF1 protein P13385 UNIPROT NODAL protein Q96S42 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-251937 TRAF2 protein Q12933 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0000785 15084608 t lperfetto "We report here that one important mechanism of nik regulation is through its dynamic interaction with the tumor necrosis factor receptor-associated factor 3 (traf3). Traf3 physically associates 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-124233 ROCK2 protein O75116 UNIPROT IRF4 protein Q15306 UNIPROT up-regulates phosphorylation Ser448 HRSIRHSsIQE 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-167471 ROCK1 protein Q13464 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT down-regulates phosphorylation Ser1150 LERGRKVsIVSKPVL 9606 BTO:0000887;BTO:0001260 19103606 t gcesareni "Rho-kinase, an effector of rhoa, phosphorylated p190a rhogap at ser(1150) and attenuated p190a rhogap activity in cos7 cells." SIGNOR-182849 TP53 protein P04637 UNIPROT PERP protein Q96FX8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10733530 f gcesareni "Perp induction is linked to p53-dependent apoptosis, including in response to e2f-1-driven hyperproliferation. Furthermore, analysis of the perp promoter suggests that perp is directly activated by p53." SIGNOR-75877 PRL protein P01236 UNIPROT KRT5 protein P13647 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20103718 f Regulation miannu "PRL up-regulated expression of keratins K5 and K14 and the epithelial stem cell-associated keratins K15 and K19 in organ-cultured HFs and/or isolated HF keratinocytes." SIGNOR-251903 IC-87114 chemical CHEBI:90686 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206190 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 GRPEL1 protein Q9HAV7 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-267691 STK39 protein Q9UEW8 UNIPROT SLC12A1 protein Q13621 UNIPROT "up-regulates activity" phosphorylation Thr100 TNTYYLQtFGHNTMD 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-263129 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 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 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser97 TIAESEDsQESVDSV 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-64254 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 ABRAXAS1 protein Q6UWZ7 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates binding 9606 17525340 t gcesareni "Full length abraxas binds the brct-repeats of brca1the rap80-abraxas complex may help recruit brca1 to dna damage sites in part through recognition of ubiquitinated proteins" SIGNOR-155144 E4F1 protein Q66K89 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" ubiquitination Lys319 TSSSPQPkKKPLDGE 9606 BTO:0001938 17110336 t miannu "E4F1 Has an Intrinsic Ubiquitin E3 Ligase Activity that Drives K48-type Ubiquitylation of p53. These data demonstrate that E4F1 stimulates the ubiquitylation of p53 on the lysine cluster K319–K321, i.e., at sites distinct from those targeted by Hdm2. p53 forms Ubiquitylated by E4F1 Are Localized on Chromatin. In striking contrast with Ub-p53 forms stimulated by Hdm2, which are mainly cytosoluble and targeted to the proteasome, we found that E4F1-stimulated Ub-p53 forms are tightly associated with chromatin, suggesting that they could be involved in transcription." SIGNOR-271394 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation Ser196 KLRRRFSsLHFMVEV -1 9812896 t "Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity." SIGNOR-251473 NANOGP8 protein Q6NSW7 UNIPROT FGFR2 protein P21802 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10900 BTO:0000667 23839044 f Luana "Constitutive NanogP8 overexpression in adult L1 mice reduced CD34+α6+ and Lrig-1+ bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun." SIGNOR-266090 PPM1B protein O75688 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-248343 CORT protein O00230 UNIPROT SSTR4 protein P31391 UNIPROT up-regulates binding 9606 BTO:0000938 11011067 t gcesareni "Cortistatin is known to bind all five cloned somatostatin receptors and share many pharmacological and functional properties with somatostatin including the depression of neuronal activity." SIGNOR-82493 PPP3CB protein P16298 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-248361 TNF protein P01375 UNIPROT AKT1 protein P31749 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-106593 STK4 protein Q13043 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr12 FSSRSSKtFKPKKNI 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-175829 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 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-271365 TP53 protein P04637 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 9122197 f gcesareni "P53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis" SIGNOR-47541 "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 Ub:E2 complex SIGNOR-C497 SIGNOR UBOX5 protein O94941 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-271150 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 EPAS1 protein Q99814 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-271588 CAMK2A protein Q9UQM7 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" phosphorylation Ser1070 DSFLQRYsSDPTGAL 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-250620 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR ID2 protein Q02363 UNIPROT down-regulates phosphorylation Ser5 sPVRSVRK 9606 9029153 t lperfetto "Id2 acts by forming heterodimers that are unable to bind to specific (e-box) dna sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (cdks). In vitro, id2 can be phosphorylated by either cyclin e-cdk2 or cyclin a-cdk2_" SIGNOR-216698 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 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 PTPRG protein P23470 UNIPROT ERBB2 protein P04626 UNIPROT "up-regulates activity" dephosphorylation Tyr1248 PTAENPEyLGLDVPV -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-254701 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 UBE3A protein Q05086 UNIPROT RAD23A protein P54725 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 10373495 t miannu " Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP.  E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B." SIGNOR-272550 MRPL22 protein Q9NWU5 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-262371 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR "BRCA1-C complex" complex SIGNOR-C299 SIGNOR "form complex" binding 25400280 t lperfetto "The BRCA1–C complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2" SIGNOR-263221 PRKCA protein P17252 UNIPROT RRAD protein P55042 UNIPROT unknown phosphorylation Ser299 KMAFRAKsKSCHDLS -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-249008 CTDSPL protein O15194 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-248313 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 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 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Thr179 FAKTFVGtPYYMSPE 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151771 ZM447439 chemical CHEBI:91376 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207923 FOXA1 protein P55317 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 19127412 f miannu "Overexpression of foxa1 promoted apoptosis" SIGNOR-256642 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 pemetrexed chemical CHEBI:63616 ChEBI GART protein P22102 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205883 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea chemical CHEBI:124917 ChEBI CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193787 BMS-265246 chemical CID:5329775 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190434 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK3 protein Q00526 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189987 SIRT1 protein Q96EB6 UNIPROT Cell_cycle_block phenotype SIGNOR-PH10 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress" SIGNOR-217878 SOX4 protein Q06945 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001545 24183681 f miannu "These data demonstrate an HSC cell intrinsic role for Sox4 on proliferation induced by loss of C/EBPα." SIGNOR-260133 EP300 protein Q09472 UNIPROT TP53 protein P04637 UNIPROT up-regulates acetylation Lys382 QSTSRHKkLMFKTEG 9606 BTO:0000567 11070080 t gcesareni "P300 acetylates and activates the tumor suppressor p53 after dna damage." SIGNOR-84074 BIRC2 protein Q13490 UNIPROT CASP2 protein P42575 UNIPROT down-regulates binding 9606 16701639 t gcesareni "However, among hiap1, hiap2 and xiap, only hiap2 binds and inhibits caspase-2." SIGNOR-146738 HDAC4 protein P56524 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 t gcesareni "Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation." SIGNOR-146122 AT9283 chemical CID:11696609 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190014 "aliskiren fumarate" chemical CHEBI:53777 ChEBI REN protein P00797 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189483 KAT2A protein Q92830 UNIPROT H3-2 protein Q5TEC6 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-269599 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine chemical CHEBI:91419 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190182 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194334 LSM-1131 chemical CHEBI:91398 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189873 3-methyladenine chemical CHEBI:38635 ChEBI PIK3C3 protein Q8NEB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205636 AMPK complex SIGNOR-C15 SIGNOR MAPK14 protein Q16539 UNIPROT "up-regulates activity" 10090 20660302 f "P38 MAPK mediates the effect of AMPK on Gr induced transcriptional activity" SIGNOR-255951 CTNNB1 protein P35222 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 19175684 f gcesareni "In-teractions between beta-catenin and runx2 play an im-portant role in bmp-9-induced osteogenic differentia-tion of mscs." SIGNOR-183532 ACVR2A protein P27037 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 9748228 t fspada "The major bmp7 type i receptor observed was alk2," SIGNOR-60234 ULK2 protein Q8IYT8 UNIPROT PRKAG3 protein Q9UGI9 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity." SIGNOR-173095 DPM1 protein O60762 UNIPROT "DPM complex" complex SIGNOR-C289 SIGNOR "form complex" binding 9606 10835346 t lperfetto "Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3." SIGNOR-262563 CUDC-101 chemical CID:24756910 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191148 R547 chemical CID:6918852 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206358 MAP3K6 protein O95382 UNIPROT MAP3K5 protein Q99683 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr838 GINPCTEtFTGTLQY 9606 17210579 t Manara "ASK2 Activates ASK1 by Phosphorylation" SIGNOR-260832 vatalanib chemical CHEBI:90620 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207648 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT "up-regulates activity" dephosphorylation 9606 23015147 t "Calcineurin is known to facilitate the nuclear translocation of the nuclear factor of activated T cells (NFAT)." SIGNOR-253329 MAP3K11 protein Q16584 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates 9606 9733513 f gcesareni "This scaffold protein selectively enhanced jnk activation by the mlk signaling pathway." SIGNOR-59884 FLT3 protein P36888 UNIPROT GRB2 protein P62993 UNIPROT "up-regulates activity" binding 10090 10080542 t gcesareni "FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc" SIGNOR-245060 ENMD-2076 chemical CID:16041424 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191469 JUN protein P05412 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding 9606 25875593 t irozzo "C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site." SIGNOR-256367 "ixazomib citrate" chemical CHEBI:90939 ChEBI PSMB5 protein P28074 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194536 TET3 protein O43151 UNIPROT OGT protein O15294 UNIPROT up-regulates binding 9606 23353889 t miannu "Tet2 and tet3 associate with the o_glcnac transferase ogt / tet2 and tet3 promote ogt_mediated glcnacylation" SIGNOR-200729 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189996 SGX-523 chemical CHEBI:90624 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206905 WWTR1 protein Q9GZV5 UNIPROT MYOD1 protein P15172 UNIPROT up-regulates binding 9606 20466877 t gcesareni "Taz physically interacts with myod through the ww domain and activates myod-dependent gene transcription." SIGNOR-165414 N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide chemical CHEBI:91336 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207666 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR3 protein Q9UBY5 UNIPROT up-regulates "chemical activation" 9606 8276865 t gcesareni "Lpa activates its own g protein-coupled receptor(s)." SIGNOR-36389 MAPK1 protein P28482 UNIPROT 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-219217 ACTL6A protein O96019 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-270718 CCT137690 chemical CID:25154041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190892 "B-WICH complex" complex SIGNOR-C447 SIGNOR MYC protein P01106 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 25883140 t miannu "The B-WICH complex allows c-Myc to bind to a site in the IGS. c-Myc requires the B-WICH complex to remodel chromatin for its function." SIGNOR-268842 NONO protein Q15233 UNIPROT TOP1 protein P11387 UNIPROT up-regulates binding 9606 BTO:0000017 9756848 t miannu "We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i" SIGNOR-60557 RPS6KB1 protein P23443 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 17181399 f gcesareni "Finally, downregulation of p70 s6 kinase by sirna significantly enhanced the fgf-2-stimulated vegf release and phosphorylation of sapk/jnk." SIGNOR-149367 GAB1 protein Q13480 UNIPROT ARHGAP32 protein A7KAX9 UNIPROT up-regulates relocalization 9606 12819203 t gcesareni "Gc-gap, a rho family gtpase-activating protein that interacts with signaling adapters gab1 and gab2." SIGNOR-102586 budesonide chemical CHEBI:3207 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 11208622 t ashma gcesareni SIGNOR-251687 AGO2 protein Q9UKV8 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR "form complex" binding 9606 23661684 t miannu SIGNOR-143102 FOXO1 protein Q12778 UNIPROT FSHB protein P01225 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004467 24065703 f miannu "We demonstrate that FOXO1 represses basal and GnRH-induced Fshb transcription in LβT2 cells." SIGNOR-254185 BRCA1 protein P38398 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 15549093 f lperfetto "The BRCA1 protein also contributes to cell-cycle arrest and DNA repair by homologous recombination" SIGNOR-251500 EPC1 protein Q9H2F5 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-269305 crizotinib chemical CHEBI:64310 ChEBI ALK protein Q9UM73 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191133 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121994 XL147 chemical CHEBI:71957 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207854 FLT3LG protein P49771 UNIPROT FLT3 protein P36888 UNIPROT up-regulates binding 9606 BTO:0001271 12681969 t gcesareni "Flt3 is activated by binding of its natural flt3-ligand (flt3-l)," SIGNOR-99750 "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25901680 f lperfetto "Ribosomes are translational machineries that catalyse protein synthesis." SIGNOR-262412 AMG-208 chemical CHEBI:90626 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189507 SKI protein P12755 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates binding 9606 12419246 t gcesareni "Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5." SIGNOR-195630 TOP2B protein Q02880 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 24463367 f lperfetto "Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells" SIGNOR-242533 PDE4DIP protein Q5VU43 UNIPROT PRKAR1A protein P10644 UNIPROT up-regulates binding 9606 21569246 t miannu "Mmgl acts as a dual-specific akap by anchoring pka regulatory isoforms r1a and r2a." SIGNOR-173769 "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI PRKACA protein P17612 UNIPROT up-regulates "chemical activation" 9606 BTO:0000007 22863277 t milica "The cAMP signaling cascade can activate protein kinase a (PKA)" SIGNOR-198492 WWTR1 protein Q9GZV5 UNIPROT PAX3 protein P23760 UNIPROT up-regulates binding 10090 BTO:0000165;BTO:0000222 16300735 t gcesareni "These results indicate that pax3 specifically interacts with taz both in vitro and in vivo." SIGNOR-236879 alvocidib chemical CHEBI:47344 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191529 "torin 2" chemical CHEBI:90682 ChEBI RPS6KB1 protein P23443 UNIPROT down-regulates 9606 23436801 f gcesareni "Torin2 inhibited mtorc1-dependent t389 phosphorylation on s6k (rps6kb1)" SIGNOR-201502 GPER1 protein Q99527 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000130 22203955 t gcesareni "However, grpr preferentially couples to galfaq proteins." SIGNOR-195320 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione chemical CHEBI:91368 ChEBI PRKCE protein Q02156 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191496 TP53INP1 protein Q96A56 UNIPROT MAP1LC3A protein Q9H492 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1-lc3 interaction occurs via a functional lc3-interacting region (lir)." SIGNOR-196670 6alpha-methylprednisolone chemical CHEBI:6888 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 1159081 t inflammation gcesareni SIGNOR-251697 PD318088 chemical CID:10231331 PUBCHEM MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205737 regorafenib chemical CHEBI:68647 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206418 olaparib chemical CHEBI:83766 ChEBI PARP2 protein Q9UGN5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195019 BTRC protein Q9Y297 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "form complex" binding 9606 10023660 t gcesareni "The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin." SIGNOR-64496 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR VAV1 protein P15498 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 11790798 t lperfetto "Thus, the c-terminal tail of vav serves as a direct substrate of bcr-abl in vitro." SIGNOR-114094 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT down-regulates dephosphorylation Tyr751 SKDESVDyVPMLDMK 9606 18567737 t gcesareni "Ptp1b blocked pdgf-induced tyr716 and tyr751 phosphorylation of the pdgfr." SIGNOR-179076 TWIST1 protein Q15672 UNIPROT CSNK2A1 protein P68400 UNIPROT down-regulates 9606 22975381 f amattioni "Ck2-mediated phosphorylation at ser392 of p53 was attenuated in the presence of recombinant twist1" SIGNOR-192064 DCC protein P43146 UNIPROT Chemoattraction_of_axon phenotype SIGNOR-PH197 SIGNOR up-regulates 9606 BTO:0001484 25881791 f miannu "DCC constitutively expresses on the axonal surface. Netrin-1-binding to DCC induces chemoattraction" SIGNOR-268163 PRKCH protein P24723 UNIPROT PTPN11 protein Q06124 UNIPROT unknown phosphorylation Ser595 GLMQQQKsFR 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-249140 "AMG 900" chemical CID:24856041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189498 AVP protein P01185 UNIPROT BAD protein Q92934 UNIPROT down-regulates 9606 BTO:0000938 BTO:0000142 18402937 f gcesareni "Vp induces phosphorylation of the pro-apoptotic protein bad and prevents cytochrome c release." SIGNOR-178197 2-(6,7-dimethoxy-4-quinazolinyl)-5-(2-pyridinyl)-1,2,4-triazol-3-amine chemical CHEBI:91330 ChEBI ATM protein Q13315 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191094 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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207669 ULK2 protein Q8IYT8 UNIPROT PRKAB1 protein Q9Y478 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C15 21460634 t gcesareni "Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity" SIGNOR-173092 MK-2461 chemical CID:44137946 PUBCHEM FLT1 protein P17948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194367 QRICH1 protein Q2TAL8 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 33384352 f miannu "QRICH1 promotes cell death and its translation is upregulated by the PERK-eIF2α axis under ER stress." SIGNOR-269399 sapitinib chemical CHEBI:132986 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190149 masitinib chemical CHEBI:63450 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194257 WAY-600 chemical CID:25229526 PUBCHEM MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-207788 CRP protein P02741 UNIPROT LPL protein P06858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18708524 f "Regulation of expression" miannu "C-reactive protein enhances macrophage lipoprotein lipase expression." SIGNOR-251852 ERBB4 protein Q15303 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 16729043 t gcesareni "Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4." SIGNOR-146888 alvocidib chemical CHEBI:47344 ChEBI CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192038 ezogabine chemical CHEBI:68584 ChEBI KCNQ2 protein O43526 UNIPROT up-regulates "chemical activation" 9606 Other t "Selleck;anticonvulsant for KCNQ2/3 currents" gcesareni SIGNOR-206483 PIDD1 protein Q9HB75 UNIPROT "Caspase-2 PIDDosome" complex SIGNOR-C292 SIGNOR "form complex" binding 9606 20158568 t miannu "The PIDDosome consists of the proteins PIDD, RAIDD and caspase-2." SIGNOR-262643 CASP3 protein P42574 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 10200555 f amattioni "Caspase-3 is required for blebbing, chromatin condensation and dna fragmentation" SIGNOR-66863 "PIK-75 Hydrochloride" chemical CID:45265864 PUBCHEM PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252652 UBAP2 protein Q5T6F2 UNIPROT ANXA2 protein P07355 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0002181 27121050 t Sara "UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination" SIGNOR-261314 "Elongator complex" complex SIGNOR-C466 SIGNOR TUBA8 protein Q9NY65 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-269721 PHA-848125 chemical CID:16718576 PUBCHEM CCNA2 protein P20248 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206148 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192780 DUSP4 protein Q13115 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 16849326 t gcesareni "This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38" SIGNOR-147958 "GW 3965" chemical CHEBI:79995 ChEBI NR1H3 protein Q13133 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-193015 SNW1 protein Q13573 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 11404076 t gcesareni "We find that Notch 3 IC, like Notch 1 IC, can bind the SKIP and PCAF proteins" SIGNOR-108499 rosiglitazone chemical CHEBI:50122 ChEBI PPARG protein P37231 UNIPROT "up-regulates activity" "chemical activation" 9534 7768881 t "An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)" SIGNOR-251646 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser253 SVEFEVEsLDSEDYS 9606 12167711 t gcesareni "Hypophosphorylation of mdm2 augments p53 stability." SIGNOR-91195 ADIPOR1 protein Q96A54 UNIPROT APPL1 protein Q9UKG1 UNIPROT up-regulates binding 9606 16622416 t milica "Appl1 interacts with adiponectin receptors in mammalian cells and the interaction is stimulated by adiponectin." SIGNOR-146212 NODAL protein Q96S42 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0004094 15531507 f Regulation miannu "Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7." SIGNOR-251935 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR RUNX2 protein Q13950 UNIPROT up-regulates "transcriptional regulation" 9606 27563484 f ggiuliani "Smad1/5/8-Smad4 complex transcribed Runx2 expression, as they complex with Runx2 to initiate other osteoblast gene expression." SIGNOR-255836 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A12 protein P48065 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207031 PHA-767491 chemical CID:11715767 PUBCHEM CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206112 PF-03814735 chemical CID:49830590 PUBCHEM PTK2 protein Q05397 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205959 NOD2 protein Q9HC29 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 18079694 f miannu "Nod1 and Nod2 stimulation activates NF-kappaB through RICK, a caspase-recruitment domain-containing kinase." SIGNOR-252412 MAPK3 protein P27361 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation 9606 23583303 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-201687 SP6 protein Q3SY56 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 19088080 f lperfetto "Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2." SIGNOR-271695 motesanib chemical CHEBI:51098 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194563 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation 9606 21808241 t "inferred from 70% family members" gcesareni "Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2." SIGNOR-270218 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT up-regulates binding 9606 12704343 t milica "Both il-4 and il-13 use the IL-4R Chain as a component of their receptors." SIGNOR-100753 SOX2 protein P48431 UNIPROT NR2E1 protein Q9Y466 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22194602 f miannu "Sox2 positively regulates tlx expression" SIGNOR-191714 dacomitinib chemical CHEBI:132268 ChEBI ERBB4 protein Q15303 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205942 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10812968 t amattioni "Signal transduction by cntf requires that it bind first to cntfr alpha. Cntf activates downstream signaling molecules" SIGNOR-77408 TRPC6 protein Q9Y210 UNIPROT PPP3CA protein Q08209 UNIPROT "up-regulates activity" 9606 27383564 f gcesareni "TRPC6 channel-dependent [Ca2+]i elevation and sequential activation of the calcineurin." SIGNOR-253328 AMOTL2 protein Q9Y2J4 UNIPROT Cell_migration phenotype SIGNOR-PH38 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-271872 TIAM1 protein Q13009 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 12393875 t gcesareni "Lpa-induced rac activation requires tiam1" SIGNOR-94691 FOS protein P01100 UNIPROT JUN protein P05412 UNIPROT "up-regulates activity" binding 10090 2516828 t "The cFos proto-oncoprotein associates with cJun to form a heterodimer with increased DNA binding and transcriptional activities." SIGNOR-252087 Frizzled proteinfamily SIGNOR-PF11 SIGNOR DVL1 protein O14640 UNIPROT up-regulates binding 19279717 t apalma "Wnt signaling is transduced through Fz independent of LRP5/6 leading to the activation of Dsh." SIGNOR-255891 GTF3C6 protein Q969F1 UNIPROT TFIIIC complex SIGNOR-C392 SIGNOR "form complex" binding 9606 29378333 t lperfetto "Both yeast and human TFIIIC consist of six polypeptides organized into two globular domains" SIGNOR-266183 MIB1 protein Q86YT6 UNIPROT DLL3 protein Q9NYJ7 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-209672 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR "up-regulates activity" 9606 BTO:0000567 22749528 f Luana "Leucine and Glutamine Activate Glutaminolysis and mTORC1" SIGNOR-268016 GNAI3 protein P08754 UNIPROT TNFAIP8 protein O95379 UNIPROT "up-regulates activity" binding 9606 20607800 t "TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation" SIGNOR-256490 seliciclib chemical CHEBI:45307 ChEBI CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206568 NFIL3 protein Q16649 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 10090 BTO:0003104 10082541 f lperfetto "the effect of NFIL3 on cytokine-mediated cell survival was independent of an effect on cell proliferation." SIGNOR-242760 CSNK2A1 protein P68400 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Thr1343 FSDFDEKtDDEDFVP 9606 9804834 t llicata "Casein kinase II catalyzes a mitotic phosphorylation on threonine 1342 of human DNA topoisomerase IIalpha" SIGNOR-250966 Telatinib chemical CID:9808844 PUBCHEM FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207221 4-[6-[4-(1-piperazinyl)phenyl]-3-pyrazolo[1,5-a]pyrimidinyl]quinoline chemical CHEBI:91387 ChEBI BMPR1A protein P36894 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193642 MTX1 protein Q13505 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-267684 GSK1059615 chemical CHEBI:71955 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192693 RHEB protein Q15382 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "down-regulates activity" binding -1 25660019 t Luana "Rheb GTPase directly binds and activates PERK in vitro" SIGNOR-260873 HIP1 protein O00291 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 11007801 f miannu "Huntingtin interacting protein 1 induces apoptosis via a novel caspase-dependent death effector domain." SIGNOR-256646 TNFAIP3 protein P21580 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "down-regulates activity" deubiquitination 9606 18164316 t lperfetto "A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6" SIGNOR-160223 CENPE protein Q02224 UNIPROT MAD1L1 protein Q9Y6D9 UNIPROT "up-regulates activity" 10090 BTO:0000452 12925705 f lperfetto "CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores" SIGNOR-252044 XAV939 chemical CHEBI:62878 ChEBI TNKS protein O95271 UNIPROT down-regulates "chemical inhibition" 9606 19759537 t gcesareni "Xav939 inhibits the poly-adp-ribosylating enzymes tankyrase 1 and tankyrase 2." SIGNOR-188054 RASSF5 protein Q8WWW0 UNIPROT RASSF1 protein Q9NS23 UNIPROT "up-regulates activity" binding 9606 22195963 t lperfetto "NORE1A can heterodimerize with RASSF1A and, thus, mediate K-Ras regulation of RASSF1A" SIGNOR-249587 TGFB1 protein P01137 UNIPROT PIK3R1 protein P27986 UNIPROT "up-regulates activity" binding 9606 19114990 t lperfetto "While association of the TGF_RI receptor with p85 requires TGF-_ stimulation." SIGNOR-217960 3-(3-oxo-1H-indol-2-ylidene)-1H-indol-2-one chemical CHEBI:92322 ChEBI GSK3B protein P49841 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193402 IGF1R protein P08069 UNIPROT IRS2 protein Q9Y4H2 UNIPROT up-regulates phosphorylation 9606 10471495 t flangone "Our results reveal that igf-1 receptors promote beta-cell development and survival through the irs-2 signalling pathway." SIGNOR-70477 TGFB1 protein P01137 UNIPROT RNF111 protein Q6ZNA4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 14657019 f lpetrilli "Expression of arkadia is down-regulated by tgf-beta." SIGNOR-119669 IL1A protein P01583 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 21304099 f lperfetto "Interleukin-1 in the pathogenesis and treatment of inflammatory diseases" SIGNOR-171873 GLS protein O94925 UNIPROT Glutaminolysis phenotype SIGNOR-PH119 SIGNOR "up-regulates activity" 9606 28053289 f "Glutaminase is the rate-limiting enzyme in glutaminolysis and it is encoded by two different genes, GLS and GLS2." SIGNOR-259999 "A5/b1 integrin" complex SIGNOR-C163 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity" 15721307 f lperfetto "Previous reports indicated that the prosurvival signal mediated through α5β1-fibronectin interactions was due to increased Bcl-2 levels" SIGNOR-253310 "SNS-314 Mesylate" chemical CID:24995523 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207102 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 20663147 t gcesareni "Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation." SIGNOR-167152 APOC3 protein P02656 UNIPROT LPL protein P06858 UNIPROT "down-regulates activity" 9606 17315402 f Regulation miannu "Apolipoprotein CIII inhibits the lipoprotein lipase." SIGNOR-251850 AGPAT3 protein Q9NRZ7 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI up-regulates "chemical modification" 9606 12401205 t gcesareni "Pa can be generated by the acylation of lyso-pa by lyso-pa acyl transferases" SIGNOR-94864 MPO-ANCA complex SIGNOR-C474 SIGNOR ROS stimulus SIGNOR-ST2 SIGNOR up-regulates -1 2161532 f lperfetto "ANCA-induced release of ROS measured by chemiluminescence." SIGNOR-270590 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Ser359 SPSTPVGsPQGLAGT 9606 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161531 F2 protein P00734 UNIPROT F2RL2 protein O00254 UNIPROT up-regulates binding 9606 11356985 t gcesareni "as noted previously, the human form of par-3 activated phosphoinositide signaling in response to thrombin when overexpressed in cos-7 cells" SIGNOR-108225 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT up-regulates binding 9606 1698556 t gcesareni "We have also provided biological and physical evidence that scf is a ligand for the c-kit receptor." SIGNOR-21193 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR IL10 protein P22301 UNIPROT "up-regulates quantity" 10090 BTO:0004732 26208884 f "The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12." SIGNOR-256080 regorafenib chemical CHEBI:68647 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206415 GSK690693 chemical CHEBI:90677 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193000 STC2 protein O76061 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 10090 BTO:0000298 29207625 f lperfetto "STC2 activates STAT3 signaling pathway in the hypothalamus and GT1-7 cells" SIGNOR-260406 "Brivanib alaninate" chemical CID:11154925 PUBCHEM FGFR2 protein P21802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190720 seliciclib chemical CHEBI:45307 ChEBI CCNE1 protein P24864 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206565 SKP1 protein P63208 UNIPROT SCF-betaTRCP complex SIGNOR-C5 SIGNOR "form complex" binding 9606 10023660 t gcesareni "The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin." SIGNOR-64514 ARSA protein P15289 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates activity" acetylation 9606 237937 t Regulation miannu "ASA acetylates hemoglobin. Purified acetylated hemoglobin had a slightly increased oxygen affinity and decreased heme-heme interaction." SIGNOR-251773 6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline chemical CHEBI:91417 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193522 orantinib chemical CHEBI:91088 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207441 PI-103 chemical CHEBI:90524 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206163 GDF2 protein Q9UK05 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 19175684 f gcesareni "Wnt3a and bmp-9 enhanced each other's ability to induce alp in mscs" SIGNOR-183535 MK-2461 chemical CID:44137946 PUBCHEM MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194384 LRIG1 protein Q96JA1 UNIPROT LRIG3 protein Q6UXM1 UNIPROT down-regulates 9606 23723069 f miannu "Lrig1 destabilizes lrig3, limiting lrig3's positive effects on receptors and identifying lrig3 as a new target of lrig1." SIGNOR-202177 MKNK1 protein Q9BUB5 UNIPROT EIF4E protein P06730 UNIPROT up-regulates phosphorylation 9606 20626350 t gcesareni "Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e." SIGNOR-166646 MET protein P08581 UNIPROT GRAP protein Q13588 UNIPROT up-regulates binding 9606 8662889 t gcesareni "To efficiently promote transformation met requires direct binding with grb2." SIGNOR-42358 "Tert-butyl 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]acetate" chemical CID:46907787 PUBCHEM BRD4 protein O60885 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20871596 t "Simone Vumbaca" "JQ1 displaces BRD4 from nuclear chromatin in cells" SIGNOR-261123 ABL1 protein P00519 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr463 NDTGSRYyKEIPLSE 9606 BTO:0000567 12637538 t "Abl Phosphorylates and Activates PKD through Tyr463 Phosphorylation" SIGNOR-251430 COL2A1 protein P02458 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR up-regulates binding 9606 9685391 t gcesareni "We have isolated a novel collagen type ii binding integrin, a10b1," SIGNOR-59349 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr471 YEDAGSHyLCLLKAR 9606 12408982 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-95242 SGI-1776 chemical CID:24795070 PUBCHEM PIM3 protein Q86V86 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206896 BUB1 protein O43683 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-168192 6-propyl-2-thiouracil smallmolecule CHEBI:8502 ChEBI DIO1 protein P49895 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001379 27347897 t scontino "The activity of D1 but not D2 or D3 is inhibited by 6n-propylthiouracil (PTU)." SIGNOR-267280 CUL4A protein Q13619 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154502 CCT129202 chemical CID:16202152 PUBCHEM AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190880 F2R protein P25116 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22972936 t milica "Par1 acts through g12/13 and rho gtpase to inhibit the lats1/2 kinase." SIGNOR-199010 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207248 CADM2 protein Q8N3J6 UNIPROT Cell_adhesion phenotype SIGNOR-PH7 SIGNOR up-regulates 9606 BTO:0000962 17967169 f Gianni "The adhesion molecule Necl-3/SynCAM-2 localizes to myelinated axons, binds to oligodendrocytes and promotes cell adhesion." SIGNOR-268856 progesterone smallmolecule CHEBI:17026 ChEBI COMT protein P21964 UNIPROT down-regulates 17138778 f "Regulation of expression" miannu "Catechol-O-methyltransferase expression was down-regulated by progesterone or estrogen." SIGNOR-251960 CHIR-124 chemical CID:11502647 PUBCHEM CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190973 dacomitinib chemical CHEBI:132268 ChEBI ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205939 FOXO3 protein O43524 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0001103 15109499 f gcesareni "Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy." SIGNOR-241949 CDK18 protein Q07002 UNIPROT RB1 protein P06400 UNIPROT unknown phosphorylation -1 28361970 t lperfetto "Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro. " SIGNOR-264558 R406 chemical CID:11984591 PUBCHEM SYK protein P43405 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206340 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide chemical CHEBI:91447 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194913 GSK256066 chemical CID:9827968 PUBCHEM PDE4B protein Q07343 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192982 LHX2 protein P50458 UNIPROT CGA protein P01215 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0001538 7513049 t Luana "In Cos cells, LH-2 activated the a-subunit promoter approximately twofold" SIGNOR-266055 LTBR protein P36941 UNIPROT Lymphoma phenotype SIGNOR-PH14 SIGNOR up-regulates 9606 17633025 f lperfetto "The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense." SIGNOR-156902 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser143 PPFPSRDsGRLSPDL 9606 21658950 t miannu "Phosphorylation by Aurora B is required for full Haspin activity toward H3T3 in mitosis" SIGNOR-262656 NUMA1 protein Q14980 UNIPROT TUBB protein P07437 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-116900 SFPQ protein P23246 UNIPROT "LMX1B/SFPQ/PSPC1 complex" complex SIGNOR-C106 SIGNOR "form complex" binding 10090 23308148 t miannu "LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo." SIGNOR-223970 CSNK2A2 protein P19784 UNIPROT HNRNPC protein P07910 UNIPROT unknown phosphorylation Ser260 SEGGADDsAEEGDLL -1 12564933 t llicata "Protein kinase CK2 phosphorylates hnRNP-C1/C2 at S247" SIGNOR-251007 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207606 "A6/b1 integrin" complex SIGNOR-C164 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-269013 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 14585074 f amattioni "Caspase-3 is responsible for apoptosis execution" SIGNOR-256474 Bafetinib chemical CID:24853523 PUBCHEM BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190224 OGT protein O15294 UNIPROT PYGL protein P06737 UNIPROT "up-regulates activity" glycosylation Ser430 VDRLRRMsLIEEEGS 9606 BTO:0002181 34939084 t Luana "O-GlcNAcylation at Ser-430 promotes PYGL activity" SIGNOR-267988 PPP1R2 protein P41236 UNIPROT PPP1CA protein P62136 UNIPROT down-regulates binding 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-160651 NCOR2 protein Q9Y618 UNIPROT SNW1 protein Q13573 UNIPROT up-regulates binding 9606 BTO:0000222 BTO:0000887 10713164 t "Ncor2 is a Skip corepressor" gcesareni "Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt." SIGNOR-74227 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193531 HDAC1 protein Q13547 UNIPROT RELA protein Q04206 UNIPROT down-regulates binding 9606 SIGNOR-C13 17183360 t gcesareni "Phosphorylation at thr505 by the chk1 inhibits rela transactivation and results in its increased association with hdac1." SIGNOR-151425 AKT1 protein P31749 UNIPROT 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-252490 MAPK8 protein P45983 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser68 GGGDEPGsPAQGKRG 9606 BTO:0000150 21502402 t gcesareni "Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness." SIGNOR-173417 Arry-380 chemical CID:42598643 PUBCHEM ERBB2 protein P04626 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189882 PTPRB protein P23467 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation 9606 21454675 t fstefani "Expression of rptp-beta inhibits both mek1/2 and erk1/2 phosphorylation." SIGNOR-173000 "imatinib methanesulfonate" chemical CHEBI:31690 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193393 pelitinib chemical CHEBI:38927 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205755 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide chemical CHEBI:131156 ChEBI CHEK2 protein O96017 UNIPROT down-regulates "chemical inhibition" 9606 20068082 t gcesareni "Azd7762 is equally potent against chk2 in vitro." SIGNOR-163119 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT unknown phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto "Dapk phosphorylates camkks511 was identified as the phosphorylation site" SIGNOR-126245 IL7 protein P13232 UNIPROT IL2RG protein P31785 UNIPROT up-regulates binding 9606 BTO:0002314 BTO:0000887;BTO:0001103;BTO:0001760 20089933 t milica "This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain." SIGNOR-163545 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation Tyr465 GEEELSNyICMGGKG 9606 17827393 t gcesareni "Furthermore, IGF-1 stimulates tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 and their association with the p85 subunit of phosphoinositide-3 kinase (PI3K)." SIGNOR-157738 EIF4A2 protein Q14240 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-108512 CEBPA protein P49715 UNIPROT USF1 protein P22415 UNIPROT "up-regulates activity" binding 9606 BTO:0004116 7862113 t irozzo "Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study." SIGNOR-255701 nintedanib chemical CHEBI:85164 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190302 NEK2 protein P51955 UNIPROT NEK11 protein Q8NG66 UNIPROT up-regulates phosphorylation 9606 15161910 t esanto "Nek2 directly phosphorylated nek11 in the c-terminal non-catalytic region and elevated nek11 kinase activity." SIGNOR-124944 AMPK complex SIGNOR-C15 SIGNOR PFKFB3 protein Q16875 UNIPROT up-regulates phosphorylation Ser461 NPLMRRNsVTPLASP 9606 BTO:0000876 BTO:0000671 12065600 t lperfetto "Ipfk-2 was phosphorylated on the homologous serine (ser-461) and activated by ampk in vitro." SIGNOR-216639 WNT1 protein P04628 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 11448771 t gcesareni "Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd)" SIGNOR-109250 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR INCA1 protein Q0VD86 UNIPROT unknown phosphorylation Ser191 GRAQLLWsPWSPLDQ -1 15159402 t miannu " GST-INCA1 was phosphorylated in vitro by cyclin A2-CDK2 but not by CDK2 or either cyclin alone.  Mutation of Ser23, Thr167, and Ser176 strongly reduced in vitro phosphorylation of INCA1.Cyclin A1 and Cyclin A2 in Complex with CDK2 Phosphorylated INCA1 in Vitro Predominantly at Ser176" SIGNOR-273592 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR INCA1 protein Q0VD86 UNIPROT unknown phosphorylation Ser23 CSRVVSRsPPPRLPS -1 15159402 t miannu " GST-INCA1 was phosphorylated in vitro by cyclin A2-CDK2 but not by CDK2 or either cyclin alone.  Mutation of Ser23, Thr167, and Ser176 strongly reduced in vitro phosphorylation of INCA1.Cyclin A1 and Cyclin A2 in Complex with CDK2 Phosphorylated INCA1 in Vitro Predominantly at Ser176" SIGNOR-273593 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR PARP10 protein Q53GL7 UNIPROT "up-regulates activity" phosphorylation Thr101 QGLPPGTtPQRLEQH -1 16455663 t miannu "The PARP activity of PARP10 depends on phosphorylation by CDK2-cyclin E in vitro. CDK-phosphorylated PARP10 is absent in growth-arrested cells. These results suggest that PARP10 functions in cell proliferation and may serve as a marker for proliferating cells.our results suggest that nucleolar PARP10 acquires CDK2-cyclin E-dependent phosphorylation at the Thr-101 residue." SIGNOR-273594 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLL protein Q9UGP5 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr553 GPGRVLPtPTEKDVF 9606 BTO:0000007 18688254 t miannu "Pol λ phosphorylation prevents degradation. Recently, we identified Pol λ as an interaction partner of cyclin-dependent kinase 2 (CDK2) that is central to the cell cycle G1/S transition and S-phase progression. This interaction leads to in vitro phosphorylation of Pol λ, and its in vivo phosphorylation pattern during cell cycle progression mimics the modulation of CDK2/cyclin A. Experiments with phosphorylation-defective mutants suggest that phosphorylation of Thr 553 is important for maintaining Pol λ stability," SIGNOR-273595 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLM protein Q9NP87 UNIPROT "down-regulates activity" phosphorylation Ser372 HQHSCCEsPTRLAQQ -1 23933132 t miannu " In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate Polμ. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site.Our evidences suggest that Polμ could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1." SIGNOR-273596 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLM protein Q9NP87 UNIPROT "down-regulates activity" phosphorylation Ser12 RRRARVGsPSGDAAS -1 23933132 t miannu " In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate Polμ. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site.Our evidences suggest that Polμ could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1." SIGNOR-273597 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR POLM protein Q9NP87 UNIPROT "down-regulates activity" phosphorylation Thr212 T-->V -1 23933132 t miannu " In vitro kinase assays showed that the S phase-associated Cdk2/cyclin A complex was able to phosphorylate Polμ. We identified Ser12, Thr21 (located in the BRCT domain) and Ser372 (located in loop1) as the target residues. Mutation of these residues to alanine indicated that Ser372 is the main phosphorylation site.Our evidences suggest that Polμ could be regulated in vivo by phosphorylation of the BRCT domain (Ser12/Thr21) and of Ser372, affecting the function of loop1." SIGNOR-273598 CDK2 protein P24941 UNIPROT RAD54L protein Q92698 UNIPROT "down-regulates activity" phosphorylation Ser49 QIQECFLsPFRKPLS -1 29295984 t miannu "Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM." SIGNOR-273599 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR TICRR protein Q7Z2Z1 UNIPROT "up-regulates activity" phosphorylation Ser1001 DIGVVEEsPEKGDEI -1 21646402 t miannu " We found that Treslin also associated with TopBP1 in a Cdk-regulated manner in human cells and that Treslin was phosphorylated within a conserved Cdk consensus target sequence (on S976 in X. laevis and S1000 in humans). Recombinant human Cdk2-cyclin E also phosphorylated this residue of Treslin in vitro very effectively." SIGNOR-273600 CDK2 protein P24941 UNIPROT TOB2 protein Q14106 UNIPROT "up-regulates activity" phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 t 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-273601 CDK4 protein P11802 UNIPROT TOB2 protein Q14106 UNIPROT "up-regulates activity" phosphorylation Ser254 PAPQSQLsPNAKEFV -1 32404348 t 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-273602 TGFBR2 protein P37173 UNIPROT USP2 protein O75604 UNIPROT "up-regulates activity" phosphorylation Ser225 SRVPEIIsPTYRPIG -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-273603 TGFBR2 protein P37173 UNIPROT USP2 protein O75604 UNIPROT "up-regulates activity" phosphorylation Ser207 ENYGRKGsASQVPSQ -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-273604 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 ULK1 protein O75385 UNIPROT FUNDC1 protein Q8IVP5 UNIPROT "up-regulates activity" phosphorylation Ser17 DYESDDDsYEVLDLT 9606 BTO:0000567 24671035 t done miannu "Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3. " SIGNOR-273606 ATM protein Q13315 UNIPROT KHDC3L protein Q587J8 UNIPROT "up-regulates activity" phosphorylation Thr156 VEVREAGtQRSVEVQ 9606 BTO:0001086 31609975 t miannu "Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. " SIGNOR-273504 CDK5 protein Q00535 UNIPROT PHACTR3 protein Q96KR7 UNIPROT "down-regulates quantity" phosphorylation Ser318 QGRESKGsPKKRLDV 10116 BTO:0000938 21487013 t miannu "We show that scapinin is phosphorylated at a highly conserved site in the central region of the protein (Ser-277) by Cdk5 in vitro. Expression of a scapinin phospho-mimetic mutant (S277D) restored normal axon elongation without affecting actin binding. Instead, phosphorylated scapinin was sequestered in the cytoplasm of neurons and away from the axon. " SIGNOR-273607 SETMAR protein Q53H47 UNIPROT CHEK1 protein O14757 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000007 25024738 f miannu "We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.  Phosphorylated Chk1 phosphorylates S495 of Metnase. Phosphorylated Metnase decreases the interaction of DDB1 with Chk1, reducing Chk1 targeting to the Cul4a E3 ubiquitin ligase, increasing Chk1 stability." SIGNOR-273609 CHEK1 protein O14757 UNIPROT SETMAR protein Q53H47 UNIPROT "down-regulates activity" phosphorylation Ser508 LYDNRRRsAQWLDQE 9606 BTO:0000007 25024738 t miannu "We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination. " SIGNOR-273610 CHEK2 protein O96017 UNIPROT PSME3 protein P61289 UNIPROT "up-regulates activity" phosphorylation Ser247 EKIKRPRsSNAETLY 9606 BTO:0001938 25361978 t miannu "REGγ interacts with DBC1 and is phosphorylated by Chk2." SIGNOR-273611 CHUK protein O15111 UNIPROT MTURN protein Q8N3F0 UNIPROT "down-regulates activity" phosphorylation Ser58 GDNFHVWsESEDCLP -1 28704656 t miannu " INKIT interacted with IKKα/β and TBK1/IKKɛ, impairing the recruitment and phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. Our findings thus uncover INKIT as a regulator of innate antiviral responses." SIGNOR-273612 GCSAM protein Q8N6F7 UNIPROT GRB2 protein P62993 UNIPROT "down-regulates activity" binding 9606 31362927 t miannu "Herein, we demonstrate that the adaptor protein HGAL, specifically expressed in GC lymphocytes and GC-derived lymphomas, directly binds to Grb2 upon BCR activation and negates the inhibitory effects of Grb2 on the BCR-induced biochemical signaling cascade. " SIGNOR-273608 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 FMNL2 protein Q96PY5 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19386263 t miannu "Phosphorylation of hCenexin1 at S796 is critical for the hCenexin1-Plk1 interaction.Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits Plk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and Plk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles." SIGNOR-273614 TOB2 protein Q14106 UNIPROT "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 18377426 t miannu "We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob. " SIGNOR-273615 TOB1 protein P50616 UNIPROT "CCR4-NOT complex" complex SIGNOR-C439 SIGNOR "down-regulates activity" binding 9606 BTO:0000567 18377426 t miannu "We found that Tob associates with the CCR4-NOT complex. The carboxyl-terminal half of Tob interacted with Cnot1, a core protein of the CCR4-NOT complex. We further showed that the deadenylase activity associated with the complex was suppressed in vitro by Tob. " SIGNOR-273616 CSNK1A1 protein P48729 UNIPROT JADE1 protein Q6IE81 UNIPROT "down-regulates activity" phosphorylation Ser20 SDDNGSLsTTWSQNS 9606 BTO:0000007 25100726 t done miannu "We demonstrate that the destruction complex component casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces the ability of Jade-1 to inhibit β-catenin signaling. " SIGNOR-273617 CSNK1A1 protein P48729 UNIPROT JADE1 protein Q6IE81 UNIPROT "down-regulates activity" phosphorylation Ser18 EDSDDNGsLSTTWSQ 9606 BTO:0000007 25100726 t done miannu "We demonstrate that the destruction complex component casein kinase 1α (CK1α) phosphorylates Jade-1 at a conserved SLS motif and reduces the ability of Jade-1 to inhibit β-catenin signaling. " SIGNOR-273618 CSNK1A1 protein P48729 UNIPROT TUT1 protein Q9H6E5 UNIPROT "up-regulates activity" phosphorylation Ser6 sDVESLPR 9606 BTO:0000007 26138484 t done miannu "We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα. " SIGNOR-273619 ATM protein Q13315 UNIPROT POLL protein Q9UGP5 UNIPROT "up-regulates activity" phosphorylation Thr204 EASDGEEtQVSAADL 9606 BTO:0000007 28109743 t done miannu "We identify threonine 204 (T204) as a main target for ATM/DNA-PKcs phosphorylation on human Polλ, and establish that its phosphorylation may facilitate the repair of a subset of IR-induced DSBs and the efficient Polλ-mediated gap-filling during NHEJ. " SIGNOR-273510 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT "up-regulates activity" phosphorylation Ser118 SELRSELsQSQHEVN 9606 BTO:0001109 21779472 t miannu "MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity." SIGNOR-273514 ATR protein Q13535 UNIPROT MCC protein P23508 UNIPROT "up-regulates activity" phosphorylation Ser120 LRSELSQsQHEVNED 9606 BTO:0001109 21779472 t miannu "MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120.  Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity." SIGNOR-273515 USP25 protein Q9UHP3 UNIPROT TRiC complex SIGNOR-C539 SIGNOR "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273583 MPO-ANCA complex SIGNOR-C474 SIGNOR superoxide smallmolecule CHEBI:18421 ChEBI up-regulates 10090 BTO:0000133 15972951 f lperfetto "Anti-MPO IgG (250 μg/ml) induces significant superoxide anion production in TNF-α-primed peritoneal exudate cells from WT C57BL/6 mice (black bars) as compared to normal mouse IgG (250 μg/ml) or buffer alone." SIGNOR-270589 CyclinK/CDK13 complex SIGNOR-C38 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-273083 PIAS1 protein O75925 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation 9606 15028714 t lperfetto "These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4" SIGNOR-123462 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1644 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-273092 "2-(Decan-2-ylamino)ethyl 4-aminobenzoate" chemical CID:50729 PUBCHEM TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000664 18258442 t Luana "As shown in Table 1 all of the bisanthrapyrazoles inhibited the decatenation activity of human topoisomerase IIα in the low micromolar concentration range" SIGNOR-257768 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 CyclinK/CDK12 complex SIGNOR-C37 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-273100 CyclinK/CDK12 complex SIGNOR-C37 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1784 TPTSPNYsPTSPSYS 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-273107 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 CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser243 TDSEVDSsCSGQPIH 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273123 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR SPDEF protein O95238 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser238 SEESWTDsEVDSSCS 9606 BTO:0000007 26885618 t lperfetto "In this study we provide evidence that the cell cycle kinase CDK11p58, a protein involved in G2/M transition and degradation of several transcription factors, directly interacts with and phosphorylates SPDEF on serine residues|Western blot analysis demonstrated that only one of the mutant constructs, consisting of mutations of serine 238, 242 and 243, resulted in increased levels of SPDEF protein expression as compared to wild type SPDEF, leading to subsequent ubiquitination and degradation of SPDEF through the proteasome pathway.|" SIGNOR-273126 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252741 GUCY1A2-B2 complex SIGNOR-C137 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-244090 MIR1-1 mirna URS000075CF56_9606 RNAcentral IGF1 protein P05019 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 25477897 t miannu "The down-regulation of miR-29b is thought to promote DNA hypermethylation in AML since miR-29b can directly target DNMT3A, DNMT3B, and Sp1 (a transcriptional regulator of DNMT1" SIGNOR-255793 HIF1A protein Q16665 UNIPROT KDM5A protein P29375 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-271565 PRKACA protein P17612 UNIPROT PPP2R5D protein Q14738 UNIPROT up-regulates phosphorylation Ser573 KVLLRRKsELPQDVY 9606 17301223 t gcesareni "Protein kinase a activates protein phosphatase 2a by phosphorylation of the b56delta subunit." SIGNOR-153218 CHRM3 protein P20309 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-256739 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Thr539 RGLDKVItVLTRSKR 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-141034 histamine smallmolecule CHEBI:18295 ChEBI HRH1 protein P35367 UNIPROT "up-regulates activity" "chemical activation" 10029 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-258483 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSEDLSAyASISFQK 9606 BTO:0000443 12220227 t lperfetto "Here we show that stimulation by insulin of freshly isolated primary adipocytes resulted in the expected rapid tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-3. Inhibition of PI 3-kinase enhanced the insulin-stimulated phosphorylation of IRS-1 on (i) Tyr(612) and Tyr(941) (p85 binding sites), concomitant with an increased association of the p85 subunit of PI 3-kinase; (ii) Tyr(896) (a Grb2 binding site); and (iii) Tyr(1229) (an SHP-2 binding site), although little or no binding of SHP-2 to IRS-1 was detectable under any conditions." SIGNOR-235983 JARID2 protein Q92833 UNIPROT NKX2-5 protein P52952 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-224787 RSPO1 protein Q2MKA7 UNIPROT ZNRF3 protein Q9ULT6 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0000007 22575959 t "Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3." SIGNOR-260113 KLF2 protein Q9Y5W3 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 15947087 f "Regulation of expression" miannu "Our results show that KLF2 positively regulates the human (ε) and murine (Ey and βh1) embryonic globin genes at both E10.5 and E12.5, in the yolk sac, which is the site of primitive erythropoiesis." SIGNOR-251830 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser15 FSFGTLSsWELEAWY 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-250851 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 dabrafenib chemical CHEBI:75045 ChEBI SIK1 protein P57059 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-259219 PTPRG protein P23470 UNIPROT SRC protein P12931 UNIPROT "down-regulates activity" dephosphorylation Tyr419 RLIEDNEyTARQGAK -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-254725 AR protein P10275 UNIPROT UBE2C protein O00762 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19632176 t 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-251543 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 ITGB1 protein P05556 UNIPROT "A2/b1 integrin" complex SIGNOR-C160 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-253172 MAPK3 protein P27361 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates activity" phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 t 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-249478 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 TACR2 protein P21452 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-256736 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 CARM1 protein Q86X55 UNIPROT PAX7 protein P23759 UNIPROT up-regulates methylation 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-198617 GFI1 protein Q99684 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 10090 BTO:0000725 17197705 t miannu "Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line." SIGNOR-256043 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-252742 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 PTPRJ protein Q12913 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-76092 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 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 ADK protein P55263 UNIPROT ADP(3-) smallmolecule CHEBI:456216 ChEBI "up-regulates quantity" "chemical modification" 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-267841 MAPK12 protein P53778 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR "form complex" binding 29681515 t apalma "Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated" SIGNOR-255981 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 YBX1 protein P67809 UNIPROT CXCR4 protein P61073 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-255611 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 AURKB protein Q96GD4 UNIPROT CHMP4C protein Q96CF2 UNIPROT up-regulates phosphorylation Ser215 RRSRAASsQRAEEED 9606 22422861 t lperfetto "Chmp4c functioned in the aurora b-dependent abscission checkpoint to prevent both premature resolution of intercellular chromosome bridges and accumulation of dna damage. Chmp4c engaged the chromosomal passenger complex (cpc) via interaction with borealin, which suggested a model whereby chmp4c inhibits abscission upon phosphorylation by aurora b" SIGNOR-196728 HMGB2 protein P26583 UNIPROT POU2F2 protein P09086 UNIPROT "up-regulates activity" binding 10090 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-240108 PLK1 protein P53350 UNIPROT CENPQ protein Q7L2Z9 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser139 EDLTNVSsLLNMERA 9606 25670858 t lperfetto "Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites." SIGNOR-265233 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 CHEK1 protein O14757 UNIPROT NFKB1 protein P19838 UNIPROT down-regulates phosphorylation Ser328 INITKPAsVFVQLRR 9606 22152481 t llicata "Taken together, the above findings suggest that chk1 phosphorylates p50 at s329 and further, that this phosphorylation blocks p50 dna binding." SIGNOR-195208 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 KLC2 protein Q9H0B6 UNIPROT FYCO1 protein Q9BQS8 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 25855459 t Giulio "Interestingly, bead capture assays indicated that the middle part of FYCO1 (residues 585–1233) interacts directly with the KLC2 light chain of kinesin 1 (Fig. 3a and Extended Data Fig. 7a, b). Residues 735–773 of FYCO1 were found to be necessary for its kinesin-1 binding (Fig. 3c and Extended Data Fig. 7b, c), and FYCO1(Δ735–773)-positive LEs failed to translocate to the cell periphery (Extended Data Fig. 7e)." SIGNOR-260599 SDCBP protein O00560 UNIPROT SOX4 protein Q06945 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 11498591 t miannu "Sox4 activation by IL-5R_ appears to be direct, with syntenin functioning as an adaptor molecule. Syntenin mediates IL-5–induced Sox4 activation." SIGNOR-223089 HSP90AA1 protein P07900 UNIPROT NOS3 protein P29474 UNIPROT up-regulates binding 9606 9580552 t miannu "The binding of hsp90 to enos enhances the activation of enos." SIGNOR-57211 MYLK protein Q15746 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-188797 serotonin smallmolecule CHEBI:28790 ChEBI HTR3E protein A5X5Y0 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-264291 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 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK -1 10734133 t miannu "Interestingly, all PTPs that were tested could completely dephosphorylate the receptor, given sufficient time, including a negative control (PTP-PEST) that failed to bind IRK as a trapping mutant." SIGNOR-75894 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Thr614 AFRLEPLtPRGVLTV 9606 BTO:0000150 17311928 t 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-153391 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 SIGNOR-C15 21205641 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-170859 IRAK1 protein P51617 UNIPROT PELI1 protein Q96FA3 UNIPROT "up-regulates activity" phosphorylation Ser82 HSISYTLsRAQTVVV 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-96747 HIPK2 protein Q9H2X6 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Thr53 KEPSEVPtPKRPRGR 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158620 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-267883 FUS protein P35637 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR down-regulates 9606 BTO:0000007 33082139 f "P35637:p.Pro525Leu (mutation increasing interaction); P35637:p.Pro521Gly (mutation increasing interaction)" "When mTORC2 is inhibited, FUS is recruited to polyribosomes to promote translation inhibition and polyribosome stalling. Panel iv, ALS-FUS R521G and P525L mutants that localize more prominently to the cytoplasm also associate more abundantly with polyribosomes to inhibit translation and protein synthesis." SIGNOR-262820 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 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 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser713 GAEIVYKsPVVSGDT 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-251591 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 HTR1E protein P28566 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-256848 VRK2 protein Q86Y07 UNIPROT NFATC2 protein Q13469 UNIPROT up-regulates phosphorylation Ser31 PQDELDFsILFDYEY 9606 23105117 t gcesareni "We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain." SIGNOR-199263 RHOA protein P61586 UNIPROT PFN1 protein P07737 UNIPROT "up-regulates activity" 9606 BTO:0000815 22820501 t lperfetto "We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells." SIGNOR-253109 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR PAK1 protein Q13153 UNIPROT "up-regulates activity" phosphorylation Ser174 TPAVPPVsEDEDDDD 19520772 t lperfetto "CDK11p58 phosphorylation of PAK1 Ser174 promotes DLC2 binding and roles on cell cycle progression|We show that PAK1 is a substrate of CDK11p58 and can be strongly activated upon phosphorylation." SIGNOR-273129 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 MAPK1 protein P28482 UNIPROT MAP2K1 protein Q02750 UNIPROT "down-regulates activity" phosphorylation Thr292 ETPPRPRtPGRPLSS 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-236335 MYC protein P01106 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 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-255146 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 SF3A3 protein Q12874 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-263949 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 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 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 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr50 FSTTPGGtRIIYDRK 9606 BTO:0000150 24247720 t lperfetto "Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation." SIGNOR-203276 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr751 SKDESVDyVPMLDMK -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-248414 KDM5A protein P29375 UNIPROT PTEN protein P60484 UNIPROT "down-regulates quantity by destabilization" "transcriptional regulation" 9606 31374292 t miannu "The retinoblastoma binding protein 2 (RBP2) belongs to the KDM5 family, and is also known as JARID1A or KDM5A. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL." SIGNOR-260079 PCBP2 protein Q15366 UNIPROT ITCH protein Q96J02 UNIPROT "up-regulates activity" binding 9606 BTO:0002181 19881509 t Giorgia "Only AIP4 associated with PCBP2 and caused MAVS degradation. The interaction between PCBP2 and AIP4 was abrogated when the linker region or WB2 of PCBP2 was deleted, which confirmed our previous data indicating that this region was critical for PCBP2-mediated degradation of MAVS" SIGNOR-260361 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 GALR2 protein O43603 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-256884 SCRIB protein Q14160 UNIPROT Scribble_complex_DLG4-LLGL1_variant complex SIGNOR-C509 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-270904 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 CALM3 protein P0DP25 UNIPROT SCN8A protein Q9UQD0 UNIPROT "down-regulates activity" binding 9606 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-266346 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 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 GSK3B protein P49841 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr46 GGTLFSTtPGGTRII 9606 23584478 t lperfetto "Glycogen synthase kinase-3_ positively regulates protein synthesis and cell proliferation through the regulation of translation initiation factor 4E-binding protein 1We found that GSK-3_ phosphorylates and inactivates 4E-BP1, thereby increasing eIF4E-dependent protein synthesis." SIGNOR-201699 Diprenorphine chemical CHEBI:4650 ChEBI OPRK1 protein P41145 UNIPROT "down-regulates activity" "chemical inhibition" 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-258662 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 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 CBL protein P22681 UNIPROT FLT3 protein P36888 UNIPROT "down-regulates activity" binding 10090 BTO:0001516 19276253 t "Functionally, CBL negatively regulated FMS-like tyrosine kinase 3 (FLT3) activity and interacted with human FLT3 via the autophosphorylation sites Y589 and Y599 and colocalized in vivo." SIGNOR-255739 PRKCQ protein Q04759 UNIPROT ICAM3 protein P32942 UNIPROT "up-regulates activity" phosphorylation Ser518 REHQRSGsYHVREES 9606 BTO:0000661 9268366 t lperfetto "Ser489 was a phosphorylation site in vitro for recombinant protein kinase Ctheta. Finally, treatment of Jurkat cells with chelerythrine chloride, a protein kinase C inhibitor, prevented ICAM-3-triggered spreading. " SIGNOR-248979 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 MAPKAPK2 protein P49137 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser272 CSLERQLsLEQEVQQ -1 11844797 t miannu "Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO." SIGNOR-250143 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 CDK1 protein P06493 UNIPROT SLBP protein Q14493 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr62 RRPESFTtPEGPKPR 9606 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-265258 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 ITK protein Q08881 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-112475 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 GSK3A protein P49840 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" phosphorylation Thr312 TMKTFCGtPEYLAPE 10090 BTO:0005655 23142783 t gcesareni "GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function." SIGNOR-252455 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 SIK2 protein Q9H0K1 UNIPROT CEP250 protein Q9BV73 UNIPROT unknown phosphorylation Ser2394 LHHSLSHsLLAVAQA 9606 20708153 t lperfetto "Remarkably, lc-ms confirmed that the predominant serine phosphorylation site of the recombinant carboxy-terminal domain of c-nap1 is s2392 at the predicted consensus phosphorylation sequence and to a lesser extent s2394." SIGNOR-167492 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-271808 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 SRC protein P12931 UNIPROT ATG9A protein Q7Z3C6 UNIPROT "up-regulates activity" phosphorylation Tyr8 MAQFDTEyQRLEASY 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-266367 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 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-258003 GRK2 protein P25098 UNIPROT RPLP2 protein P05387 UNIPROT up-regulates phosphorylation Ser102 KDEKKEEsEESDDDM 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-94254 CSNK2A2 protein P19784 UNIPROT NKX3-1 protein Q99801 UNIPROT up-regulates phosphorylation Thr89 AAPEEAEtLAETEPE 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-145501 TP53 protein P04637 UNIPROT HK2 protein P52789 UNIPROT "down-regulates quantity by repression" "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-267466 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR EIF3F protein O00303 UNIPROT "up-regulates activity" phosphorylation Ser46 PAAAPASsSDPAAAA 19245811 t lperfetto "EIF3f is phosphorylated by CDK11p46 at Ser46 during apoptosis.|Phosphorylation of eIF3f plays an important role in regulating its function in translation and apoptosis. Phosphorylation of eIF3f enhances the association of eIF3f with the core eIF3 subunits during apoptosis. " SIGNOR-273134 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 PSENEN protein Q9NZ42 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates cleavage 9606 12522139 t gcesareni "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-97113 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser285 NHTLAPAsPAPARPR -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250650 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser385 RYSDTTDsDPENEPF 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-89822 STK11 protein Q15831 UNIPROT BRSK1 protein Q8TDC3 UNIPROT up-regulates phosphorylation Thr189 VGDSLLEtSCGSPHY 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-122413 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 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 CD38 protein P28907 UNIPROT OXT protein P01178 UNIPROT "up-regulates quantity" relocalization 10090 17287729 f lperfetto "CD38 is critical for social behaviour by regulating oxytocin secretion|Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice." SIGNOR-268544 MAP3K12 protein Q12852 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 11781833 t gcesareni "Zip kinase (hzipk) phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. In this study, we demonstrate that hzipk also induces the diphosphorylation of mrlc in nonmuscle cells." SIGNOR-113664 CRYBB2 protein P43320 UNIPROT CRYBB1 protein P53674 UNIPROT "up-regulates activity" binding 9606 16319073 t miannu "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-252153 p38 proteinfamily SIGNOR-PF16 SIGNOR Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 9606 11591790 f "The p21 G protein Rho and its targets, Rho-associated coiled-coil forming protein kinases (p160ROCK/ROCK I/ROKβ and Rho kinase/ROCK II/ROKα), play a crucial role in actin cytoskeleton reorganization" SIGNOR-254360 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 CD27 protein P26842 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-93317 AKT proteinfamily SIGNOR-PF24 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000887;BTO:0001103;BTO:0001760 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-217586 "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 CAMK1 protein Q14012 UNIPROT NUMB protein P49757 UNIPROT down-regulates phosphorylation Ser276 EQLARQGsFRGFPAL 9606 17022975 t esanto "Based on experiments using numb mutants, both the initial phosphorylation of ser(264) and the subsequent phosphorylation of ser(283) are sufficient to abolish the binding of numb to ap-2." SIGNOR-149993 MACROD2 protein A1Z1Q3 UNIPROT acetate smallmolecule CHEBI:30089 ChEBI "up-regulates quantity" "chemical modification" 9606 32257385 t miannu "MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins" SIGNOR-269842 S1PR1 protein P21453 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-256713 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1423 AVLEQHGsQPSNSYP 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." SIGNOR-106436 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr581 SDGHEYIyVDPMQLP 9606 BTO:0000599 9642269 t miannu "We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins." SIGNOR-250255 HEY1 protein Q9Y5J3 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 t gcesareni "These findings suggest a novel mechanism for negative feedback on notch signaling that requires rbp-jkappa to interact physically with hrt and hes." SIGNOR-146687 PLK3 protein Q9H4B4 UNIPROT BCL2L1 protein Q07817 UNIPROT up-regulates phosphorylation Ser49 ESEMETPsAINGNPS 9606 21336504 t lperfetto "Polo kinase 3 (plk3) was implicated in bcl-xl(ser49) phosphorylation. These data indicate that, during g2 checkpoint, phospho-bcl-xl(ser49) is another downstream target of plk3, acting to stabilize g2 arrest." SIGNOR-172230 PTPN12 protein Q05209 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-39147 SREBF1 protein P36956 UNIPROT MTTP protein P55157 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11111091 f miannu "SREBP1 increased the expression of MTP and increased the assembly and secretion of VLDL containing apo B100." SIGNOR-252113 "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 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 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 TTC8 protein Q8TAM2 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-262554 arformoterol chemical CHEBI:408174 ChEBI ADRB2 protein P07550 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-257882 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 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 PRKCI protein P41743 UNIPROT LLGL1 protein Q15334 UNIPROT "up-regulates activity" phosphorylation Ser659 RVKSLKKsLRQSFRR 9615 12725730 t miannu "This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner." SIGNOR-263179 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 IRAK1 protein P51617 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation Ser376 GSSPSQSsMVARTQT -1 11960013 t "In vitro the IRAK-1 activation loop is a good substrate for IRAK-4, and that T387 and S376 are the main sites of phosphorylation by both IRAK-1 and IRAK-4." SIGNOR-251326 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser46 VKVNGDAsPAAAESG -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-248908 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT unknown phosphorylation Tyr857 DIMRDSNyISKGSTF 9606 2550144 t llicata "We have identified two platelet-derived growth factor (pdgf)-dependent autophosphorylation sites in the beta subunit of the human pdgf receptor (pdgf-r). The major site of phosphorylation (tyr-857) corresponds to the major autophosphorylation site in many other tyrosine kinases. Tyr-751, which lies within the kinase insert region, is a second in vivo site and the major in vitro site." SIGNOR-22997 ARHGAP30 protein Q7Z6I6 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-260485 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 MAPK1 protein P28482 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-209876 hydromorphone chemical CHEBI:5790 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 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-258037 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 "double-stranded DNA" chemical CHEBI:4705 ChEBI "BRCA1-C complex" complex SIGNOR-C299 SIGNOR "form complex" binding 25400280 t lperfetto "The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2" SIGNOR-269477 PLK1 protein P53350 UNIPROT SUGT1 protein Q9Y2Z0 UNIPROT "up-regulates activity" phosphorylation Ser331 VKRAMNKsFMESGGT 9606 22869522 t lperfetto "Plk1 phosphorylates Sgt1 at the kinetochores to promote timely kinetochore-microtubule attachment|Plk1 is required for the kinetochore localization of Sgt1 and phosphorylates serine 331 of Sgt1 at the kinetochores. This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone" SIGNOR-265222 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 "Caspase 6 complex" complex SIGNOR-C228 SIGNOR CASP8 protein Q14790 UNIPROT up-regulates cleavage 9606 11455969 t gcesareni "This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8." SIGNOR-256468 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 PLEKHA7 protein Q6IQ23 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." SIGNOR-261250 PRKG1 protein Q13976 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation Ser784 GVPFRRPsTFGIPRL 9606 BTO:0000671 12082086 t lperfetto "G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells" SIGNOR-89853 PRKCE protein Q02156 UNIPROT OPRD1 protein P41143 UNIPROT unknown phosphorylation Ser344 CGRPDPSsFSRAREA 9606 BTO:0000007 11085981 t lperfetto "In the current study, we identified a PKC-mediated phosphorylation site in the delta-opioid receptor (DOR) and demonstrated that activation of PKC by stimulation of other types of GPCR or increase in intracellular Ca2+concentration in HEK 293 cells induces heterologous phosphorylation of DOR. Our results further established that DOR phosphorylation at Ser-344 by PKC results in internalization of DOR in HEK 293 cells through a beta-arrestin- and clathrin-mediated mechanism." SIGNOR-249064 CSNK1A1 protein P48729 UNIPROT AXIN1 protein O15169 UNIPROT "up-regulates activity" phosphorylation Ser75 LGYEPEGsASPTPPY -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-249189 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 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 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 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 DNMT3B protein Q9UBC3 UNIPROT BAG1 protein Q99933 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001109 18413740 f lperfetto "DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation" SIGNOR-254109 NDUFB5 protein O43674 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-262168 F11 protein P03951 UNIPROT HGF protein P14210 UNIPROT "up-regulates activity" cleavage Arg424 KNMEDLHrHIFWEPD -1 12372819 t miannu "the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain." SIGNOR-256515 DNMT3A protein Q9Y6K1 UNIPROT TIMP2 protein P16035 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 19786833 f 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-255807 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6K proteinfamily SIGNOR-PF26 SIGNOR "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-252744 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 MAP2K4 protein P45985 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 10715136 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif." gcesareni "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) and p38 subs of map kinases, respectively. 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-75792 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser177 AKELDQGsLCTSFVG 9606 BTO:0000176 19607706 t "Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)" SIGNOR-248581 MYF5 protein P13349 UNIPROT mir-206 mirna URS0000389B41_9606 RNAcentral "up-regulates quantity" "transcriptional regulation" 10090 16731620 t "Moreover, both loci encoding miR-1, miR-1-1, and miR-1-2, and two of the three encoding miR-133, miR-133a-1 and miR-133a-2, are strongly induced during myogenesis.[…]By using CHIP analysis, we demonstrate that the myogenic factors Myogenin and MyoD bind to regions upstream of these microRNAs and, therefore, are likely to regulate their expression." SIGNOR-255917 TNFSF10 protein P50591 UNIPROT TNFRSF10B protein O14763 UNIPROT up-regulates binding 9606 14585074 t amattioni "Trail interacts with tril-r1 and trail-r2 and activetes them" SIGNOR-101313 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 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 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 NGFR protein P08138 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates 9606 14699954 f amattioni "Jnk3 is expressed exclusively in the nervous system and recent evidence indicates that this jnk isoform may be required for p75ntr-mediated cell death" SIGNOR-120561 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 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 PRKCD protein Q05655 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-249124 quetiapine chemical CHEBI:8707 ChEBI HTR1A protein P08908 UNIPROT "up-regulates activity" "chemical activation" 10029 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-258842 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 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT "up-regulates activity" phosphorylation Thr134 KKVRKPRtIYSSYQL -1 11343707 t lperfetto "Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3." SIGNOR-249097 SCN2A protein Q99250 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-253450 PTPRR protein Q15256 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 11711538 t gcesareni "As shown, gst-ptp-sl dephosphorylated efficiently both erk2 and p38 wild typetogether, these results indicate that the defective association of the tyrosine phosphatase ptp-sl with erk2 d319n and p38 d316n mutations impairs the retention and inactivation in the cytosol of these map kinases by ptp-sl." SIGNOR-111762 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT down-regulates phosphorylation Thr806 NQMAKGTtEEMKYVL 9606 18680479 t miannu "We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / t806d mps1 was significantly less active than t806a, demonstrating a potential negative correlation between phosphorylation and activity at this site." SIGNOR-179908 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 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 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 PRKCD protein Q05655 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser23 PAPIRRRsSNYRAYA 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-178880 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 (+)-pilocarpine chemical CHEBI:8207 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-258628 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 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-52691 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 PLK1 protein P53350 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007;BTO:0001914 23887393 t gcesareni "Here, we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces MYC phosphorylation and protein accumulation. We show that PDK1-PLK1-MYC signaling is critical for cancer cell growth and survival, and small-molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting of MYC dependency" SIGNOR-243522 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 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-250098 Ub:E2 complex SIGNOR-C497 SIGNOR RING1 protein Q06587 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-270984 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 DUSP3 protein P51452 UNIPROT MAPK1 protein P28482 UNIPROT "down-regulates activity" dephosphorylation Tyr187 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t "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.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-248536 ARAF protein P10398 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser218 VSGQLIDsMANSFVG 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-236451 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 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 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 "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 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 IFNG protein P01579 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-260259 PPARGC1A protein Q9UBK2 UNIPROT GPX1 protein P07203 UNIPROT up-regulates 10090 18074631 f lperfetto "In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat." SIGNOR-253396 MYLK protein Q15746 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-188801 MAPK1 protein P28482 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-196030 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 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 MECOM protein Q03112 UNIPROT ANGPT2 protein O15123 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 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-266060 AMPK complex SIGNOR-C15 SIGNOR EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 22669845 t lperfetto "In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation" SIGNOR-216503 MYBL2 protein P10244 UNIPROT CLU protein P10909 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000298 10770937 t miannu "Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA." SIGNOR-269800 "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 NOTCH1 protein P46531 UNIPROT RBPJ/NOTCH complex SIGNOR-C97 SIGNOR "form complex" binding 9606 7566092 t "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-254381 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 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 MED1 protein Q15648 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-266667 SCF-betaTRCP complex SIGNOR-C5 SIGNOR YAP1 protein P46937 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23431053 t lperfetto "This cascade of phosphorylation allows the binding of scfbetatrcp that promotes the ubiquitination and degradation of yap." SIGNOR-217187 SRC protein P12931 UNIPROT PRKD1 protein Q15139 UNIPROT "up-regulates activity" phosphorylation Tyr502 TTANVVYyVGENVVN 9606 12637538 t lperfetto "Here we report that PKD is tyrosine-phosphorylated within the PH domain, leading to activation. This phosphorylation is mediated by a pathway that consists of the Src and Abl tyrosine kinases and occurs in response to stimulation with pervanadate and oxidative stress. Mutational analysis revealed three tyrosine phosphorylation sites (Tyr(432), Tyr(463), and Tyr(502)), which are regulated by the Src-Abl pathway, and phosphorylation of only one of these (Tyr(463)) leads to PKD activation." SIGNOR-247328 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 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 HSPA5 protein P11021 UNIPROT UPR phenotype SIGNOR-PH131 SIGNOR up-regulates 28286085 f lperfetto "The HSPA5 gene encodes the binding immunoglobulin protein (BiP), an Hsp70 family chaperone localized in the ER lumen.|When unfolded/misfolded proteins in the ER overwhelm the capacity of protein folding machinery, BiP can initiate the unfolded protein response (UPR), decrease unfolded/misfolded protein load, induce autophagy, and crosstalk with apoptosis machinery to assist in the cell survival decision." SIGNOR-265282 EGR1 protein P18146 UNIPROT COL7A1 protein Q02388 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-251920 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 NOTCH proteinfamily SIGNOR-PF30 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 16990763 f gcesareni "Addition of jag-1 peptide induced ikkalpha mediated nf-kappab activation, as well as increased ppargamma expression." SIGNOR-254344 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 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 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation 6239 SIGNOR-C15 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-219247 "MLL2 complex" complex SIGNOR-C88 SIGNOR KDM6A protein O15550 UNIPROT "up-regulates quantity by stabilization" binding 9606 28669924 t miannu "KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. UTX is the complex’s H3K27 demethylase." SIGNOR-268813 NR3C1 protein P04150 UNIPROT DUSP1 protein P28562 UNIPROT "up-regulates quantity" 10090 BTO:0000944 11742987 t gcesareni "Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1|Both induction of MKP-1 expression and inhibition of its degradation are necessary for glucocorticoid-mediated inhibition of Erk-1/2 activation. In NIH-3T3 fibroblasts, although glucocorticoids up-regulate the MKP-1 level, they do not attenuate the proteasomal degradation of this protein and consequently they are unable to inhibit Erk-1/2 activity." SIGNOR-253546 ABL1 protein P00519 UNIPROT RAD9A protein Q99638 UNIPROT "up-regulates activity" phosphorylation Tyr28 AVHSLSRiGDELYLE 9606 11971963 t Manara "The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress." SIGNOR-260843 MECP2 protein P51608 UNIPROT TFF1 protein P04155 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 15870696 f miannu "Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters" SIGNOR-254572 Ub:E2 complex SIGNOR-C497 SIGNOR "RBR E3 ligase" proteinfamily SIGNOR-PF107 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-270945 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 CDK1 protein P06493 UNIPROT CDC27 protein P30260 UNIPROT up-regulates phosphorylation Ser426 TQPNINDsLEITKLD 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-119873 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 SRC protein P12931 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr478 PPPPPPVyEPVSYHV 9606 15623525 t lperfetto "Src phosphorylates ezrin at tyrosine 477 and induces a phosphospecific association between ezrin and a kelch-repeat protein family member" SIGNOR-132907 GATA1 protein P15976 UNIPROT KIT protein P10721 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 27858941 f miannu "DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene" SIGNOR-254771 SH3GLB2 protein Q9NR46 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-263887 ATM protein Q13315 UNIPROT BRCA1 protein P38398 UNIPROT up-regulates phosphorylation Ser1457 SEKAVLTsQKSSEYP 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" SIGNOR-72056 MAPK1 protein P28482 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR up-regulates phosphorylation 9606 12359725 t lperfetto "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-217499 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 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-150480 MAPK3 protein P27361 UNIPROT DUSP1 protein P28562 UNIPROT down-regulates phosphorylation Ser296 KQRRSIIsPNFSFMG 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-141605 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 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 HSP90AA1 protein P07900 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t "Here we show that the stability of the tumour suppressor folliculin (FLCN) depends on the chaperone function of Hsp90." SIGNOR-256505 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 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 ARHGEF25 protein Q86VW2 UNIPROT RHOA protein P61586 UNIPROT up-regulates "guanine nucleotide exchange factor" 10090 BTO:0000165;BTO:0000222 16314529 t gcesareni "Exogenous expression of geft promotes myogenesis ofc2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process." SIGNOR-236885 ATF4 protein P18848 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-269428 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana "AMPK phosphorylates CFTR in vitro at two essential serines (Ser737and Ser768) in the R domain, formerly identified as ""inhibitory"" PKA sites." SIGNOR-21316 AGRP protein O00253 UNIPROT MC1R protein Q01726 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-268699 CSNK2A1 protein P68400 UNIPROT HDAC3 protein O15379 UNIPROT "up-regulates activity" phosphorylation Ser424 DHDNDKEsDVEI 9606 15805470 t llicata "A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity." SIGNOR-250889 "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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-141581 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 "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR F10 protein P00742 UNIPROT "up-regulates activity" binding 9606 BTO:0000131 32665005 t lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263543 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 8500166 f "This indicates that pref-1 functions as a negative regulator of adipocyte differentiation, possibly in a manner analogous to EGF-like proteins that govern cell fate decisions in invertebrates." SIGNOR-254980 PAX5 protein Q02548 UNIPROT BZLF1 protein P03206 UNIPROT "down-regulates activity" binding 9606 BTO:0000776 23678172 t Gianni "... we demonstrate that Pax5 inhibits Z-mediated lytic viral gene expression and the release of infectious viral particles in latently infected epithelial cell lines. Conversely, we found that shRNA-mediated knockdown of endogenous Pax5 in a Burkitt lymphoma B-cell line leads to viral reactivation. Furthermore, we show that Pax5 reduces Z activation of early lytic viral promoters in reporter gene assays and inhibits Z binding to lytic viral promoters in vivo. We confirm that Pax5 and Z directly interact" SIGNOR-269082 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 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 Delta(9)-tetrahydrocannabinol smallmolecule CHEBI:66964 ChEBI CNR2 protein P34972 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000142 29751001 t miannu "Endocannabinoids (eCBs) are the body’s natural agonists for cannabinoid receptors (G protein-coupled CB1 and CB2) that also recognize Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana." SIGNOR-264268 SRC protein P12931 UNIPROT TERT protein O14746 UNIPROT down-regulates phosphorylation Tyr707 QDPPPELyFVKVDVT 9606 12808100 t lperfetto "Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707" SIGNOR-102097 CDK1 protein P06493 UNIPROT DDX3X protein O00571 UNIPROT down-regulates phosphorylation Thr323 GCHLLVAtPGRLVDM 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-141569 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 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 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 PTPRC protein P08575 UNIPROT SKAP1 protein Q86WV1 UNIPROT "up-regulates activity" dephosphorylation Tyr232 EEEKEETyDDIDGFD 9606 BTO:0000661 11909961 t "Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling." SIGNOR-248360 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr248 GSETPGAtPGSKIWD 9606 SIGNOR-C16 12105215 t gcesareni "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptides. Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-90438 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 CSF2 protein P04141 UNIPROT CSF2RA protein P15509 UNIPROT up-regulates binding 9606 10572088 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-72458 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 PBX3 protein P40426 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-265805 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 CSNK2A1 protein P68400 UNIPROT SPTBN1 protein Q01082 UNIPROT down-regulates phosphorylation Thr2159 NGATEQRtSSKESSP 9606 BTO:0000938 17088250 t miannu "We show here that the short c-terminal splice variant of betaii-spectrin (betaiisigma2) is a substrate for phosphorylation. In vitro, protein kinase ck2 phosphorylates ser-2110 and thr-2159 / phosphorylation of ?II?2 C-terminal fragment inhibits its interaction with ?II N-terminal fragment." SIGNOR-150471 LYL1 protein P12980 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21261500 f miannu "TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C" SIGNOR-254208 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 CSNK2A1 protein P68400 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser380 EPDHYRYsDTTDSDP 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-152348 GRM6 protein O15303 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-264937 MARCHF8 protein Q5T0T0 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-271411 TWIST2 protein Q8WVJ9 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255513 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT up-regulates phosphorylation Ser398 DSLPSSPsSATPHSQ 9606 SIGNOR-C15 22669845 t gcesareni "In response to genotoxic stress, eef2k was activated by ampk (adenosine monophosphate-activated protein kinase)-mediated phosphorylation on serine 398. Activated eef2k phosphorylated eef2 and induced a temporary ribosomal slowdown at the stage of elongation" SIGNOR-197734 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 MAML1 protein Q92585 UNIPROT EP300 protein Q09472 UNIPROT up-regulates relocalization 9606 19304754 t gcesareni "We show that maml1 potentiates p300 autoacetylation and p300 transcriptional activation. Maml1 directly enhances p300 hat activity, and this coincides with the translocation of maml1, p300 and acetylated histones to nuclear bodies." SIGNOR-184853 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 9606 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-217110 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 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 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR BCL2L11 protein O43521 UNIPROT down-regulates binding 9606 16282323 t gcesareni "Cytokine stimulation promotes bim(el) binding to 14-3-3 proteins. Akt could directly phosphorylate a gst-bim(el) fusion protein and identified the akt phosphorylation site in the bim(el) domain as ser(87). we propose that ser87 of bimel is an important regulatory site that is targeted byakt to attenuate thepro-apoptotic function of bim el, thereby promoting cell survival." SIGNOR-141577 CDKN1A protein P38936 UNIPROT CDK3 protein Q00526 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-29954 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 LPAR2 protein Q9HBW0 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 15856019 t gcesareni "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. lpa2 also can couple to the gi/o, g12/13, and gqfamilies." SIGNOR-135834 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 TADA3 protein O75528 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-269584 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 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 "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 PPP1R1B protein Q9UD71 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" binding 9606 BTO:0000938 10604473 t miannu "DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ " SIGNOR-264957 DAPK3 protein O43293 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Thr19 KKRPQRAtSNVFAMF 9606 12429016 t gcesareni "Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge." SIGNOR-95524 BRCA1 protein P38398 UNIPROT ERCC6 protein Q03468 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21756275 t miannu "BRCA1 polyubiquitinates CSB and this polyubiquitination and subsequent degradation of CSB occur following UV irradiation, even in the absence of Cockayne syndrome A (CSA) protein. " SIGNOR-272754 RHEB protein Q15382 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates binding 9606 18550814 t gcesareni "Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb." SIGNOR-178892 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 COL1A2 protein P08123 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-253248 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 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 BCR protein P11274 UNIPROT YWHAQ protein P27348 UNIPROT unknown phosphorylation Ser232 LTLWTSDsAGEECDA -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-250594 SREBF2 protein Q12772 UNIPROT PON1 protein P27169 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20728021 t miannu "we conclude that quercetin exhibits its antiatherogenic property by eliciting the translocation of the mature SREBP2 from endoplasmic reticulum to the nucleus, where it binds to SRE-like sequence in the PON1 promoter and up-regulates PON1 gene transcription and PON1 activity." SIGNOR-255224 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 MRE11/RAD50/NBS1 complex SIGNOR-C147 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 17713585 f lperfetto "The mre11_rad50_nbs1 (mrn) complex is among the earliest respondents to dna double-strand breaks (dsbs).|Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein--nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB." SIGNOR-251502 DLG4 protein P78352 UNIPROT GRIN2B protein Q13224 UNIPROT "up-regulates activity" relocalization 9606 9278515 t brain lperfetto "The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses." SIGNOR-264195 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 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 PRKCA protein P17252 UNIPROT GRM1 protein Q13255 UNIPROT "down-regulates activity" phosphorylation Thr695 GSKKKICtRKPRFMS 9606 10823959 t lperfetto "Furthermore, we demonstrate that the selectivity of PKC action on receptor signaling rests on phosphorylation of a threonine residue located in the G protein-interacting domain of the receptor. Modification at Thr(695) selectively disrupts mGluR1alpha-G(q/11) interaction without affecting signaling through G(s)." SIGNOR-249043 MITF protein O75030 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 12086670 t lperfetto "MITF directly occupies the BCL2 promoter in vivo and this suggest that BCL2 may be a direct transcriptional target of MITF" SIGNOR-249618 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR BRAP protein Q7Z569 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-271112 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Thr1031 ASSTDHQtPPTSPVQ 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-244549 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 TRIP13 protein Q15645 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 32860853 t lperfetto "Mechanistically, TRIP13 enhanced EGFR protein abundance in part by preventing Cbl-mediated ubiquitination and proteasomal degradation." SIGNOR-265084 sunitinib chemical CHEBI:38940 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 21423276 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-172911 fentanyl chemical CHEBI:119915 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-258937 mTORC2 complex SIGNOR-C2 SIGNOR mTORC2 complex SIGNOR-C2 SIGNOR "up-regulates activity" phosphorylation 10090 BTO:0000944 20022946 t lperfetto "These data suggest that mTORC1- and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity" SIGNOR-235484 AURKB protein Q96GD4 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser278 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-198650 PTPN11 protein Q06124 UNIPROT NRAS protein P01111 UNIPROT "up-regulates activity" dephosphorylation Tyr32 QNHFVDEyDPTIEDS 9606 BTO:0000007 26617336 t miannu "Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling." SIGNOR-255754 DLG4 protein P78352 UNIPROT GRIN2A protein Q12879 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000007 9278515 t brain lperfetto "The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses." SIGNOR-264194 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 DAMPS stimulus SIGNOR-ST18 SIGNOR "AP-1/clathrin vescicle" complex SIGNOR-C251 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-267854 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser29 IEDSQPEsQVLEDDS 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-100645 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 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 SMCR8 protein Q8TEV9 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 28195531 t "While focusing on the role of SMCR8 during autophagy initiation, we found that kinase activity and gene expression of ULK1 are increased upon SMCR8 depletion." SIGNOR-252029 TRAF2 protein Q12933 UNIPROT RIPK1 protein Q13546 UNIPROT up-regulates 9606 10795740 t "We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation" SIGNOR-256252 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR RB1 protein P06400 UNIPROT "down-regulates activity" phosphorylation Ser780 STRPPTLsPIPHIPR 9606 BTO:0000150 23336272 t lperfetto "Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression." SIGNOR-216988 CDK2 protein P24941 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158612 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser641 GKVYGKTsHLRAHLR 9606 16943418 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-149287 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 NRG3 protein P56975 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 14967450 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-122059 zotepine chemical CHEBI:32316 ChEBI DRD3 protein P35462 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-258556 NUTF2 protein P61970 UNIPROT NUP62 protein P37198 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 7744965 t Simone "Our data suggest that NTF2 interacts directly with NPC protein 1362 and exerts its effect at a relatively late step in the nuclear protein import pathway. We obtained a cDNA encoding NTF2 and showed that the recombinant protein restores transport activity to p62-pretreated cytosol." SIGNOR-261255 RAD21 protein O60216 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-263311 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 SCF-betaTRCP complex SIGNOR-C5 SIGNOR LPCAT1 protein Q8NF37 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys221 RTCLITFkPGAFIPG 10090 BTO:0004299 21068446 t miannu "Here, we show that lipopolysaccharide (LPS) causes LPCAT1 degradation using the Skp1-Cullin-F-box ubiquitin E3 ligase component, β-transducin repeat-containing protein (β-TrCP), that polyubiquitinates LPCAT1, thereby targeting the enzyme for proteasomal degradation.Lys221 Is a Bona Fide Site for LPCAT1 Ubiquitination" SIGNOR-272759 LPCAT1 protein Q8NF37 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 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-272760 CDK9 protein P50750 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" 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-161589 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser43 FGYQRRAsDDGKLTD 9606 11971957 t gcesareni "Serine 43 phosphorylation decreased the binding to ras in serum-starved but not in mitogen-stimulated cells. However, the kinase activity of a rafs43a mutant was fully inhibited by pka." SIGNOR-86145 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 DYRK1B protein Q9Y463 UNIPROT HNF1A protein P20823 UNIPROT up-regulates phosphorylation Ser249 IQRGVSPsQAQGLGS 9606 BTO:0000887;BTO:0001103 11980910 t lperfetto "Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk" SIGNOR-86728 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI ADRA1B protein P35368 UNIPROT "up-regulates activity" "chemical activation" 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-258443 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-261720 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 CDK5 protein Q00535 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Ser732 SSEGFYPsPQHMVQT 9606 BTO:0000938 12941275 t gcesareni "Here, we show that fak phosphorylation by cdk5 at s732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, s732-phosphorylated fak is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant fak s732a results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo." SIGNOR-86223 ARHGAP22 protein Q7Z5H3 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-260477 DLGAP2 protein Q9P1A6 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-264591 SLN protein O00631 UNIPROT ATP2A2 protein P16615 UNIPROT "down-regulates activity" binding -1 23455424 t lperfetto "The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+." SIGNOR-264779 GABRB2 protein P47870 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-263769 CSNK2A2 protein P19784 UNIPROT CASQ2 protein O14958 UNIPROT unknown phosphorylation Ser385 DDDDDDNsDEEDNDD -1 1985907 t llicata "Both cardiac and skeletal muscle calsequestrins were phosphorylated by casein kinase II, but cardiac calsequestrin was phosphorylated to a higher stoichiometry and at least 50 times more rapidly. The site of rapid phosphorylation of cardiac calsequestrin was localized to the distinct COOH terminus, where a cluster of three closely spaced serine residues are found (S378DEESN-DDSDDDDE-COOH)." SIGNOR-250980 PRKACA protein P17612 UNIPROT HNRNPD protein Q14103 UNIPROT up-regulates phosphorylation Ser87 SNSSPRHsEAATAQR 9606 11903055 t gcesareni "Protein kinase a enhances, whereas glycogen synthase kinase-3 beta inhibits, the activity of the exon 2-encoded transactivator domain of heterogeneous nuclear ribonucleoprotein d in a hierarchical fashion." SIGNOR-116144 "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 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-262139 CDK1 protein P06493 UNIPROT PLEC protein Q15149 UNIPROT down-regulates phosphorylation Thr4539 GGLIEPDtPGRVPLD 9606 BTO:0000567 SIGNOR-C17 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-41319 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 AKT2 protein P31751 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Ser196 KLRRRFSsLHFMVEV 9606 15004527 t gcesareni "Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity" SIGNOR-123243 LPCAT1 protein Q8NF37 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-272761 LPCAT1 protein Q8NF37 UNIPROT 1-O-acyl-sn-glycero-3-phosphocholine chemical CHEBI:58168 ChEBI "down-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-272762 CHL1 protein O00533 UNIPROT ANK2 protein Q01484 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-266722 PTGS2 protein P35354 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 BTO:0000007 32995789 f miannu "Given our finding that COX-2 signaling does not regulate viral entry or replication, the role of COX-2 induction upon SARS-CoV-2 infection remains an area for future investigation. Rather than directly affecting viral entry or replication, COX-2 induction may regulate the severe lung inflammation and injury seen in COVID-19 patients (35, 36), though it is unclear whether COX-2 would be beneficial, neutral, or detrimental to disease. COX-2 could enhance lung injury in COVID-19, as PGE2 has been reported to induce IL-1β and exacerbate lung injury in bone marrow transplant mice" SIGNOR-262509 LPAR6 protein P43657 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-257212 Calcineurin complex SIGNOR-C155 SIGNOR 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-252339 G3BP1 protein Q13283 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" binding 9606 BTO:0001938;BTO:0000567 25784705 t SARA "PKR directly interacts with G3BP1 through the NTF2-like and PXXP domains of G3BP1. The recruitment of inactive PKR to SGs through this interaction correlates with its activation" SIGNOR-260981 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 YARS1 protein P54577 UNIPROT tRNA(Tyr) smallmolecule CHEBI:29182 ChEBI "down-regulates quantity" "chemical modification" 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-270517 HIF1A protein Q16665 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-271564 tandutinib chemical CHEBI:90237 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207209 NDUFS7 protein O75251 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-262181 SRC protein P12931 UNIPROT ANXA1 protein P04083 UNIPROT unknown phosphorylation Thr216 AGERRKGtDVNVFNT 9606 24103589 t lperfetto "Location of sites in human lipocortin i that are phosphorylated by protein tyrosine kinases and protein kinases a and cthe primary site of phosphorylation by protein kinase c was also near the amino terminus at ser-27. The major site of phosphorylation by adenosine cyclic 3',5'-phosphate dependent protein kinase was on the carboxy-terminal half of the molecule at thr-216" SIGNOR-202800 MAPK1 protein P28482 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser294 QLSKWPGsPTSRSSD 9606 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-252957 MRGPRX2 protein Q96LB1 UNIPROT GNAS protein Q5JWF2 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-256787 MYO7A protein Q13402 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-262577 BABAM2 protein Q9NXR7 UNIPROT "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR "form complex" binding 9606 BTO:0000007 14636569 t lperfetto "These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.|Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer" SIGNOR-263209 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KA1 protein Q15418 UNIPROT "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-250557 ESR2 protein Q92731 UNIPROT TGFA protein P01135 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-253944 CRYBB2 protein P43320 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 16319073 f miannu "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-252151 SIK3 protein Q9Y2K2 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-249170 SDHA protein P31040 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-266271 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 GABRG2 protein P18507 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-263755 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 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 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-165212 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 LPCAT1 protein Q8NF37 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI "down-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-272763 LPCAT2 protein Q7L5N7 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 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-272764 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 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM60 protein Q495X7 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-271161 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 NR3C1 protein P04150 UNIPROT TIMELESS protein Q9UNS1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19805059 t miannu "GR directly regulates transcription of circadian clock components in mouse and human primary MSCs. Per2, E4bp4, Per1, and Timeless rapidly respond to glucocorticoid stimulation. Primary glucocorticoid receptor (GR) target genes are those at which GR occupies a nearby genomic glucocorticoid response element (GRE) and regulates target gene transcription" SIGNOR-268052 CSNK2A2 protein P19784 UNIPROT SLC18A2 protein Q05940 UNIPROT unknown phosphorylation Ser511 PIGEDEEsESD -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-251038 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 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 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 PBK protein Q96KB5 UNIPROT GPSM2 protein P81274 UNIPROT up-regulates phosphorylation Thr457 LKGKKYKtNSSTKVL 9606 BTO:0000150 20589935 t lperfetto "We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase." SIGNOR-166461 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 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 GATA1 protein P15976 UNIPROT TAL1 protein P17542 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7632958 f irozzo "Moreover, GATA-1 but not GATA-2 or GATA-3 was able to transactivate SCL promoter 1a in a T-cell environment. These results suggest that inactivity of SCL promoter 1a in T cells reflected the absence of GATA-1 rather than the presence of trans-dominant negative regulators." SIGNOR-256047 Ub:E2 complex SIGNOR-C497 SIGNOR CBLL2 protein Q8N7E2 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-271198 P2RY13 protein Q9BPV8 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-257299 CDK1 protein P06493 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser442 STFLAFPsPEKLLRL 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 . Alternatively, phosphorylated rangap1 may recruit specific sumo target proteins to ranbp2's catalytic domain." SIGNOR-123520 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 DOCK8 protein Q8NF50 UNIPROT CDC42 protein P60953 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 28028151 t lperfetto "Recently, DOCK8 was identified as a guanine-nucleotide exchange factor (GEF) for Cdc42 activation and has been associated with human mental retardation. " SIGNOR-268412 WRN protein Q14191 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 9606 19652551 f "Our work provides the first demonstration of the major importance of WRN in repair of a specific class of DSB in human cells." SIGNOR-258983 LPCAT2 protein Q7L5N7 UNIPROT acyl-CoA(4-) chemical CHEBI:58342 ChEBI "down-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-272767 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 "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 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 MRPL55 protein Q7Z7F7 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-262335 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 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-252848 STK33 protein Q9BYT3 UNIPROT AKAP3 protein O75969 UNIPROT "up-regulates quantity by stabilization" phosphorylation -1 37146716 t lperfetto "Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components AKAP3 and AKAP4, whose expression levels decreased in testis after deletion of Stk33." SIGNOR-272955 STK33 protein Q9BYT3 UNIPROT AKAP4 protein Q5JQC9 UNIPROT "up-regulates quantity by stabilization" phosphorylation -1 37146716 t lperfetto "Differential phosphoproteomic analysis and in vitro kinase assay identified novel phosphorylation substrates of STK33, fibrous sheath components AKAP3 and AKAP4, whose expression levels decreased in testis after deletion of Stk33." SIGNOR-272956 STK33 protein Q9BYT3 UNIPROT STK33 protein Q9BYT3 UNIPROT "up-regulates activity" phosphorylation 18811945 t lperfetto "Our results show that the serine/threonine kinase Stk33 phosphorylates the intermediate filament protein vimentin in vitro specifically in the vimentin head domain. Stk33 undergoes obligatory autophosphorylation, which might be a prerequisite for its kinasing activity." SIGNOR-272957 STK33 protein Q9BYT3 UNIPROT HPD protein P32754 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr382 QNLRGNLtNMETNGV 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-272958 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 TTC36 protein A6NLP5 UNIPROT HPD protein P32754 UNIPROT "up-regulates quantity by stabilization" binding 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-272960 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 risperidone chemical CHEBI:8871 ChEBI HTR1F protein P30939 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-258524 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 HOPX protein Q9BPY8 UNIPROT FLG protein P20930 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 21256618 f miannu "In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation." SIGNOR-254463 CALM2 protein P0DP24 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-266323 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 NFIB protein O00712 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-268870 ITCH protein Q96J02 UNIPROT LAPTM5 protein Q13571 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22009753 t miannu "Here, we found that the level of LAPTM5 protein is regulated negatively by the degradation through ubiquitination by ITCH, an E3 ubiquitin ligase. ITCH directly binds to the PPxY motif of LAPTM5 via its WW domains and promotes ubiquitination through a HECT-type ligase domain." SIGNOR-272721 "coenzyme A(4-)" smallmolecule CHEBI:57287 ChEBI acyl-CoA(4-) chemical CHEBI:58342 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-272769 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 1373652 t gcesareni "The question of whether protein tyrosine phosphatases (ptpases) dephosphorylate a multiply phosphorylated peptide in a random or ordered manner was investigated using the synthetic triphosphotyrosyl peptide trdiy(p)etdy(p)y(p)rk, corresponding to the major sites of autophosphorylation of the insulin receptor, as a substrate for four purified ptpases." SIGNOR-18018 IKBKB protein O14920 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates phosphorylation Ser450 SHNSALYsQVQKSGA 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-131556 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 EPHB2 protein P29323 UNIPROT RRAS protein P10301 UNIPROT "down-regulates activity" phosphorylation Tyr66 DPTIEDSyTKICSVD 9606 10570155 t "Tyrosine 66 of R-Ras is phosphorylated by EphB2|. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. |Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated." SIGNOR-251125 PAK1 protein Q13153 UNIPROT ELF3 protein P78545 UNIPROT up-regulates phosphorylation Ser207 GTGASRSsHSSDSGG 9606 BTO:0000150 17491012 t lperfetto "Phosphorylation-dependent regulation of stability and transforming potential of ets transcriptional factor ese-1 by p21-activated kinase 1. Pak1 selectively phosphorylates ese-1 at ser(207). Intriguingly, pak1 phosphorylation inactive mutant ese1-s207a is more unstable" SIGNOR-154743 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 LATS2 protein Q9NRM7 UNIPROT 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-177071 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 MAPK1 protein P28482 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser195 PNSSYPNsPGSSSST 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-52678 ZAP70 protein P43403 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1203 IFPARDTyHPMSEYP 9606 BTO:0000661 14766232 t lperfetto "Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin." SIGNOR-247039 buprenorphine chemical CHEBI:3216 ChEBI OPRK1 protein P41145 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-258769 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 PTPN1 protein P18031 UNIPROT ROS1 protein P08922 UNIPROT down-regulates dephosphorylation Tyr2110 FGLARDIyKNDYYRK 9606 17416557 t gcesareni "In an approach to gain insight into the sequence-dependent dephosphorylation of multiple phosphotyrosyl-containing peptides by the phosphatases shp-1 and ptp1b, we applied a chromatographic technique for the analysis of the dephosphorylation products." SIGNOR-154199 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 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr763 DMKGDVKyADIESSN 9823 10391677 t miannu "Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2." SIGNOR-250258 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 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 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 OGT protein O15294 UNIPROT PFK proteinfamily SIGNOR-PF79 SIGNOR "down-regulates activity" glycosylation 9606 BTO:0000007 22923583 t lperfetto "O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway| O-GlcNAc transferase (OGT) catalyzes the transfer of N-acetylglucosamine from uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) to serine or threonine residues" SIGNOR-267586 FBXL5 protein Q9UKA1 UNIPROT NABP2 protein Q9BQ15 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000018 25249620 t miannu "Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation." SIGNOR-271655 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 TFIIH complex SIGNOR-C457 SIGNOR ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 10949034 t lperfetto "Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7." SIGNOR-269356 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 PPP1CA protein P62136 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 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-248556 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 MAPK8 protein P45983 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Thr265 GQSSAAAtPSTTGTK 9606 15767678 t gcesareni "Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro." SIGNOR-134541 SCF-SKP2 complex SIGNOR-C136 SIGNOR IDH1 protein O75874 UNIPROT "down-regulates quantity by destabilization" ubiquitination phosphorylation:Thr157 GKVEITYtPSDGTQK 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-267623 MAPK12 protein P53778 UNIPROT SH3BP5 protein O60239 UNIPROT unknown phosphorylation Ser351 PGSLDLPsPVSLSEF -1 15158451 t miannu "Activated SAPK3 phosphorylates the mitochondrial protein Sab. 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-250140 resveratrol chemical CHEBI:27881 ChEBI AHR protein P35869 UNIPROT "down-regulates activity" "chemical inhibition" -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-253640 "sorafenib tosylate" chemical CHEBI:50928 ChEBI FLT3 protein P36888 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-259223 SCF-betaTRCP complex SIGNOR-C5 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 23431053 t lperfetto "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-230750 CNR1 protein P21554 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-256724 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 TRADD protein Q15628 UNIPROT TRAF2 protein Q12933 UNIPROT "up-regulates activity" binding 10090 BTO:0000459 18621737 t lperfetto "The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively." SIGNOR-179446 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 MYO5A protein Q9Y4I1 UNIPROT VAMP2 protein P63027 UNIPROT "up-regulates activity" binding 9606 21077886 t miannu "Another potential role of myosin Va in LDCV exocytosis lies in facilitating the formation of the SNARE complex, which is needed for fusion of the vesicle with the plasma membrane. Notably, myosin Va binds to at least two SNARE proteins in a Ca2+-dependent manner: at micromolar Ca2+-levels, it binds to VAMP2 located in the membrane of the cargo vesicle via its globular tail domain" SIGNOR-269281 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 BAG6 protein P46379 UNIPROT PCK1 protein P35558 UNIPROT "down-regulates quantity by destabilization" acetylation 9606 BTO:0000007 21726808 t lperfetto "These results indicate that BAT3 and P300 can both exist in the PEPCK1 protein complex, suggesting the possibility that BAT3 could be an enhancer of PEPCK1 acetylation. | indicating a synergistic effect of BAT3 and P300 to promote PEPCK1 acetylation." SIGNOR-267598 PTGER2 protein P43116 UNIPROT GNAS protein P63092 UNIPROT up-regulates binding 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-elementdriven reporter gene (cre-luc)." SIGNOR-141597 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 NUP58 protein Q9BVL2 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-261260 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" 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. These results indicate that phosphorylation by PKB/Akt negatively regulates FKHR1 by promoting export from the nucleus." SIGNOR-252346 MAPKAPK2 protein P49137 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15688025 t gcesareni "Hdm2 phosphorylation by mapkap kinase 2 enhances hdm2 activity and promote the degradation of p53." SIGNOR-133560 PPP2CA protein P67775 UNIPROT TFCP2 protein Q12800 UNIPROT up-regulates dephosphorylation Ser309 SLGEGNGsPNHQPEP 9606 20682773 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. This predominant cis conformation would also limit dephosphorylation of ser-291 and ser-309 by phosphatases such as pp2a" SIGNOR-167389 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF2 protein Q9P0N8 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-271245 IQSEC2 protein Q5JU85 UNIPROT GRIA2 protein P42262 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-264913 PRKCD protein Q05655 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" phosphorylation Thr758 NPLFKSAtTTVMNPK 9606 BTO:0000782 11700305 t lperfetto "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. Pkc-mediated phosphorylation of cd18 after cell stimulation could lead to the recruitment of 14-3-3 proteins to the activated integrin, which may play a role in regulating its adhesive state or ability to signal." SIGNOR-111495 MITF protein O75030 UNIPROT TPSAB1 protein Q15661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000830 20513998 t lperfetto "The transcription of tryptase gene in human mast cells is regulated by mi transcription factor |Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A." SIGNOR-251725 PRKCA protein P17252 UNIPROT ADD3 protein Q9UEY8 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser693 KKKFRTPsFLKKNKK -1 11895774 t lperfetto "Results of in vitro experiments with recombinant alpha adducin demonstrated that PKC-phosphorylated adducin was proteolyzed by calpain more quickly than unphosphorylated adducin. | Phosphorylation of adducin by PKC may be a common mechanism for regulating adducin proteolysis by several proteases. | The antibody used in panel B is specific for the PKC-phosphorylated form of adducin. This antibody was raised against the phosphopeptide CKKFRTP[pS]FLKKNK, corresponding to amino acids 656-668 of human gamma adducin" SIGNOR-249143 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 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 LPCAT4 protein Q643R3 UNIPROT 1,2-diacyl-sn-glycero-3-phosphocholine chemical CHEBI:57643 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-272770 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 MECP2 protein P51608 UNIPROT GRIA2 protein P42262 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 22262897 t Luana "Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A." SIGNOR-264684 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 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg707 ESTVMATrKMHDRLE -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-263630 PAK1 protein Q13153 UNIPROT ITGB3BP protein Q13352 UNIPROT up-regulates phosphorylation Ser28 SKITRKKsVITYSPT 9606 BTO:0000150 18521086 t lperfetto "Serine 28 phosphorylation of nrif3 confers its co-activator function for estrogen receptor-alpha transactivation. p21-activated protein kinase 1 (pak1) phosphorylates eralpha at ser305 and this modification is important in eralpha transactivation function." SIGNOR-178795 BID protein P55957 UNIPROT BAK1 protein Q16611 UNIPROT up-regulates binding 9606 17289999 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 c. these data support a two-class model for bh3 domains: bid-like domains that activate bax, bak and bad-like domains that sensitize by occupying the pocket of antiapoptotic members." SIGNOR-152992 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT unknown phosphorylation Thr355 EPSTVPGtPPPKKFR 9606 24376897 t "The effect has been demonstrated using Q9UKI8-2" llicata "Here we show that rad9 is phosphorylated in a tlk-dependent manner in vitro and in vivo, and that t355 within the c-terminal tail is the primary targeted residue." SIGNOR-203503 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 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR CASP9 protein P55211 UNIPROT "down-regulates activity" phosphorylation 12792650 t "inferred from 70% family members" lperfetto "Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2" SIGNOR-270222 FOXO proteinfamily SIGNOR-PF27 SIGNOR Proliferation phenotype SIGNOR-PH4 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-252938 Ub:E2 complex SIGNOR-C497 SIGNOR MKRN1 protein Q9UHC7 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-271234 GATA4 protein P43694 UNIPROT TDO2 protein P48775 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" BTO:0000575 19003156 t lperfetto "GATA4 inhibits expression of the tryptophan oxygenase gene by binding to the TATA box in fetal hepatocytes." SIGNOR-268994 CHUK protein O15111 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates phosphorylation Ser1382 MKSRFVDsGEMSESF 9606 BTO:0000551 17434128 t lperfetto "Phosphorylation of cbp by ikkalpha promotes cell growth by switching the binding preference of cbp from p53 to nf-kappabhere, we show that ikkalpha phosphorylates cbp at serine 1382 and serine 1386 and consequently increases cbp's hat and transcriptional activities" SIGNOR-154329 RUSC1 protein Q9BVN2 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates quantity by stabilization" 9606 BTO:0000007 19365808 t miannu "NESCA interacts with the IKK complex by the N-terminal region of NEMO. This experiment revealed that the overexpression of NESCA completely abolished the TRAF6-mediated polyubiquitination of NEMO, as it appears by using either anti-HA (Fig. 5A) or anti-NEMO (Fig. 5B) antibodies on immunoprecipitated extracts." SIGNOR-272775 RUSC1 protein Q9BVN2 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates binding 9606 15024033 f miannu "Overexpression studies in PC12 cells indicate that Nesca facilitates neurotrophin-dependent neurite outgrowth at nonsaturating doses of nerve growth factor (NGF)." SIGNOR-272776 LNX1 protein Q8TBB1 UNIPROT ZBTB8A protein Q96BR9 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19668196 t miannu "LNX (ligand of Numb protein-X) is a RING finger and four PDZ domain-containing E3 ubiquitin ligase. Lnx-l induced K48-linked polyubiquitylation of Boz, leading to its proteasomal degradation in human 293T cells and in zebrafish embryos." SIGNOR-272777 BFAR protein Q9NZS9 UNIPROT TMBIM6 protein P55061 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 21068390 t miannu "BAR overexpression promotes BI-1 ubiquitination and proteasomal degradation.We show here that bifunctional apoptosis regulator (BAR) functions as an ER-associated RING-type E3 ligase, interacts with BI-1, and promotes proteasomal degradation of BI-1. " SIGNOR-272778 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates 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-120040 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 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 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 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 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 PRKN protein O60260 UNIPROT MFN2 protein O95140 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-272780 MCM7 protein P33993 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-261677 RACK1 protein P63244 UNIPROT CLEC1B protein Q9P126 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 19785988 t miannu "In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex" SIGNOR-272781 RACK1 protein P63244 UNIPROT "Elongin E3-Cul-5" complex SIGNOR-C531 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 19785988 t miannu "In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex" SIGNOR-272782 BRIP1 protein Q9BX63 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-263219 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr230 DSKEIFLtVPVGGGE 9606 19530738 t lperfetto "We found that substitutions at borealin t230, recently identified as an mps1 phosphorylation site, can modulate the dimerization state of borealin. Mutation of this single residue to alanine or valine impairs aurora b activity during mitosis and causes chromosome segregation defects" SIGNOR-186147 YY1 protein P25490 UNIPROT TNFRSF10B protein O14763 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000848 34589486 t miannu "Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis." SIGNOR-268793 HMGA2 protein P52926 UNIPROT E4F1 protein Q66K89 UNIPROT down-regulates binding 9606 14645522 t miannu "Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter" SIGNOR-119537 CEBPD protein P49716 UNIPROT SOD1 protein P00441 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000792 20385105 f miannu "Expression of CEBPD reduced cisplatin-induced reactive oxygen species (ROS) and apoptosis in NTUB1 cells by inducing the expression of Cu/Zn-superoxide dismutase (SOD1) via direct promoter transactivation." SIGNOR-253774 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1644 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-248748 SMURF1 protein Q9HCE7 UNIPROT TBX6 protein O95947 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 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-272784 tRNA(Gly) smallmolecule CHEBI:29176 ChEBI Gly-tRNA(Gly) smallmolecule CHEBI:29156 ChEBI "up-regulates quantity" "precursor of" 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-270483 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 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-257910 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 PROK2 protein Q9HC23 UNIPROT PROKR2 protein Q8NFJ6 UNIPROT up-regulates binding 9606 12024206 t gcesareni "We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2)" SIGNOR-87919 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 UHMK1 protein Q8TAS1 UNIPROT SF1 protein Q15637 UNIPROT up-regulates phosphorylation Ser80 PPNPEDRsPSPEPIY 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-143837 MRGPRX1 protein Q96LB2 UNIPROT GNAS protein Q5JWF2 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-256786 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 ATM protein Q13315 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000552 15254178 t lperfetto "Deltanp63 transcriptionally regulates atm to control p53 serine-15 phosphorylation. We next aimed to identify novel factors that control damage-induced p53 phosphorylation in a keratinocyte model system, and discovered that the epithelial stem cell marker _Np63_ is a novel ATM regulator that controls p53 Serine-15 phosphorylation through transcription of the ATM kinase." SIGNOR-126753 GPR132 protein Q9UNW8 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-256945 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 "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 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-268603 MCU_MICU3_variant complex SIGNOR-C501 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-270873 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 UBR5 protein O95071 UNIPROT PAIP2 protein Q9BPZ3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 16601676 t miannu "We demonstrate a mechanism for this co-regulation that involves an E3 ubiquitin ligase, EDD, which targets Paip2 for degradation. PABP depletion by RNA interference (RNAi) causes co-depletion of Paip2 protein without affecting Paip2 mRNA levels. Upon PABP knockdown, Paip2 interacts with EDD, which leads to Paip2 ubiquitination." SIGNOR-272648 THRSP protein Q92748 UNIPROT MID1IP1 protein Q9NPA3 UNIPROT "down-regulates activity" binding 10029 BTO:0000457 20952657 t miannu "In the current study, we have determined the crystal structure of mouse S14 to 2.65-Å resolution. The structure of S14 reveals a helical protein arranged as a symmetric dimer. Cultured cell experiments indicate that S14 can form heterodimers with MIG12, suggesting a mechanism through which S14 could modulate ACC activity and subsequently rates of fatty acid synthesis via heterodimer formation with MIG12.In the current study, we have shown that regulating the levels of S14∶MIG12 heterodimers regulates the ability of MIG12 to activate ACC. Increasing S14∶MIG12 heterodimers by the overexpression of S14 resulted in decreased ACC activity and polymerization, whereas decreasing S14∶MIG12 heterodimers by knockdown of S14 increased ACC activity and polymerization." SIGNOR-267113 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 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 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser748 RFARRSVsDNDIRKY 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-252493 ERK1/2 proteinfamily SIGNOR-PF1 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-270183 MYC protein P01106 UNIPROT ST3GAL4 protein Q11206 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-253959 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser236 DDSGTEEs 9606 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-110403 PRKN protein O60260 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-272749 CDK1 protein P06493 UNIPROT NIFK protein Q9BYG3 UNIPROT "up-regulates activity" phosphorylation Thr238 QGPTPVCtPTFLERR -1 16244663 t miannu "The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1." SIGNOR-262696 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 CDK2 protein P24941 UNIPROT TK1 protein P04183 UNIPROT down-regulates phosphorylation Ser13 LPTVLPGsPSKTRGQ 9606 14697231 t gcesareni "Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase." SIGNOR-120372 AURKA protein O14965 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0001225 19060929 t lperfetto "The recombinant human aurka protein phosphorylated the gsk-3beta protein at ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (ser33/37/thr41) by gsk-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-gsk-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (ser33/37/thr41) and accumulation of beta-catenin protein." SIGNOR-227923 RPS6K proteinfamily SIGNOR-PF26 SIGNOR DEPTOR protein Q8TB45 UNIPROT down-regulates phosphorylation Ser291 CGSSGYFsSSPTLSS 9606 22017877 t lperfetto "We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1" SIGNOR-252799 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 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 MAGEL2 protein Q9UJ55 UNIPROT WASHC1 protein A8K0Z3 UNIPROT "up-regulates activity" binding 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-253515 ETFBKMT protein Q8IXQ9 UNIPROT ETFB protein P38117 UNIPROT "down-regulates activity" methylation Lys200 ATLPNIMkAKKKKIE -1 25416781 t miannu "Accordingly, we found that METTL20-mediated methylation of ETFβ in vitro reduced its ability to receive electrons from the medium chain acyl-CoA dehydrogenase and the glutaryl-CoA dehydrogenase. In conclusion, the present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases." SIGNOR-269450 TACR1 protein P25103 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-257316 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 "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 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 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 SCF-SKP2 complex SIGNOR-C136 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 20852628 t gcesareni "The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain" SIGNOR-243551 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT down-regulates phosphorylation Ser155 FPLRKTVsEPNLKLR 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-132894 SPRY2 protein O43597 UNIPROT CBLC protein Q9ULV8 UNIPROT down-regulates 9606 12234920 f gcesareni "Hspry2 prevents c-cbl-mediated ubiquitylation of egfrs. hspry2 interacts specifically with the c-cbl ring finger domain and displaces ubch7 from its binding site on the e3 ligase." SIGNOR-92926 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 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 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 DAPK3 protein O43293 UNIPROT RPL13A protein P40429 UNIPROT up-regulates phosphorylation Ser77 PYHFRAPsRIFWRTV 9606 BTO:0000801 18995835 t lperfetto "Zipk phosphorylates l13a in vitro / l13a is phosphorylated on ser77 in vitro" SIGNOR-182117 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 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 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 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 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Thr32 QSRPRSCtWPLQRPE 9606 19188143 t gcesareni "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-183652 "GABA-A (a5-b1-g2) receptor" complex SIGNOR-C335 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-263815 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 ethanol chemical CHEBI:16236 ChEBI GLRA1 protein P23415 UNIPROT "up-regulates activity" "chemical activation" 8355 BTO:0000964 8700149 t 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-258495 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 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-257965 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates 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-252353 malonyl-CoA smallmolecule CHEBI:15531 ChEBI CPT1A protein P50416 UNIPROT down-regulates binding 9606 17452323 t "Carnitine palmitoyltransferase 1 (CPT1) catalyzes the conversion of palmitoyl-CoA to palmitoylcarnitine in the presence of l-carnitine, thus facilitating the entry of fatty acids to mitochondria, in a process that is physiologically inhibited by malonyl-CoA" SIGNOR-267758 canertinib chemical CHEBI:61399 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000017;BTO:0000195 10753475 t "Canertinib is an irreversible tyrosine-kinase inhibitor with activity against EGFR (IC50 0.8 nM), HER-2 (IC50 19 nM) and ErbB-4 (IC50 7 nM)." gcesareni "Quinazoline analogues with 7-alkoxyamine solubilizing s were potent irreversible inhibitors of the isolated egfr enzyme, with ic(50[app]) values from 2 to 4 nm, and potently inhibited both egfr and erbb2 autophosphorylation in cells." SIGNOR-76554 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 PIM1 protein P11309 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 f 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-249623 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 YAP1 protein P46937 UNIPROT TEAD4 protein Q15561 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201474 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 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 SEMA3B protein Q13214 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-261814 PTPRJ protein Q12913 UNIPROT LAT protein O43561 UNIPROT "down-regulates activity" dephosphorylation 9606 11259588 t "Protein tyrosine phosphatase CD148-mediated inhibition of T-cell receptor signal transduction is associated with reduced LAT and phospholipase Cgamma1 phosphorylation" SIGNOR-248696 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 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 EGFR protein P00533 UNIPROT GRB2 protein P62993 UNIPROT unknown phosphorylation Tyr209 TGMFPRNyVTPVNRN 9606 BTO:0000017 11726515 t lperfetto "Phosphorylation of grb2 by bcr/abl or egf receptor reduced its sh3-dependent binding to sos in vivo, but not its sh2-dependent binding to bcr/abl. Tyr209 within the c-terminal sh3 domain of grb2 was identified as one of the tyrosine phosphorylation sites" SIGNOR-235738 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 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 FOXO4 protein P98177 UNIPROT FBXO32 protein Q969P5 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-236554 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 BVES protein Q8NE79 UNIPROT VAMP3 protein Q15836 UNIPROT "up-regulates activity" binding -1 20057356 t llicata "Taken together, these data demonstrate that Bves interacts with VAMP3 and facilitates receptor recycling both in vitro and during early development." SIGNOR-237771 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 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 LPAR3 protein Q9UBY5 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-256747 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 Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR IFIH1 protein Q9BYX4 UNIPROT up-regulates 9606 19052324 t miannu "Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication.Once one or both of these sensors are activated, they interact with a mitochondrial membrane protein called MAVS (mitochondrial antiviral) (also called IPS1, Cardif, and VISA). They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ." SIGNOR-260142 NOTCH3 protein Q9UM47 UNIPROT RBPJ protein Q06330 UNIPROT up-regulates binding 9606 11404076 t gcesareni "Both notch 1 and notch 3 ics displace the co-repressor smrt from the dna-binding protein rbp-j kappa on the hes promoter. The latter observation suggests that both notch 3 ic and notch 1 ic can access rbp-j kappa in vivo, and that the difference in activation capacity instead stems from structural differences in the two ics when positioned on rbp-j kappa." SIGNOR-86128 RIMBP2 protein O15034 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-264366 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "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-252866 TRAF3 protein Q13114 UNIPROT TBK1 protein Q9UHD2 UNIPROT "up-regulates activity" binding 9606 24622840 t miannu "MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1." SIGNOR-260156 MAPK9 protein P45984 UNIPROT ATN1 protein P54259 UNIPROT "down-regulates activity" phosphorylation Ser739 EEYETPEsPVPPARS 9606 BTO:0000142 12812981 t 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-102402 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser20 PLSQETFsDLWKLLP 9606 11896587 t llicata "These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells." SIGNOR-115831 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 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1654 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-269369 UBE3A protein Q05086 UNIPROT "26S Proteasome" complex SIGNOR-C307 SIGNOR "down-regulates activity" ubiquitination 9606 BTO:0000007 28559284 t "Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A" SIGNOR-270339 ADRM1 protein Q16186 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-263342 methoxamine chemical CHEBI:6839 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-258455 SMO protein Q99835 UNIPROT OPALIN protein Q96PE5 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-269225 STK11 protein Q15831 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser380 EPDHYRYsDTTDSDP 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-161118 AKT1 protein P31749 UNIPROT NCOR1 protein O75376 UNIPROT down-regulates phosphorylation Ser1450 TVRSRHTsVVSSGPS 9606 BTO:0001271 23940660 t llicata "Akt-induced phosphorylation of n-cor at serine 1450 contributes to its misfolded conformational dependent loss (mcdl) in acute myeloid leukemia of the m5 subtype." SIGNOR-198913 FGA protein P02671 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-263392 (-)-anisomycin chemical CHEBI:338412 ChEBI JUNB protein P17275 UNIPROT up-regulates "chemical activation" 9606 Other t "CellSignaling;phospho-JunB (Thr102/Thr104) (D3C6) Rabbit mAb #8053" gcesareni SIGNOR-189644 RIN1 protein Q13671 UNIPROT KRAS protein P01116 UNIPROT up-regulates binding 9606 11784866 t gcesareni "We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1." SIGNOR-113970 BCL3 protein P20749 UNIPROT HDAC1 protein Q13547 UNIPROT up-regulates binding 9606 15469820 t gcesareni "We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6" SIGNOR-129801 CTTN protein Q14247 UNIPROT Dendritic_spine_morphogenesis phenotype SIGNOR-PH183 SIGNOR up-regulates 9606 14684878 f miannu "Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting." SIGNOR-266595 CDK20 protein Q8IZL9 UNIPROT CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 14597612 t gcesareni "P42 is essential for the phosphorylation of thr-160 and activation of cdk2." SIGNOR-118986 LPAR3 protein Q9UBY5 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-257297 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 PCDHA5 protein Q9Y5H7 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-265669 SLBP protein Q14493 UNIPROT H2AC20 protein Q16777 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-265398 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 tRNA(Asn) smallmolecule CHEBI:29172 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-270467 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 COLGALT1 protein Q8NBJ5 UNIPROT COL3A1 protein P02461 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-261154 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 STK4 protein Q13043 UNIPROT FOXO3 protein O43524 UNIPROT up-regulates phosphorylation Ser209 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." SIGNOR-178190 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 (-)-anisomycin chemical CHEBI:338412 ChEBI JUND protein P17535 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189672 "Histone H2A" proteinfamily SIGNOR-PF70 SIGNOR "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-267756 EIF2AK2 protein P19525 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser32 LLDDRHDsGLDSMKD 10723127 t lperfetto "As described for other stimuli, following pIC treatment, PKR phosphorylates the NF-kappa B inhibitor I kappa B alpha at serine 32 before degradation." SIGNOR-249335 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 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-271322 DOCK3 protein Q8IZD9 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-260548 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 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 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 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR "up-regulates activity" 9606 25910399 f "Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged." SIGNOR-266901 PAK4 protein O96013 UNIPROT ITGB5 protein P18084 UNIPROT up-regulates phosphorylation Ser762 AKFQSERsRARYEMA 9606 20507994 t llicata "Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration." SIGNOR-165706 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr453 SGPIIIRtPTVGPNG 9606 BTO:0000887;BTO:0001260 14593115 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-248066 RARA protein P10276 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11788593 f gcesareni "We show that retinoic acid receptor (rar)-selective ligands reduce egfr level and the magnitude and duration of egfr activation in egf-stimulated cells" SIGNOR-114087 EIF1 protein P41567 UNIPROT "40S cytosolic small ribosomal subunit" complex SIGNOR-C286 SIGNOR "up-regulates activity" relocalization 9606 20921384 t lperfetto "Genetic and biochemical studies have revealed several eukaryotic factors involved in selecting the correct initiation codon (3–6). Further analyses pointed toward eukaryotic initiation factor 1 (eIF1) as the key mediator of this process (7–10). eIF1 binds near the P-site of the small ribosomal subunit (11); this binding is thought to lead to an open conformation of the preinitiation complex favoring scanning" SIGNOR-269143 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 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT "up-regulates activity" phosphorylation Thr404 SSMSTEQtLASDTDS -1 11062067 t "MKK7 also phosphorylates JNK2 alpha 2 at Thr-404 and Ser-407 in vitro. 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-251418 SMURF1 protein Q9HCE7 UNIPROT ASCC2 protein Q9H1I8 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-272692 MMP2 protein P08253 UNIPROT DCN protein P07585 UNIPROT "down-regulates quantity by destabilization" cleavage Ser240 ISRVDAAsLKGLNNL -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-256350 "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 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 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 EIF3_complex complex SIGNOR-C401 SIGNOR EIF4G3 protein O43432 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-269157 UBR1 protein Q8IWV7 UNIPROT RECQL4 protein O94761 UNIPROT up-regulates binding 9606 BTO:0000567 15317757 t miannu "The isolated recql4, assayed as a complex with ubr1 and ubr2, exhibited dna-stimulated atpase activity but was inactive as either dna helicase or dna translocase / the discovery, in the present work, that these ub ligases, ubr1 and ubr2, interact with the putative helicase recql4 (fig. 2), and that recql4 is a long-lived, non-ubiquitylated protein in hela cells" SIGNOR-128169 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates quantity by destabilization" cleavage Asp372 EFEVSFLdSPGAQAQ 9606 BTO:0000567 11815631 t Giulio "Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage" SIGNOR-260603 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 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 PLAU protein P00749 UNIPROT Epithelial-mesenchymal_transition phenotype SIGNOR-PH45 SIGNOR up-regulates 9606 19055748 f lperfetto "Our data show that functional blockade of SNAI1 (SNAI1-dominant negative (DN)) leads to a partial re-expression of E-cadherin, and induces differential expression of EMT-related genes. This is confirmed by RT-PCR of PA system genes, where PAI-1 and uPA are decreased." SIGNOR-252264 SLC9A7 protein Q96T83 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-265597 AKT2 protein P31751 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 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-252867 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Thr183 ACTNFMMtPYVVTRY 9606 11062067 t "phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif" gcesareni "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). These results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway." SIGNOR-83744 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 USP8 protein P40818 UNIPROT RNF41 protein Q9H4P4 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0002181 23750007 t irozzo "Ubiquitin-specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins." SIGNOR-259105 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1892 TPKYSPTsPTYSPTS 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-120052 AKT1 protein P31749 UNIPROT FOXO3 protein O43524 UNIPROT "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-249625 F10 protein P00742 UNIPROT APOH protein P02749 UNIPROT "down-regulates activity" cleavage Lys336 HSSLAFWKTDASDVK -1 9596664 t lperfetto "In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). |The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI." SIGNOR-266997 MYOCD protein Q8IZQ8 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 f "miR-143 and miR-145 target KLF4" gcesareni "These results further confirm that bmp4 requires mrtf-a, whereas tgf-_ requires myocd for the induction of pri-mir-143/145 and down-regulation of klf4." SIGNOR-174319 FANCL protein Q9NW38 UNIPROT FANCD2 protein Q9BXW9 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000567 SIGNOR-C300 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-263250 DAPK1 protein P53355 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser511 RREERSLsAPGNLLT 9606 BTO:0000938 BTO:0000142 15209507 t lperfetto "Dapk phosphorylates camkk. S511 was identified as the phosphorylation site . a potential mechanism of action was identified on the basis of the location of s511 near the cam recognition domain of camkk and demonstrated by attenuation of cam-stimulated camkk autophosphorylation after dapk phosphorylation." SIGNOR-126241 N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide chemical CHEBI:91332 ChEBI ROCK2 protein O75116 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000007 19740074 t miannu "We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2." SIGNOR-262230 PRKCA protein P17252 UNIPROT NOS3 protein P29474 UNIPROT "down-regulates activity" phosphorylation Thr495 TGITRKKtFKEVANA 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-251620 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 GAMT protein Q14353 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 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-265795 PRKD1 protein Q15139 UNIPROT HDAC7 protein Q8WUI4 UNIPROT unknown phosphorylation Ser358 WPLSRTRsEPLPPSA -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-249274 BTRC protein Q9Y297 UNIPROT ATF2 protein P15336 UNIPROT "down-regulates quantity by destabilization" ubiquitination 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-267830 CASP8 protein Q14790 UNIPROT RIPK1 protein Q13546 UNIPROT "down-regulates activity" cleavage Asp324 RMQSLQLdCVAVPSS 9606 BTO:0000007;BTO:0000093;BTO:0000567 10521396 t amattioni "These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability." SIGNOR-71265 SLC25A13 protein Q9UJS0 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-265155 AMPK complex SIGNOR-C15 SIGNOR PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 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-209936 PRKCA protein P17252 UNIPROT PSEN1 protein P49768 UNIPROT "up-regulates activity" phosphorylation Ser346 EWEAQRDsHLGPHRS 9606 14576165 t lperfetto "A phosphorylation site at serine residue 346 was identified that is selectively phosphorylated by PKC but not by PKA. This site is localized within a recognition motif for caspases, and phosphorylation strongly inhibits proteolytic processing of PS1 by caspase activity during apoptosis." SIGNOR-249236 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 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLQRPE 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-252869 BMP7 protein P18075 UNIPROT DLK1 protein P80370 UNIPROT down-regulates "transcriptional regulation" 9606 20584981 f fspada "Bmp7 could directly suppress pref-1 expression, thereby allowing the initiation of the adipogenic program. " SIGNOR-210074 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr24 LPRPRSCtWPLPRPE 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-252872 PCDHA2 protein Q9Y5H9 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-265693 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu72 CSYEEAFeALESSTA -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-263683 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 GAS6 protein Q14393 UNIPROT AXL protein P30530 UNIPROT up-regulates binding 9606 7867073 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-34339 F11 protein P03951 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000131 20110423 t lperfetto "Factor XI (FXI) is the zymogen of an enzyme (FXIa) that contributes to hemostasis by activating factor IX.|The characterization of the apple disk structure, and its relationship to the catalytic domain, have provided new insight into the mechanism of FXI activation, the interaction of FXIa with the substrate factor IX, and the binding of FXI to platelets." SIGNOR-263537 RIMBP3C protein A6NJZ7 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-264367 Calcineurin complex SIGNOR-C155 SIGNOR DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t "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-252317 Ub:E2 complex SIGNOR-C497 SIGNOR ZFPL1 protein O95159 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-271151 vorinostat chemical CHEBI:45716 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-257921 OXGR1 protein Q96P68 UNIPROT GNAS protein Q5JWF2 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-256770 JAK2 protein O60674 UNIPROT IFNGR2/INFGR1 complex SIGNOR-C142 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000801 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-249493 SOCS6 protein O14544 UNIPROT KIT protein P10721 UNIPROT down-regulates ubiquitination 9606 21030588 t miannu "Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells" SIGNOR-169145 NTRK2 protein Q16620 UNIPROT KCNA3 protein P22001 UNIPROT down-regulates phosphorylation Tyr161 PSFDAILyYYQSGGR 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-183515 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 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 GEM protein P55040 UNIPROT ROCK2 protein O75116 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-261721 STAT3 protein P40763 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 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-263821 ABL1 protein P00519 UNIPROT PTPN6 protein P29350 UNIPROT "up-regulates activity" phosphorylation Tyr536 QKGQESEyGNITYPP 9606 BTO:0001412 8692915 t gcesareni "Treatment with ionizing radiation is associated with c-Abl-dependent tyrosine phosphorylation of SHPTP1. The results demonstrate that the SH3 domain of c-Abl interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that c-Abl phosphorylates C terminal Y536 and Y564 sites." SIGNOR-246227 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 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Ser272 SNHGLAIsPGMKTRI 9606 8846784 t fstefani "Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk." SIGNOR-44339 GTF2A2 protein P52657 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-266196 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI (R)-2-hydroxyglutarate(2-) smallmolecule CHEBI:15801 ChEBI "up-regulates quantity" "precursor of" 25406093 t lperfetto "Here we show that, in addition to catalyzing oxidation of 3-phosphoglycerate, PHGDH catalyzes NADH-dependent reduction of alpha-ketoglutarate (AKG) to the oncometabolite d-2-hydroxyglutarate (d-2HG)." SIGNOR-268573 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 TFDP1 protein Q14186 UNIPROT RRM1 protein P23921 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-253866 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-254373 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 RPS6KA3 protein P51812 UNIPROT GSK3A protein P49840 UNIPROT "down-regulates activity" phosphorylation Ser21 SGRARTSsFAEPGGG 9606 BTO:0000130 11583116 t lperfetto "P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively." SIGNOR-110827 MAPK3 protein P27361 UNIPROT SPHK2 protein Q9NRA0 UNIPROT up-regulates phosphorylation Ser387 PATVEPAsPTPAHSL 9606 BTO:0000150 17311928 t 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-153387 ROCK1 protein Q13464 UNIPROT DES protein P17661 UNIPROT unknown phosphorylation Thr77 RASRLGTtRTPSSYG 9606 BTO:0000971 10574968 t lperfetto "We developed antibodies specifically recognizing the kinase-dependent phosphorylation of desmin at Thr-16, Thr-75, and Thr-76. With these antibodies, phosphorylation of desmin was observed specifically at the cleavage furrow in late mitotic Saos-2 cells. We then found that treatment of the interphase cells with calyculin A revealed phosphorylation at all the three sites of desmin" SIGNOR-249033 PDPK1 protein O15530 UNIPROT PDPK1 protein O15530 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser241 SKQARANsFVGTAQY -1 12177059 t miannu "PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated" SIGNOR-250077 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "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-252864 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Sec) smallmolecule CHEBI:29264 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-269495 ABL1 protein P00519 UNIPROT SRCIN1 protein Q9C0H9 UNIPROT unknown phosphorylation Tyr264 IYRKEPLyAAFPGSH 9606 BTO:0000142 23383002 t llicata "Furthermore, we identify abl as the major tyrosine kinase that can trigger p140cap phosphorylation on these sequences." SIGNOR-200854 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 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-244723 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 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 PIM2 protein Q9P1W9 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr454 RAPIIAVtRNPQTAR 9606 24142698 t Manara "Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels." SIGNOR-260905 JAK2 protein O60674 UNIPROT STAT6 protein P42226 UNIPROT "up-regulates activity" phosphorylation 9606 9852261 t gcesareni "Stat6 activation is mediated through jak1 and jak2 tyrosine kinases." SIGNOR-62585 IRX2 protein Q9BZI1 UNIPROT CCL5 protein P13501 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003885 26560478 f Luana "Our results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression. " SIGNOR-266043 ESR1 protein P03372 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 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-252675 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 JUNB protein P17275 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 21799768 f "Our results suggest that the prolonged IL-4 expression in NFAT1 deficient Th2 cells is mediated by preferential binding of JUNB/SATB1 to the IL-4 promoter with permissive chromatin architecture" SIGNOR-254503 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1647 SPSYSPTsPSYSPTS -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-248770 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 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 TRIM13 protein O60858 UNIPROT CD3D protein P04234 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 17314412 t miannu "RFP2, a gene frequently lost in various malignancies, encodes a protein with RING finger, B-box, and coiled-coil domains that belongs to the RBCC/TRIM family of proteins.Rfp2 Regulates the Stability of the ERAD Substrate CD3-δ. In summary, these experiments demonstrate that Rfp2 functions as a RING-dependent ERAD E3 ubiquitin ligase and regulates the degradation of the ER substrate, CD3-δ." SIGNOR-271644 U0126 chemical CHEBI:90693 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 9873633 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-62892 GSK3A protein P49840 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser641 KVTSKCGsLGNIHHK 9606 BTO:0000590 7706316 t lperfetto "Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262." SIGNOR-249342 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 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1185 FGMTRDIyETDYYRK 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-248408 GMPS protein P49915 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 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-267340 "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 Three different subunits have been identified in humans: PFK-M (muscle), PFK-L (liver), and PFK-P (platelet).The subunits are expressed in a tissue-specific manner and, in erythrocytes, 5 isoenzymes of varying subunit composition (M4, M3L1, M2L2, ML3, and L4) can be identified." SIGNOR-266464 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 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 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 PTPN1 protein P18031 UNIPROT INSR protein P06213 UNIPROT "down-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL 9606 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-248410 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser372 PSPEPSMsPKMHRRR -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-265962 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 FADD protein Q13158 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" binding 9606 21525013 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-173429 GLI2 protein P10070 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates NBK6142 f "Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development. " SimoneGraziosi SIGNOR-269215 resiquimod chemical CHEBI:36706 ChEBI TLR8 protein Q9NR97 UNIPROT "up-regulates activity" "chemical activation" 9606 15661881 t miannu "Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively." SIGNOR-259247 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-259863 CDK1 protein P06493 UNIPROT UBXN2B protein Q14CS0 UNIPROT "down-regulates activity" phosphorylation Ser56 PKATVFKsPRTPPQR 23500464 t lperfetto "At mitosis, Cdc2 kinase phosphorylates p47 on Serine-140 and p37 on Serine-56 and Threonine-59, respectively. The phosphorylated p47 and p37 are unable to bind to Golgi membranes, resulting in mitotic inhibition of the p97/p47 and the p97/p37 pathways, respectively." SIGNOR-265040 CDC42BPA protein Q5VT25 UNIPROT MYL2 protein P10916 UNIPROT "up-regulates activity" phosphorylation Ser19 GANSNVFsMFEQTQI BTO:0000567 9418861 t llicata "These approximately 190-kDa myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs) preferentially phosphorylate nonmuscle myosin light chain at serine 19, which is known to be crucial for activating actin-myosin contractility." SIGNOR-250723 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 azelastine chemical CHEBI:2950 ChEBI HRH1 protein P35367 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-257894 AMPK complex SIGNOR-C15 SIGNOR CRY1 protein Q16526 UNIPROT down-regulates phosphorylation Ser71 ANLRKLNsRLFVIRG 9606 phosphorylation:Ser71 ANLRKLNsRLFVIRG 21892142 t lperfetto "Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation" SIGNOR-216546 PTPN1 protein P18031 UNIPROT NTRK2 protein Q16620 UNIPROT "down-regulates activity" dephosphorylation Tyr707 DVYSTDYyRVGGHTM 9606 26214522 t Luana "Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling" SIGNOR-264553 "AP-1/clathrin vescicle" complex SIGNOR-C251 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-267860 Ub:E2 complex SIGNOR-C497 SIGNOR RNF133 protein Q8WVZ7 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-271205 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 MAPK1 protein P28482 UNIPROT GSK3B protein P49841 UNIPROT down-regulates phosphorylation Thr43 KVTTVVAtPGQGPDR 9606 BTO:0000150;BTO:0000680 16039586 t lperfetto "Erk, which is activated by hbx, associates with gsk-3beta through a docking motif ((291)fkfp) of gsk-3beta and phosphorylates gsk-3beta at the (43)thr residue, which primes gsk-3beta for its subsequent phosphorylation at ser9 by p90rsk, resulting in inactivation of gsk-3beta and upregulation of beta-catenin." SIGNOR-138894 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 PAK2 protein Q13177 UNIPROT ABL1 protein P00519 UNIPROT down-regulates phosphorylation Ser619 PTPPKRSsSFREMDG 9606 18161990 t lperfetto "The interaction of c-abl with the abl interactor protein abi2 is shown to be negatively regulated by phosphorylation of serines 637 and 638. These serines are adjacent to the pxxp motif (ptppkrs637s638sfr) that binds the sh3 domain of abi. phosphorylation of c-abl by pak2 inhibits the interaction between the sh3 domain of abi2 and the pxxp motif of c-abl." SIGNOR-160219 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 ASXL1 protein Q8IXJ9 UNIPROT PPARG protein P37231 UNIPROT "down-regulates activity" binding 9606 21047783 t miannu "Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ. " SIGNOR-260064 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 afatinib chemical CHEBI:61390 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-258066 CAPN3 protein P20807 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" cleavage 9606 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-251605 ruxolitinib chemical CHEBI:66919 ChEBI JAK1 protein P23458 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-258276 FIG4 protein Q92562 UNIPROT MCOLN1 protein Q9GZU1 UNIPROT "up-regulates activity" 9606 23165282 f miannu "PI(3,5)P2 begins to be synthesized on endosomal membranes and is additionally required for the activation of lysosomal TRPML1/MCOLN1 channels. Thus, a deficiency of FIG4/PI(3,5)P2 would impair TRPML1/MCOLN1 channel function, leading to the accumulation of calcium in the lysosomes." SIGNOR-253536 PTPN12 protein Q05209 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" dephosphorylation 10090 11163214 t gcesareni "Several experiments suggest that the PEST-type PTPs negatively regulate c-Abl activity: c-Abl was hyperphosphorylated in PTP-PEST-deficient cells; disruption of the c-Abl-PSTPIP1-PEST-type PTP ternary complex by overexpression of PSTPIP1 mutants increased c-Abl phosphotyrosine content" SIGNOR-246222 ATM protein Q13315 UNIPROT MRE11 protein P49959 UNIPROT up-regulates phosphorylation Ser264 EQQLFYIsQPGSSVV 9606 10608806 t lperfetto "In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage." SIGNOR-73366 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 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 C5AR1 protein P21730 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-263462 PRKAB2 protein O43741 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" 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-139167 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser482 RRIAVEYsDSEDDSS 9606 19012317 t gcesareni "Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo." SIGNOR-182350 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 PAK2 protein Q13177 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Thr89 QSSNGHItTTPTPTQ 9606 BTO:0000848 21177766 t lperfetto "P21-activated protein kinase (pak2)-mediated c-jun phosphorylation at 5 threonine sites promotes cell transformationour data showed that pak2 binds and phosphorylates c-jun at five threonine sites (thr2, thr8, thr89, thr93 and thr286)" SIGNOR-170772 PTPN6 protein P29350 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 9606 9261115 t "To determine whether the COOH-terminal or other phosphotyrosine residues within Src are subject to dephosphorylation by SHP-1, the effects of this phosphatase on Src tyrosine phosphorylation were initially examined using CNBr cleavage analysis. As illustrated in Fig.1 A, CNBr treatment of 32P-labeled human Src has been shown previously to yield phosphorylated cleavage fragments of about 31, 9.7, and 4.7 kDa, which, respectively, contain the Src NH2-terminal region encompassing the major sites for serine phosphorylation on Src, Ser-12 and Ser-17 (31-kDa fragment), the inhibitory tyrosine phosphorylation site, Tyr-530 (4.7-kDa fragment), and a key site for autophosphorylation on activated Src, Tyr-419 [} These observations, together with the finding of reduced Src activity in HEY cells expressing a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation." SIGNOR-248473 EXOSC10 protein Q01780 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-261390 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 S1PR3 protein Q99500 UNIPROT GNAS protein Q5JWF2 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-256790 CHL1 protein O00533 UNIPROT ANK3 protein Q12955 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-266723 3-iodo-L-tyrosine smallmolecule CHEBI:27847 ChEBI "L-tyrosine zwitterion" smallmolecule CHEBI:58315 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-267031 BRD2 protein P25440 UNIPROT TP53BP1 protein Q12888 UNIPROT "up-regulates activity" relocalization 9606 BTO:0001938 29018219 t lperfetto "BRD2 is required to recruit 53BP1 to DSBs.|When BRD2 recruitment was blocked with shRNA or JQ1 (Fig. 3a and Supplementary Figure 3c) or a panel of BRD2 siRNAs (Supplementary Figure 3a), the recruitment of 53BP1 to DSBs was significantly delayed." SIGNOR-262035 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 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 NADPH(4-) smallmolecule CHEBI:57783 ChEBI NADP(3-) smallmolecule CHEBI:58349 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-268088 AREL1 protein O15033 UNIPROT HTRA2 protein O43464 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 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-267669 PTPN3 protein P26045 UNIPROT VCP protein P55072 UNIPROT "down-regulates activity" dephosphorylation Tyr805 EDNDDDLyG 9606 BTO:0000007 10364224 t "Identification of VCP as a substrate of PTPH1in vivo.|The tyrosines (Tyr796 and Tyr805) at the C terminus of VCP have been reported to be the major sites of phosphorylation, with Tyr805 accounting for more than 90% of the tyrosine phosphorylation on the protein |The Y796F/Y805F VCP mutant was not associated with any of the PTPH1 constructs." SIGNOR-248461 AHCYL2 protein Q96HN2 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-268332 DYRK2 protein Q92630 UNIPROT EDVP complex SIGNOR-C530 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 19287380 t miannu "DYRK2 functions as an adaptor in the EDVP E3 ligase complex. These experiments suggest that DYRK2 functions as a molecular assembler required for the specific recruitment of EDD to DDB1-VPRBP, thus forming a novel EDVP E3 ligase complex." SIGNOR-271792 EDVP complex SIGNOR-C530 SIGNOR KATNA1 protein O75449 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19287380 t miannu "EDVP-DYRK2 complex regulates Katanin p60 ubiquitination. Katanin p60 was polyubiquitinated in the presence of the intact DYRK2-EDVP, but its ubiquitination was severely reduced by the depletion of DYRK2, EDD, DDB1 or VPRBP (Fig. 3d)." SIGNOR-271793 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser295 LQASVPGsVPGVLGP 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250730 ADRA1B protein P35368 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-257190 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BANP protein Q8N9N5 UNIPROT "down-regulates activity" phosphorylation Thr337 VKSFSRRtPNSSSYC 9606 BTO:0000567 26080397 t miannu "ERK-MAPK pathway that regulates alternative splicing facilitates ERK-1/2-mediated phosphorylation of SMAR1 at threonines 345 and 360 and localizes SMAR1 to the cytoplasm, preventing its interaction with Sam68." SIGNOR-266377 GSK3B protein P49841 UNIPROT DROSHA protein Q9NRR4 UNIPROT "up-regulates activity" phosphorylation Ser302 RDNRRSPsLERSYKK -1 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-264846 CDK4 protein P11802 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 SIGNOR-C18 18071316 t llicata "This skp2-dependent destruction of rassf1a requires phosphorylation of the latter on serine-203 by cyclin d-cyclin-dependent kinase 4." SIGNOR-159849 vorapaxar chemical CHEBI:82702 ChEBI F2R protein P25116 UNIPROT "down-regulates activity" "chemical inhibition" -1 18447380 t Luana "The discovery of an exceptionally potent series of thrombin receptor (PAR-1) antagonists based on the natural product himbacine is described. " SIGNOR-257792 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-264438 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 PABPC1 protein P11940 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-268318 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 SERPINC1 protein P01008 UNIPROT F10 protein P00742 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-264138 ELL protein P55199 UNIPROT ELL/ICE1 complex SIGNOR-C48 SIGNOR "form complex" binding 9606 BTO:0001271 22195968 t miannu "The ell-ice complex is called lec for its proposed role in transcriptional regulation of the littlesnrna genes." SIGNOR-193458 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 pazopanib chemical CHEBI:71219 ChEBI KIT protein P10721 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-257736 MAPK3 protein P27361 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Thr456 KVYFLPItPHYVTQV 9606 15890648 t lperfetto "Cad is a multifunctional protein that initiates and regulates mammalian de novo pyrimidine biosynthesis. The activation of the pathway required for cell proliferation is a consequence of the phosphorylation of cad thr-456 by mitogen-activated protein (map) kinase.Activated map kinase (erk1/2), the enzyme responsible for the phosphorylation of thr-456, was also present in larger amounts in the nucleus than the cytosol" SIGNOR-137179 MTA2 protein O94776 UNIPROT FSHR protein P23945 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001238 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-254226 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 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser341 GTMSRPAsVDGSPVS -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-251294 RELA protein Q04206 UNIPROT BCL2A1 protein Q16548 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 10049356 f gcesareni "Here we show thata1,abcl-2homolog up-regulated in primary lymphocytes by different mitogens, represents a novel class of rel/nf-kb-regulated prosurvival genes." SIGNOR-65020 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT "up-regulates activity" phosphorylation Tyr101 EGLSMGNyIGLINRI -1 16373505 t Manara "PKR autophosphorylates on Y101, Y162, and Y293 in vitro. Site-specific tyrosine phosphorylation is essential for efficient dsRNA-binding, dimerization, kinase activation and eIF2alpha phosphorylation of PKR." SIGNOR-260782 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr740 TGESDGGyMDMSKDE -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-248413 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser318 SRTNSNAsTVSGRLS 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-252899 SHMT1 protein P34896 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 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-268226 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 "AP-2 complex" complex SIGNOR-C245 SIGNOR EPS15 protein P42566 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 15496985 t Giorgia "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-260394 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 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 "D1-D2-G-X3 complex" complex SIGNOR-C301 SIGNOR 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-263262 CDK1 protein P06493 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT down-regulates phosphorylation Ser368 PNPSTSAsPKKSPPP 9606 17488717 t gcesareni "Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation." SIGNOR-154681 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 "Melanotan II" chemical CID:92432 PUBCHEM MC3R protein P41968 UNIPROT "up-regulates activity" binding BTO:0000614 17702843 t lperfetto "Centrally administered melanotan II (MTII), a synthetic melanocortin 3/4-receptor agonist, decreases adiposity beyond that accountable by food intake decreases." SIGNOR-253065 TACR1 protein P25103 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-257048 HTR1B protein P28222 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-257207 CREBL2 protein O60519 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 21728997 f Luana "Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression." SIGNOR-261573 MAST2 protein Q6P0Q8 UNIPROT PTEN protein P60484 UNIPROT up-regulates phosphorylation 9606 15951562 t gcesareni "We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status." SIGNOR-138051 NTN3 protein O00634 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR "up-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-268185 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 MARCHF1 protein Q8TCQ1 UNIPROT HLA-DRB4 protein P13762 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys254 FIYFRNQkGHSGLQP 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-271409 SLC1A3 protein P43003 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). In glia or in neurons, EAATs mediate the re-uptake of synaptically released glutamate via the coupled co-transport of three Na+, one H+, and one glutamate, in counter-transport to one K+." SIGNOR-264802 "Obatoclax mesylate" chemical CID:46930996 PUBCHEM MCL1 protein Q07820 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|The ability of obatoclax to inhibit MCL-1 may be particularly important, given that several hematological malignancies appear to depend on this protein for survival, such as acute lymphoblastic leukemia (ALL),44 CLL,44 multiple myeloma,45 and diffuse large B-cell lymphoma (DLBCL)" SIGNOR-262025 SRC protein P12931 UNIPROT NOXA1 protein Q86UR1 UNIPROT up-regulates phosphorylation Tyr110 RGHAAIDyTQLGLRF 9606 20943948 t llicata "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-168545 SETD1B protein Q9UPS6 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" methylation Lys5 kQTARKST 9606 32546566 t miannu "SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks." SIGNOR-265576 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT unknown phosphorylation Ser483 IRRPRNYsVGSRPLK 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-251485 TP53 protein P04637 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14985507 t gcesareni "Northern blot analysis with a specific probe demonstrates an increase in siah-1b transcription on activation of endogenous and inducible exogenous p53. To explore whether this effect is directly mediated by p53 we analyzed 20 kb of chromosome x dna, containing the siah-1b locus. A p53-binding site was identified in the siah-1b promoter, located at nucleotides -2155/-2103 relative to the translational start site." SIGNOR-122986 GAB1 protein Q13480 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 11043767 t lperfetto "We have shown that gab1 colocalizes pi3k with sh2 domain-containing inositol phosphatase (ship) and shp2, two enzymes that regulate pi3k-dependent signaling. The src homology 2 (sh2) domain of the phosphatidylinositol 3-kinase (pi3k) regulatory subunit binds gab1 in a phosphorylation-independent manner. Moreover, the regulatory subunit of pi3k can mediate the association of gab1 and receptor protein-tyrosine kinases including the insulin, egf, and ngf receptors, all of which phosphorylate gab1." SIGNOR-252676 FBXO30 protein Q8TB52 UNIPROT Muscle_atrophy phenotype SIGNOR-PH40 SIGNOR up-regulates 10090 BTO:0000887 24076600 f "gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1)" SIGNOR-256489 LCK protein P06239 UNIPROT TCR complex SIGNOR-C153 SIGNOR "up-regulates activity" phosphorylation 10090 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-259932 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 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-258000 "MTA1/DJ1 complex" complex SIGNOR-C123 SIGNOR TH protein P07101 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000793 21368136 f 1 miannu "we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3." SIGNOR-239773 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 torkinib chemical CHEBI:90679 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206313 PRKN protein O60260 UNIPROT SNCA protein P37840 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000938 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-249705 PRKACG protein P22612 UNIPROT PHKA1 protein P46020 UNIPROT "down-regulates activity" phosphorylation 9606 10487978 t "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-267415 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser23 ITDESLEsTRRILGL 9606 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249228 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 MYLK protein Q15746 UNIPROT MYL6B protein P14649 UNIPROT up-regulates phosphorylation 9606 BTO:0000567 BTO:0000671 10092231 t gcesareni "Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin ii that are regulated by myosin light chain kinase (mlck)-mediated phosphorylation of the regulatory myosin light chain (mlc)." SIGNOR-65865 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser392 FKTEGPDsD 9606 23603988 t gcesareni "We recently demonstrated that through their physical interaction, cdk9 phosphorylates p53 on ser-392, leading to p53 stability and accumulation" SIGNOR-201931 SRC protein P12931 UNIPROT CDC42 protein P60953 UNIPROT up-regulates phosphorylation Tyr64 DTAGQEDyDRLRPLS 9606 14506284 t gcesareni "Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation." SIGNOR-118206 AMPK complex SIGNOR-C15 SIGNOR ARMC10 protein Q8N2F6 UNIPROT "up-regulates activity" phosphorylation Ser45 LGIRSSKsAGALEEG 9606 30631047 t miannu "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. Moreover, ARMC10 overexpression was sufficient to promote mitochondrial fission, whereas ARMC10 knockout prevented AMPK-mediated mitochondrial fission. These results demonstrate that ARMC10 is an effector of AMPK that participates in dynamic regulation of mitochondrial fission and fusion." SIGNOR-266413 PTGER4 protein P35408 UNIPROT GNAS protein Q5JWF2 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-256760 TGFB1 protein P01137 UNIPROT ENPP1 protein P22413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000249 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-252200 AXIN1 protein O15169 UNIPROT RNF111 protein Q6ZNA4 UNIPROT up-regulates binding 9606 14657019 t gcesareni "Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia. Axin is a scaffold protein in tgf-beta signaling that promotes degradation of smad7 by arkadia." SIGNOR-119660 RUNX3 protein Q13761 UNIPROT TRAF6 protein Q9Y4K3 UNIPROT "up-regulates quantity by expression" "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-255098 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244553 MFGE8 protein Q08431 UNIPROT TNF protein P01375 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 22114683 f Giorgia "Our study demonstrated the direct anti-inflammatory role of MFG-E8 in terms of attenuating TNF-α production in mouse peritoneal macrophages and RAW264.7 cells treated with LPS" SIGNOR-260650 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 TGFB3 protein P10600 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-252284 AKT1 protein P31749 UNIPROT VCP protein P55072 UNIPROT up-regulates phosphorylation Ser746 AMRFARRsVSDNDIR 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-252492 Scribble_complex_DLG2-LLGL1_variant complex SIGNOR-C510 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-270910 MRPL32 protein Q9BYC8 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-262339 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-269088 IL1R1 protein P14778 UNIPROT MAPK8 protein P45983 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-249513 RPA2 protein P15927 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 19586055 t esanto "The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex." SIGNOR-186651 PAF1C complex SIGNOR-C471 SIGNOR "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "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-269837 "2-deoxy-alpha-D-ribose 1-phosphate" smallmolecule CHEBI:11563 ChEBI "2-deoxy-D-ribose 5-phosphate" smallmolecule CHEBI:16132 ChEBI "up-regulates quantity" "precursor of" 9606 17804405 t miannu "Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses." SIGNOR-267093 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 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 IL1A protein P01583 UNIPROT FBN1 protein P35555 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 9036927 f Regulation miannu "UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. UVB irradiation (50 mJ) of cultured skin fibroblasts suppressed fibrillin mRNA by 50%, consistent with a direct effect of radiation. Addition to the cultured fibroblasts of several cytokines upregulated by UVB showed that IL-1alpha had no effect on fibrillin mRNA in unirradiated cells, but in irradiated cells, this cytokine enhanced the suppression of fibrillin mRNA." SIGNOR-251890 IKBKB protein O14920 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000567 11971985 t "We demonstrated the in vitro phosphorylation of SRC-3 by the two catalytic subunits of the IKK complex, IKKα and IKKβ.  IKK kinase activity is required for synergistic activation with SRC-3" SIGNOR-251298 CDK1 protein P06493 UNIPROT CEP55 protein Q53EZ4 UNIPROT down-regulates phosphorylation Ser428 KVAASPKsPTAALNE 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140886 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 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation Ser324 LTSVSRGsSLKILSK 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-260898 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN2B protein P42772 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17873901 f gcesareni "Foxo1a strongly activated p15ink4b transcription and p19ink4d transcription, while foxo3a showed higher p19ink4d transcription activity than p15ink4b transcription activity" SIGNOR-252917 RYBP protein Q8N488 UNIPROT ABL1 protein P00519 UNIPROT down-regulates binding 9606 8943360 t gcesareni "We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity" SIGNOR-45325 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 TESK1 protein Q15569 UNIPROT TESK1 protein Q15569 UNIPROT "up-regulates activity" phosphorylation Ser220 EPLAVVGsPYWMAPE -1 10207045 t Manara "These results suggest that autophosphorylation of Ser-215 is an important step to positively regulate the kinase activity of TESK1." SIGNOR-260825 LATS2 protein Q9NRM7 UNIPROT WWTR1 protein Q9GZV5 UNIPROT down-regulates phosphorylation Ser89 AQHVRSHsSPASLQL 9606 22658639 t "Together the YAP/TAZ-TEAD complex promotes proliferative and survival programs." milica "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-197651 ECM stimulus SIGNOR-ST20 SIGNOR "Av/b5 integrin" complex SIGNOR-C178 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-259038 ABL1 protein P00519 UNIPROT ATR protein Q13535 UNIPROT up-regulates phosphorylation Tyr291 DTDQLKLyEEPLSKL 9606 20798688 t lperfetto "C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress." SIGNOR-167632 C8G protein P07360 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-263446 ACSS3 protein Q9H6R3 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-271834 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 KPNB1 protein Q14974 UNIPROT SMAD3 protein P84022 UNIPROT up-regulates relocalization 9606 10846168 t gcesareni "Here we show that the isolated smad 3 mh1 domain displays significant specific binding to importin beta. we propose that activation of all of the pathway-specific smad proteins (smads 1, 2, 3, 5, 8, and 9) exposes the conserved nls motif, which then binds directly to importin beta and triggers nuclear translocation." SIGNOR-78191 TNFRSF1B protein P20333 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-253601 NR3C1 protein P04150 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR down-regulates 9606 25910399 f "Glucocorticoids (GCs) are the most commonly used anti-inflammatory agents to treat inflammatory and immune diseases [.. }The dogma that transrepression of genes, by tethering of the glucocorticoid receptor (GR) to DNA-bound pro-inflammatory transcription factors, is the main anti-inflammatory mechanism, is now challenged." SIGNOR-257599 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 PPP2CB protein P62714 UNIPROT HDAC7 protein Q8WUI4 UNIPROT "up-regulates activity" dephosphorylation Ser181 NPLLRKEsAPPSLRR 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-248604 PGM2 protein Q96G03 UNIPROT "2-deoxy-D-ribose 5-phosphate" smallmolecule CHEBI:16132 ChEBI "up-regulates quantity" "chemical modification" 9606 17804405 t miannu "Biochemical characterization of phosphoglucomutase (PGM) isozymes indicated that one of them, designated PGM2 in man (PGM1 in mouse) was more active as a phosphopentomutase than as a phosphoglucomutase, whereas mammalian PGM1 (equivalent to PGM2 in mouse) has a phosphopentomutase activity representing only about 0.2% of its phosphoglucomutase activity. Phosphopentomutase catalyzes the conversion of the nucleoside breakdown products ribose 1-phosphate and deoxyribose 1-phosphate to the corresponding 5-phosphopentoses." SIGNOR-267095 PTPN13 protein Q12923 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr999 YASSNPEyLSASDVF 9606 15611135 t gcesareni "We demonstrate that ptpl1, like ptp1b, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that ptpl1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines." SIGNOR-132563 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 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR MEIS1 protein O00470 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-255862 PHF10 protein Q8WUB8 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-270716 profenamine chemical CHEBI:313639 ChEBI MAPK10 protein P53779 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000142 19261605 t "Inhibitor of p38;ATP binding pocket" gcesareni "Indazole-based inhibitors exemplified by sr-3737 were potent inhibitors of both jnk3 (ic50 12 nm)." SIGNOR-184443 PRKCE protein Q02156 UNIPROT KIR3DL1 protein P43629 UNIPROT down-regulates phosphorylation Ser415 QRKITRPsQRPKTPP 9606 17911614 t gcesareni "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-158129 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 ROCK1 protein Q13464 UNIPROT RND3 protein P61587 UNIPROT up-regulates phosphorylation Ser11 RRASQKLsSKSIMDP 9606 15775972 t lperfetto "We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability." SIGNOR-134703 SESN3 protein P58005 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-253561 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 LCK protein P06239 UNIPROT PRKCD protein Q05655 UNIPROT "up-regulates activity" phosphorylation Tyr334 MQDNSGTyGKIWEGS 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-251385 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser503 NDEITDEsLENFPSS 9606 16874298 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-148327 PRKACA protein P17612 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1223 SSSTRRSsEDLSAYA 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" SIGNOR-236603 BHLHE41 protein Q9C0J9 UNIPROT BHLHE40 protein O14503 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14672706 f lperfetto "We show here an autofeedback loop of Dec1 encoding a basic helix–loop–helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression." SIGNOR-253714 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 ALDOB protein P05062 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-266488 (S)-malate(2-) smallmolecule CHEBI:15589 ChEBI oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-regulates quantity" "precursor of" 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-266281 MAPK10 protein P53779 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. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress." SIGNOR-166690 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 MRPL20 protein Q9BYC9 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-262373 EXOSC2 protein Q13868 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-261387 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 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 ABL1 protein P00519 UNIPROT TP63 protein Q9H3D4 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr171 AIPSNTDyPGPHSFD 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-260932 RIMS3 protein Q9UJD0 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-264380 KLF16 protein Q9BXK1 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-222460 ATM protein Q13315 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-176008 protein P0DOX5 UNIPROT Pr3-ANCA complex SIGNOR-C475 SIGNOR "form complex" binding 9606 27464484 t lperfetto "Although the majority of PR3-ANCAs are of the IgG isotype, the results of one study showed that PR3-ANCAs of the IgA isotype were present in up to 30% of patients with GPA" SIGNOR-270594 protein P0DOX5 UNIPROT MPO-ANCA complex SIGNOR-C474 SIGNOR "form complex" binding 9606 27464484 t lperfetto "Although MPO-ANCAs of the IgA isotype are sometimes found in patients with IgA nephropathy or IgA vasculitis45, isotypes other than IgG have not been reported in patients with typical AAV, with the exception of a single patient with pauci-immune crescentic glomerulonephritis" SIGNOR-270595 Ub:E2 complex SIGNOR-C497 SIGNOR RNF225 protein M0QZC1 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-271261 STK3 protein Q13188 UNIPROT RCC1 protein P18754 UNIPROT up-regulates phosphorylation Ser11 KRIAKRRsPPADAIP 9606 BTO:0000007 19559616 t miannu "MST2 Phosphorylates RCC1 In Vitro and In Vivo. Using an antibody generated against phospho-S2/11 in RCC1 [18], we found that these two residues were also efficiently phosphorylated by MST1 and MST2 (Figure 2D), further supporting that S2 and/or S11 are genuine MST2 phosphorylation targets." SIGNOR-263145 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr868 GSVEMCRyDPLQDNT 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-236298 "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 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 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 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 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI AURKB protein Q96GD4 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193534 SRC protein P12931 UNIPROT RAF1 protein P04049 UNIPROT up-regulates phosphorylation Tyr340 RGQRDSSyYWEIEAS 9606 7692235 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-32081 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 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser276 PLPSPTAsPNHTLAP -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250649 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 ChEBI HDAC1 protein Q13547 UNIPROT down-regulates "chemical inhibition" 9606 17891169 t fspada "Hydroxamate derivatives are the most powerful category of hdaci, active on class i and ii hdac,especially on hdac1 and hdac2. In the study reported here, we described the anti-leukaemic properties of itf2357, a recently synthesized, orally active hydroxamate derivative." SIGNOR-157857 BMX protein P51813 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr577 YMEDSTYyKASKGKL 9606 23716717 t llicata "Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity." SIGNOR-202139 DPM3 protein Q9P2X0 UNIPROT "DPM complex" complex SIGNOR-C289 SIGNOR "form complex" binding 9606 10835346 t lperfetto "Human dolichol-phosphate-mannose synthase consists of three subunits, DPM1, DPM2 and DPM3." SIGNOR-262565 TUBA3D protein P0DPH8 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-269723 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM 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-257977 SRC protein P12931 UNIPROT KCNA3 protein P22001 UNIPROT up-regulates phosphorylation Tyr499 EGEEQSQyMHVGSCQ 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-114645 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 PAX8 protein Q06710 UNIPROT TPO protein P07202 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001073 27347897 t scontino "TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8." SIGNOR-267277 SYK protein P43405 UNIPROT SHC1 protein P29353 UNIPROT up-regulates phosphorylation Tyr350 EPPDHQYyNDFPGKE 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-59639 RAP1GDS1 protein P52306 UNIPROT RAP1A protein P62834 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-171482 KIT protein P10721 UNIPROT KIT protein P10721 UNIPROT up-regulates phosphorylation Tyr703 DHAEAALyKNLLHSK 9606 10377264 t miannu "Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr" SIGNOR-68643 PRPF19 protein Q9UMS4 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR "form complex" binding 9606 BTO:0000567 20176811 t miannu "In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27." SIGNOR-271968 NFIA protein Q12857 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-268872 WNT6 protein Q9Y6F9 UNIPROT MYF5 protein P13349 UNIPROT up-regulates 9606 9753670 f gcesareni "Wnt4, wnt5a and wnt6 exert an intermediate effect activating both myf5 and myod equivalently in paraxial mesoderm." SIGNOR-60415 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCH protein P24723 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-242593 ITPR1 protein Q14643 UNIPROT calcium(2+) smallmolecule CHEBI:29108 ChEBI "up-regulates quantity" "chemical modification" 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-256238 PRKAR2A protein P13861 UNIPROT PRKAR2A protein P13861 UNIPROT "up-regulates activity" phosphorylation Ser99 SRFNRRVsVCAETYN -1 6293815 t miannu "RII subunit containing the 'autophosphorylation' site (Ser-95)" SIGNOR-250073 DAB2IP protein Q5VWQ8 UNIPROT PROX1 protein Q92786 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 27476001 f miannu "DAB2IP regulates EMT and metastasis of prostate cancer through targeting PROX1 transcription and destabilizing HIF1α protein. In this study, based on different PCa cell lines and knockout mice, we showed that PROX1 could be suppressed by DAB2IP, a novel member of the Ras GTPase-activating protein family and a critical player in control of epithelial-mesenchymal transition (EMT) and PCa metastasis." SIGNOR-254764 NMDA proteinfamily SIGNOR-PF56 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-264691 ADORA2A protein P29274 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-257306 PTCRA protein Q6ISU1 UNIPROT LCK protein P06239 UNIPROT "up-regulates activity" binding 9606 20626350 t lperfetto "However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck." SIGNOR-166658 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 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 TRIM21 protein P19474 UNIPROT FASN protein P49327 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 27758890 t "FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels." SIGNOR-267368 HTR1A protein P08908 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-256972 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 ritonavir chemical CHEBI:45409 ChEBI CYP2B6 protein P20813 UNIPROT "up-regulates activity" "chemical activation" 9606 18285471 t Luana "These results show that ritonavir induces human CYP2B6 activity. " SIGNOR-257770 MAPK14 protein Q16539 UNIPROT TAB1 protein Q15750 UNIPROT "down-regulates activity" phosphorylation Ser423 QMVNGAHsASTLDEA 9606 19393267 t lperfetto "Egfr-mediated phosphorylation of tab1 was completely inhibited by a chemical inhibitor and sirna of p38alpha. The phosphorylation of tab1 was occurred at ser-423 and thr-431, the residues underlying the p38-mediated feedback inhibition of tak1." SIGNOR-185580 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 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 PFDN6 protein O15212 UNIPROT "Prefoldin co-chaperone" complex SIGNOR-C513 SIGNOR "form complex" binding 9606 32699605 t miannu "The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)" SIGNOR-270930 LATS2 protein Q9NRM7 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t "Uninhibited YAP/TAZ localize to the nucleus where they serve as coactivators for the TEA-domain family member (TEAD) of DNA-binding transcription factors." milica "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-197655 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 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 "[4,5,6,7-Tetrabromo-2-(Dimethylamino)-1h-Benzimidazol-1-Yl]acetic Acid" chemical CID:46943415 PUBCHEM CSNK2A2 protein P19784 UNIPROT "down-regulates activity" "chemical inhibition" -1 22115617 t Federica "4,5,6,7-tetrabromo- and 4,5,6,7-tetraiodo-1H-benzimidazoles and their newly obtained N1- and 2-S-carboxyalkyl derivatives showed potent inhibitory activity against both these subunits. CK2α was up to 6 times more sensitive to the studied compounds than CK2α." SIGNOR-261112 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 TTK protein P33981 UNIPROT CDCA8 protein Q53HL2 UNIPROT up-regulates phosphorylation Thr169 KRSSRANtVTPAVGR 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-186143 CREB1 protein P16220 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000876 10540320 f mianu "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-254522 oxymetazoline chemical CHEBI:7862 ChEBI HTR1D protein P28221 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-258927 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 AR protein P10275 UNIPROT Survival phenotype SIGNOR-PH13 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-251539 KLF3 protein P57682 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 18391014 f fspada "We find that c/ebpalpha is derepressed in klf3 and ctbp knockout fibroblasts and adipocytes from klf3 knockout mice." SIGNOR-161370 ASXL3 protein Q9C0F0 UNIPROT BRD4 protein O60885 UNIPROT "up-regulates activity" binding 9606 BTO:0000189 32669118 t miannu "We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers." SIGNOR-266762 BMP2 protein P12643 UNIPROT ALPL protein P05186 UNIPROT up-regulates 9606 22298955 f gcesareni "FGF-2 null mice have impaired nuclear accumulation of Runx2 and hindered BMP-2 induced bone formation and ALP activity" SIGNOR-114589 nicotine smallmolecule CHEBI:18723 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-264259 "1-phosphatidyl-1D-myo-inositol 3-phosphate(3-)" smallmolecule CHEBI:58088 ChEBI 1-phosphatidyl-1D-myo-inositol(1-) smallmolecule CHEBI:57880 ChEBI "up-regulates quantity" "precursor of" 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-269809 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation -1 8929531 t lperfetto "The rapid phosphorylation of bad following il-3 connects a proximal survival signal with the bcl-2 family, modulating this checkpoint for apoptosis.phosphorylatedBAD is bound to 14-3-3 within the cytosol, while only nonphosphorylated BAD is heterodimerized with membrane-bound BCL-XL." SIGNOR-244497 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 TLE5 protein Q08117 UNIPROT SIX3 protein O95343 UNIPROT "down-regulates activity" binding -1 12441302 t lperfetto "Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. AES abrogates SIX3- and SIX6-induced phenotypes" SIGNOR-234586 CSNK2A2 protein P19784 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" phosphorylation Ser133 NAIRYIEsLQELLRE -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-251016 Hexocyclium chemical CHEBI:5707 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-258389 14-3-3 proteinfamily SIGNOR-PF7 SIGNOR KHSRP protein Q92945 UNIPROT down-regulates binding 9606 17177604 t gcesareni "Akt phosphorylates ksrp at a unique serine residue, creating a functional binding site for the molecular chaperone 14-3-3. As a consequence, akt activation impairs ksrp ability to interact with the exoribonucleolytic complex exosome and, in turn, to promote rapid mrna decay." SIGNOR-151212 "A9/b1 integrin" complex SIGNOR-C166 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-257708 "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 UNC5A protein Q6ZN44 UNIPROT Chemorepulsion_of_axon phenotype SIGNOR-PH198 SIGNOR up-regulates 9606 30108487 f miannu "Netrin binding to the receptor deleted in colorectal cancer (DCC) results in attractive responses, viahomodimerization of DCC (covered in detail in later sections), whereas heterodimerization between DCC and receptor uncoordinated locomotion 5 (UNC5) converts this attractive response into repulsion" SIGNOR-268182 SPI1 protein P17947 UNIPROT TAL2 protein Q16559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24086757 f irozzo "We show that Tal2 is a direct target gene of the myeloid transcription factor PU.1, which is a key transcription factor for osteoclast gene expression" SIGNOR-259086 PRKACA protein P17612 UNIPROT LRP1 protein Q07954 UNIPROT "up-regulates activity" phosphorylation Ser4520 GGHGSRHsLASTDEK 10029 11158305 t miannu "LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis." SIGNOR-250000 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 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 CCL4 protein P13236 UNIPROT CCR5 protein P51681 UNIPROT "up-regulates activity" binding 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. " SIGNOR-255116 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 GLI1 protein P08151 UNIPROT PTCH1 protein Q13635 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-188875 PRKAA1 protein Q13131 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 SIGNOR-C15 19217427 t gcesareni "Amp-activated protein kinase phosphorylates retinoblastoma protein. Rb phosphorylation sites, ser804 (ser811 in human), resembled the ampk consensus phosphorylation site." SIGNOR-184052 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 EXOC6B protein Q9Y2D4 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-270781 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 PDIA6 protein Q15084 UNIPROT ERN1 protein O75460 UNIPROT "down-regulates activity" 10090 BTO:0000944 24508390 t "A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor," SIGNOR-256536 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 "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 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-269170 CDC42BPB protein Q9Y5S2 UNIPROT MSN protein P26038 UNIPROT "up-regulates activity" phosphorylation Thr558 LGRDKYKtLRQIRQG 9606 10947843 t Manara "In this study, we have shown that MRCKb phosphorylated moesin at Thr-558 | We have shown that the phosphorylation is important to the formation of ®lopodia, and that MRCK may regulate this formation through the phosphorylation of ERM proteins at the tip of ®lopodia." SIGNOR-260802 CSNK1E protein P49674 UNIPROT DVL1 protein O14640 UNIPROT "up-regulates activity" phosphorylation Ser142 TGTESMVsHRRERAR 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-217849 Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "Mitochondrial respiratory chain complex III" complex SIGNOR-C279 SIGNOR up-regulates relocalization 9606 25627476 t lperfetto "One of the main functions of the IMM is the housing of proteins that make up the electron transport chain (ETC) which ultimately produces ATP. " SIGNOR-267007 PTPN1 protein P18031 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-248415 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 PKM protein P14618 UNIPROT 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-266536 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 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 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-269190 SIRT7 protein Q9NRC8 UNIPROT SAR1A protein Q9NR31 UNIPROT "up-regulates activity" deacetylation 9606 BTO:0002181 28790157 t SARA "SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding" SIGNOR-260978 SEC13 protein P55735 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-262091 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Thr183 AGTSFMMtPYVVTRY 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-244982 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 NMBR protein P28336 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-257160 ITGB3BP protein Q13352 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-265206 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 CSNK2A2 protein P19784 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" phosphorylation Ser421 IACEEEFsDSEEEGE 9606 BTO:0000661 11602581 t llicata "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-250999 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 KDM4C protein Q9H3R0 UNIPROT H2AX protein P16104 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29207681 f miannu "Knockdown of JMJD2C gene led to the up-regulation of basal γ-H2AX expression. and γ-H2AX together with its phosphorylated C-terminal (Sre residues 139–140, γ-H2AX) are crucial for DNA repair" SIGNOR-263872 PRKCA protein P17252 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-91826 FBXW5 protein Q969U6 UNIPROT SEC23B protein Q15437 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 30596474 t lperfetto "SCFFBXW5 interacts with SEC23B and targets it for ubiquitylation and proteasome-mediated degradation." SIGNOR-265286 "RFX complex" complex SIGNOR-C104 SIGNOR HLA-DPA1 protein P20036 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-253995 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser527 RFRKRTHsAGTSPTI -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-251296 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 PTPN1 protein P18031 UNIPROT PDGFRB protein P09619 UNIPROT "down-regulates activity" dephosphorylation Tyr1009 LDTSSVLyTAVQPNE -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-248416 IGF1 protein P05019 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-254802 2-(2-amino-3-methoxyphenyl)chromen-4-one chemical CHEBI:77954 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000142 11782488 t gcesareni "Bmk1 activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2." SIGNOR-113773 Pr3-ANCA complex SIGNOR-C475 SIGNOR Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000133 2161532 f lperfetto "ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation." SIGNOR-270584 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 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 20736164 t irozzo "USP8 is known to deubiquitinate EGFR in response to ligand stimulation. USP8 depletion accelerates receptor turnover, whereas loss of hepatocyte growth factor-regulated substrate (Hrs) rescues this phenotype, indicating that USP8 protects EGFR from degradation via an Hrs-dependent pathway. [..]As EGFR stabilization against lysosomal turnover requires deubiquitination by USP8." SIGNOR-259102 phentolamine chemical CHEBI:8081 ChEBI ADRA1B protein P35368 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-258446 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT "down-regulates activity" phosphorylation Ser102 KDGNGYIsAAELRHV -1 26675311 t miannu "Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third." SIGNOR-266354 KCNQ5 protein Q9NR82 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-265983 TNFSF4 protein P23510 UNIPROT TNFRSF4 protein P43489 UNIPROT up-regulates binding 9606 BTO:0000007 9488716 t gcesareni "Activation of nf-kappab in ox40-transfected hsb-2 cells was detected by electrophoretic mobility shift assay within 30 min after the binding of the ligand gp34." SIGNOR-54927 ROCK1 protein Q13464 UNIPROT MAPK8IP3 protein Q9UPT6 UNIPROT up-regulates phosphorylation Ser314 RAREKRDsRNMEVQV 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-134580 CSNK2B protein P67870 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser24 GYLRKPKsMHKRFFV -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-251072 YES1 protein P07947 UNIPROT CDK4 protein P11802 UNIPROT down-regulates phosphorylation Tyr17 AEIGVGAyGTVYKAR 9606 18479465 t lperfetto "We purified tyrosine 17 kinases from hela cells and found that the src family non-receptor tyrosine kinase c-yes contributes a large fraction of the tyrosine 17 kinase activity in hela lysatesthis site is equivalent to tyrosine 15 of cyclin dependent kinase 1, which undergoes inhibitory phosphorylation by wee1 and myt1" SIGNOR-178624 LPAR1 protein Q92633 UNIPROT GNAI1 protein P63096 UNIPROT up-regulates binding 9606 12393875 t gcesareni "We conclude that lpa(1) receptors couple to a g(i)-phosphoinositide 3-kinase-tiam1 pathway to activate rac." SIGNOR-94635 ATP5PD protein O75947 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-261404 MYO1E protein Q12965 UNIPROT PTK2 protein Q05397 UNIPROT "up-regulates activity" binding 9606 BTO:0000848 28348210 t miannu "Myosin-1E (MYO1E), an actin-dependent molecular motor protein, directly interacts with FAK to induce Y397 autophosphorylation, which, in turn, causes changes in gene expression commonly observed in aggressive cancer." SIGNOR-265427 HBA1 protein P69905 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-251765 FYN protein P06241 UNIPROT ITCH protein Q96J02 UNIPROT "down-regulates activity" phosphorylation Tyr420 QFNQRFIyGNQDLFA 10090 BTO:0002417 16387660 t gcesareni "Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation" SIGNOR-245332 PRKDC protein P78527 UNIPROT FH protein P07954 UNIPROT "up-regulates activity" phosphorylation Thr236 IKIGRTHtQDAVPLT -1 26237645 t miannu "We show that exposure to ionizing radiation induces DNA-PK-dependent phosphorylation of nuclear fumarase at Thr 236, which leads to an interaction between fumarase and the histone variant H2A.Z at DNA double-strand break (DSB) regions. " SIGNOR-266349 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 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 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 CEBPA protein P49715 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0001056 11283671 t apalma "Here, we demonstrate that C/EBPα indeed activates its promoter in transient transfection assays in myeloid cells." SIGNOR-255673 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR GOLGB1 protein Q14789 UNIPROT "down-regulates activity" cleavage Asp1881 LSQISTKdGELKMLQ 9606 14970262 t miannu "Giantin and syntaxin 5 are cleaved by caspase-3. Given that both giantin and syntaxin 5 are cleaved at an early stage during apoptosis, we anticipated that, at the very least, the delivery of ER-derived transport intermediates to the Golgi would be impaired in apoptotic cells." SIGNOR-261235 MAPK14 protein Q16539 UNIPROT ZNHIT1 protein O43257 UNIPROT up-regulates phosphorylation Thr103 AEGPNYLtACAGPPS 9606 17380123 t llicata "Our results indicate that p38 mapk plays an important role in the regulation of p18hamlet half?life. In particular, p38 mapk activation is required for the accumulation of p18hamlet induced by dna damage?inducing Agents such as uv. We also showed that several sites that are phosphorylated by p38? In vitro are also important for p18hamlet protein stability in cells. the high conservation of thr103 as a phosphorylation site in p18hamlet proteins from different species (figure 1a), together with the in vitro phosphorylation experiments, suggested that this residue could be an important target for p38 mapk" SIGNOR-153899 EPAS1 protein Q99814 UNIPROT KDM5B protein Q9UGL1 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-271578 PRKCD protein Q05655 UNIPROT DNM1L protein O00429 UNIPROT up-regulates phosphorylation Ser616 PIPIMPAsPQKGHAV 9606 17301055 t gcesareni "Drp1 was specifically phosphorylated in mitosis by cdk1/cyclin b on ser-585. Exogenous expression of unphosphorylated mutant drp1s585a led to reduced mitotic mitochondrial fragmentation." SIGNOR-153148 CDC14A protein Q9UNH5 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 t "The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification" SIGNOR-248828 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu76 CSFEEAReVFENTER 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-263694 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 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 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 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR RNF146 protein Q9NTX7 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-271078 SOCS3 protein O14543 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" binding 9606 23454976 t miannu "SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition" SIGNOR-253051 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT "up-regulates activity" cleavage Arg243 KTKESLGrKIQIQRS 9606 BTO:0000392 11907111 t lperfetto "The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase" SIGNOR-263417 ACP1 protein P24666 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" dephosphorylation Tyr530 FTSTEPQyQPGENL 10090 19088431 t "LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src." SIGNOR-248454 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 TSHZ3 protein Q63HK5 UNIPROT HDAC1 protein Q13547 UNIPROT "up-regulates activity" relocalization 9606 BTO:0000938 19343227 t miannu "We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex.Endogenous HDAC1 was co-immunoprecipitated with FE65 when both FE65 and Teashirt3 were co-transfected (lane 4), but not when Teashirt3 or FE65 was omitted (lane 5 and 6), confirming that the association of HDAC1 with FE65 is dependent on, and mediated, by Teashirt3." SIGNOR-264814 PRKAA2 protein P54646 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 t miannu "AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250319 GHSR protein Q92847 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-257322 BABAM2 protein Q9NXR7 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-263212 arecoline chemical CHEBI:2814 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-258638 HCK protein P08631 UNIPROT HCK protein P08631 UNIPROT up-regulates phosphorylation Tyr411 RVIEDNEyTAREGAK 9606 BTO:0000007 10934191 t gcesareni "Tyr(416) is the autophosphorylation site in the activation loop. Autophosphorylation of tyr(416) is required for hck activation." SIGNOR-80340 RCAN1 protein P53805 UNIPROT PPP3CA protein Q08209 UNIPROT "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-252025 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 sorafenib chemical CHEBI:50924 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-258283 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 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 FGF14 protein Q92915 UNIPROT SCN2A protein Q99250 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-253429 MAPKAPK2 protein P49137 UNIPROT TH protein P07101 UNIPROT "up-regulates activity" phosphorylation Ser40 GQGAPGPsLTGSPWP -1 11359875 t miannu "MAPKAP-K2 phosphorylates both Ser19 and Ser40 of TH. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation." SIGNOR-250150 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 ING2 protein Q9H160 UNIPROT MMP13 protein P45452 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001913 19437536 f miannu "ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression." SIGNOR-254491 "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 MAPK8 protein P45983 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation 9606 9724739 t amattioni "Activated jnk phosphorylates p53" SIGNOR-59812 RET protein P07949 UNIPROT DOK1 protein Q99704 UNIPROT up-regulates binding 9606 12087092 t amattioni "Dok proteins directly associate with tyrosine 1062 of ret and could be its substrates. Phosphorylation of dok1 is necessary for interaction with ras-gap in vitro and in vivo. Dok1 is a negative regulator for the ras/erk signaling pathway activated by ret." SIGNOR-90158 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation 9606 16508002 t "inferred from 70% family members" 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-270043 DENND3 protein A2RUS2 UNIPROT RAB12 protein Q6IQ22 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 9606 BTO:0000007 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.|active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy." SIGNOR-264734 INSR protein P06213 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Tyr66 LHQEDNDyINASLIK -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-249370 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 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser262 DSEDYSLsEEGQELS 9606 12167711 t gcesareni "Hypophosphorylation of mdm2 augments p53 stability." SIGNOR-91199 GSN protein P06396 UNIPROT F-actin_assembly phenotype SIGNOR-PH18 SIGNOR "down-regulates quantity" binding 9606 BTO:0000132 27871158 t lperfetto "Gelsolin is an actin binding protein that severs and caps the barbed-end actin filaments to prevent actin monomer exchange upon intracellular calcium increase in the initial step." SIGNOR-261835 bethanechol chemical CHEBI:3084 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-258624 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 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 MZF1 protein P28698 UNIPROT CCN2 protein P29279 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 25899830 f miannu "we report the regulation of the CTGF and NOV genes by Myeloid Zinc Finger-1 (MZF-1), a hematopoietic transcription factor. We show the interaction of MZF-1 with the CTGF and NOV promoters in several cell types. Up-regulation of MZF-1 via calcitriol and vitamin A induces expression of CTGF and NOV, implicating a role for these vitamins in the functions of these two genes. Lastly, knockdown of MZF1 reduces levels of CTGF and NOV." SIGNOR-226307 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 EEF1A2 protein Q05639 UNIPROT His-tRNA(His) smallmolecule CHEBI:29155 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-269531 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 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 PPARGC1A protein Q9UBK2 UNIPROT NRF1 protein Q16656 UNIPROT "up-regulates activity" 9606 26971449 f lperfetto "PGC-1 family transcriptional coactivators enhance the activities of the nuclear respiratory factors NRF1 and NRF2, which induce transactivation of many genes encoding mitochondria-specific proteins involved in respiratory chain, mitochondrial DNA transcription/replication and protein import/assembly" SIGNOR-253391 NFIB protein O00712 UNIPROT GAS6 protein Q14393 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-268882 POU5F1 protein Q01860 UNIPROT CDX2 protein Q99626 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-254933 "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 DOCK7 protein Q96N67 UNIPROT RAC1 protein P63000 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-261887 BIRC5 protein O15392 UNIPROT CASP3 protein P42574 UNIPROT down-regulates binding 9606 10587640 t gcesareni "Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21." SIGNOR-72882 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 INPP5D protein Q92835 UNIPROT PIP3 smallmolecule CHEBI:16618 ChEBI "down-regulates quantity" "chemical modification" 9606 12421919 t gcesareni "Two inositol phosphatases implicated in the degradation of PI(3, 4, 5)P3, namely the 5_ phosphatase Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP) and the 3_ phosphatase and tensin homolog deleted on chromosome ten" SIGNOR-252428 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 DYRK1A protein Q13627 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser329 STISGRLsPIMTEQD 9606 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-252909 CCNA2 protein P20248 UNIPROT CyclinA2/CDK1 complex SIGNOR-C420 SIGNOR "form complex" binding 9606 29870721 t lperfetto "Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis." SIGNOR-267571 RIPK3 protein Q9Y572 UNIPROT OGDC complex SIGNOR-C397 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-268066 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR POU5F1 protein Q01860 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser12 LASDFAFsPPPGGGG -1 31306665 t lperfetto "Recent work found that CyclinE/CDK2 can phosphorylate OCT4 on serine 12 (S12), serine 355 (S355) and threonine 322 (T322) in vitro|Phosphorylation of OCT4 on S12 has been previously implicated to stabilize OCT4 by binding to PIN1, thereby preventing ubiquitinylation by WWP2." SIGNOR-264436 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR tRNA(Lys) smallmolecule CHEBI:29185 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-270403 SRP19 protein P09132 UNIPROT SRP72 protein O76094 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-261166 CLK2 protein P49760 UNIPROT PTPN1 protein P18031 UNIPROT "up-regulates activity" phosphorylation Ser242 MDKRKDPsSVDIKKV -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-250775 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 MAPK1 protein P28482 UNIPROT MITF protein O75030 UNIPROT down-regulates phosphorylation Ser180 PGSSAPNsPMAMLTL 9606 10673502 t "The effect has been demonstrated using O75030-9" gcesareni "The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation." SIGNOR-75030 MAPK1 protein P28482 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Ser295 PARPRSPsQTRKGPP 9606 BTO:0000142 15262992 t 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-126863 EGFR protein P00533 UNIPROT TRIP13 protein Q15645 UNIPROT "up-regulates quantity" phosphorylation Tyr56 HNIVFGDyTWTEFDE 9606 BTO:0000007 32860853 t lperfetto "Reciprocally, TRIP13 was phosphorylated at tyrosine(Y) 56 by EGFRvIII and EGF-activated EGFR. Abrogating TRIP13 Y56 phosphorylation dramatically attenuated TRIP13 expression-enhanced EGFR signaling and GBM cell growth." SIGNOR-265083 olaparib chemical CHEBI:83766 ChEBI PARP3 protein Q9Y6F1 UNIPROT "down-regulates activity" "chemical inhibition" 9606 25981132 t miannu "The PARP inhibitor olaparib is currently tested in clinical phase 1 trials to define safe dose levels in combination with RT." SIGNOR-259320 PKN1 protein Q16512 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser256 SPRRRAAsMDNNSKF 9606 BTO:0000150 12560069 t lperfetto "Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1." SIGNOR-252968 NEDD4 protein P46934 UNIPROT SPRY2 protein O43597 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 19864419 t miannu "Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability. " SIGNOR-271425 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 BTO:0000093 11258706 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-105737 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 PRKCD protein Q05655 UNIPROT CHN2 protein P52757 UNIPROT down-regulates phosphorylation Ser171 EKVSRRLsRSKNEPR 9606 20335173 t lperfetto "A novel cross-talk in diacylglycerol signaling: the rac-gap beta2-chimaerin is negatively regulated by protein kinase cdelta-mediated phosphorylation. phosphorylation of beta2-chimaerin on ser(169) located in the sh2-c1 domain linker region via protein kinase cdelta, which retained beta2-chimaerin in the cytosol and prevented its c1 domain-mediated translocation to membranes" SIGNOR-164687 EXOSC1 protein Q9Y3B2 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-261381 RPS6K proteinfamily SIGNOR-PF26 SIGNOR 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-268527 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 WDR83 protein Q9BRX9 UNIPROT MAP2K1 protein Q02750 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-124470 GGCX protein P38435 UNIPROT F2 protein P00734 UNIPROT "up-regulates activity" carboxylation Glu57 EVRKGNLeRECVEET -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-263677 STK11 protein Q15831 UNIPROT SIK2 protein Q9H0K1 UNIPROT up-regulates phosphorylation Thr175 KSGELLAtWCGSPPY 9606 14976552 t llicata "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-122788 ACVR1 protein Q04771 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-33287 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 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 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 MAPK1 protein P28482 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates activity" phosphorylation Ser274 DPLPGPGsPSHSAPD 10116 BTO:0000951 15834132 t miannu "Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events." SIGNOR-262841 DDX5 protein P17844 UNIPROT "RNA helicases p68/p72" complex SIGNOR-C34 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001103 17011493 t lperfetto "We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod." SIGNOR-149964 EIF6 protein P56537 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "down-regulates activity" binding 9606 14654845 t lperfetto "The assembly of 80S ribosomes requires joining of the 40S and 60S subunits, which is triggered by the formation of an initiation complex on the 40S subunit. This event is rate-limiting for translation, and depends on external stimuli and the status of the cell. Here we show that 60S subunits are activated by release of eIF6 (also termed p27BBP). | 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." SIGNOR-269150 "acetylsalicylic acid" chemical CHEBI:15365 ChEBI PTGS2 protein P35354 UNIPROT down-regulates "chemical inhibition" 9606 11809688 t gcesareni "Nsaids inhibit cyclooxygenase (cox) isozymes, which are responsible for the committed step in prostaglandin biosynthesis, and this has been considered the primary mechanism by which nsaids exert their antitumorigenic effects." SIGNOR-114380 "peptide antigen" smallmolecule CHEBI:166824 ChEBI "Class II MHC:Antigen" complex SIGNOR-C429 SIGNOR "form complex" binding 9606 33374673 t scontino "The major histocompatibility complex (MHC) molecules, or human leukocyte antigens (HLA) in humans, bind these peptides to present them to T cells that recognise them with their surface T cell receptors (TCR)." SIGNOR-267871 NCOA4 protein Q13772 UNIPROT AR protein P10275 UNIPROT up-regulates binding 9606 10347167 t miannu "We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar." SIGNOR-67684 MAPK1 protein P28482 UNIPROT NR4A1 protein P22736 UNIPROT "up-regulates activity" phosphorylation Thr143 CSAPSPStPSFQPPQ 10116 BTO:0001009 11883936 t lperfetto "NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro." SIGNOR-249430 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser222 EVEEEADsCFGDDED 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-110395 PRKACA protein P17612 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS -1 12853467 t miannu "PFK-2 that was phosphorylated on Ser466, but not Ser483, by PKA did not bind to 14-3-3s‚ " SIGNOR-250025 AURKB protein Q96GD4 UNIPROT HDAC9 protein Q9UKV0 UNIPROT down-regulates phosphorylation Ser239 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-198654 CEBPB protein P17676 UNIPROT CSRP1 protein P21291 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000972 14522018 t "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-254049 Ub:E2 complex SIGNOR-C497 SIGNOR SMURF2 protein Q9HAU4 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-271298 P2RY2 protein P41231 UNIPROT GNAS protein Q5JWF2 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-256759 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 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 IRF2BPL protein Q9H1B7 UNIPROT PDYN protein P01213 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-267156 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1714 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-248822 ZBTB14 protein O43829 UNIPROT ZBTB14 protein O43829 UNIPROT "up-regulates activity" binding 9606 10080939 t miannu "ZF5, which we have cloned as a transcriptional repressor on the mouse c-myc promoter, has the POZ domain at the amino-terminus and the Kruppel-type zinc finger domain at the carboxy-terminus. We demonstrated that the POZ domain has a function mediating homomeric protein-protein interaction and this interaction requires the zinc finger domain." SIGNOR-220534 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 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 P2RY1 protein P47900 UNIPROT GNAS protein Q5JWF2 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-256800 SMAD3/PIAS3 complex SIGNOR-C204 SIGNOR STAT3 protein P40763 UNIPROT down-regulates 9606 26194464 t mrosina "In summary, the TGF-b/IL-6/TCR-pERK-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-255036 RND1 protein Q92730 UNIPROT MAPK8 protein P45983 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" SIGNOR-152811 isoleucine smallmolecule CHEBI:24898 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-264749 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252829 STK39 protein Q9UEW8 UNIPROT SLC12A2 protein P55011 UNIPROT "up-regulates activity" phosphorylation 16990453 t lperfetto "This phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1" SIGNOR-264642 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT "up-regulates activity" dephosphorylation 9606 BTO:0000093 11154267 t lperfetto "Expression of Cdc25A mRNA and protein was induced by E(2) in control and p16(INK4a)-expressing MCF-7 cells; however, functional activity of Cdc25A was inhibited in cells expressing p16(INK4a). Inhibition of Cdc25A activity in p16(INK4a)-expressing cells was associated with depressed Cdk2 activity" SIGNOR-245449 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 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI RORB protein Q92753 UNIPROT "down-regulates activity" "chemical inhibition" 9606 12958591 t miannu "ATRA and related retinoids inhibit ROR beta but not ROR alpha transcriptional activity suggesting that high-affinity, subtype-specific ligands could be designed for the identification of ROR beta target genes. Our results identify ROR beta as a retinoid-regulated nuclear receptor, providing a novel pathway for retinoid action." SIGNOR-266845 HTR1D protein P28221 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-256721 S protein P59594 UNIPROT EIF3F protein O00303 UNIPROT "down-regulates activity" binding 9606 18231581 t lperfetto "Coronavirus spike protein inhibits host cell translation by interaction with eIF3f" SIGNOR-260255 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 "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 "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 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 miR221 mirna URS0000245997_9606 RNAcentral MEOX2 protein P50222 UNIPROT "down-regulates quantity" 10090 20819939 t "We show that miR-1 and miR-206 facilitate satellite cell differentiation by restricting their proliferative potential. We identify Pax7 as one of the direct regulatory targets of miR-1 and miR-206. Inhibition of miR-1 and miR-206 substantially enhances satellite cell proliferation and increases Pax7 protein level in vivo" SIGNOR-255922 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 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 PRKCA protein P17252 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-248925 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM26 protein Q12899 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-271086 DISP1 protein Q96F81 UNIPROT SHH protein Q15465 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 22902404 t lperfetto "We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion" SIGNOR-191888 ESR1 protein P03372 UNIPROT GREB1 protein Q4ZG55 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000356 17666587 f miannu "Long-range activation of GREB1 by estrogen receptor via three distal consensus estrogen-responsive elements in breast cancer cells. . GREB1 (gene regulated by estrogen in breast cancer 1) is an ER target gene that regulates estrogen-induced proliferation in breast cancer cells." SIGNOR-254074 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 Ub:E2 complex SIGNOR-C497 SIGNOR BARD1 protein Q99728 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-271102 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 DRD4 protein P21917 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-256703 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser291 PVSSLQAsVPGSVPG 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250729 ELANE protein P08246 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-263565 PRKACA protein P17612 UNIPROT NOXA1 protein Q86UR1 UNIPROT down-regulates phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 20110267 t llicata "We identified ser-282 as target of mapk and ser-172 as target of pkc and pka in vitro and in a transfected human embryonic kidney 293 (hek293) cell model using site directed mutagenesis and phosphopeptide mapping analysis. In hek293 cells, phosphorylation of these sites occurred at a basal level and down-regulated constitutive nox1 activity. I" SIGNOR-163663 ADRB2 protein P07550 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-257081 CBX1 protein P83916 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-264491 CHRM3 protein P20309 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-257224 "erlotinib hydrochloride" chemical CHEBI:53509 ChEBI JAK2 protein O60674 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-151274 SPRY4 protein Q9C004 UNIPROT TIMP1 protein P01033 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-253038 F2RL1 protein P55085 UNIPROT TXNIP protein Q9H3M7 UNIPROT "down-regulates quantity by repression" "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-254857 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 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 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 PKI-402 chemical CID:44187953 PUBCHEM PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206256 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 PD318088 chemical CID:10231331 PUBCHEM MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck lperfetto SIGNOR-244927 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR2 protein Q9HBW0 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-257529 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 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 MEPCE protein Q7L2J0 UNIPROT P-TEFb complex SIGNOR-C238 SIGNOR "down-regulates activity" binding 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-261038 IL7R protein P16871 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 BTO:0000776 18445337 t milica "For instance, jak1 is associated with the ? Subunits of ?c Cytokines such as il-7r? And IL-4R. jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation." SIGNOR-178494 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 20233713 t flangone "Employing an mtor active-site inhibitor wye-125132 (wye-132), we have performed quantitative phospho-proteomics and identified a ser-75-containing phosphopeptide from maf1, a known repressor of rna polymerase iii (pol iii) transcriptionmaf1 mutant proteins carrying s75a alone or with s60a, t64a, and s68a (maf1-s75a, maf1-4a) progressively enhanced basal repression of trna in actively proliferating cells and attenuated amino acid-induced trna transcription" SIGNOR-164352 DVL2 protein O14641 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates binding 9606 23151663 t 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-199500 CSNK2A2 protein P19784 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-251018 MFGE8 protein Q08431 UNIPROT "Av/b5 integrin" complex SIGNOR-C178 SIGNOR "up-regulates activity" binding 10116 BTO:0000452 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-260645 AURKA protein O14965 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Ser83 ALREIRYsLLPFANE 9606 15147269 t lperfetto "On the basis of these observations, we conclude that s83 of lats2 is a phosphorylation target of aurora-a and this phosphorylation plays a role of the centrosomal localization of lats2." SIGNOR-124830 PTAFR protein P25105 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-257329 Ub:E2 complex SIGNOR-C497 SIGNOR RNF187 protein Q5TA31 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-271165 MC4R protein P32245 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-257069 ZMYM2 protein Q9UBW7 UNIPROT NANOG protein Q9H9S0 UNIPROT "down-regulates activity" binding 10090 BTO:0004593 31363497 t miannu "In this work, we identified ZMYM2/ZFP198, which physically associates with NANOG as a key negative regulator of NANOG-mediated reprogramming of both epiblast stem cells and somatic cells." SIGNOR-269802 SUGT1 protein Q9Y2Z0 UNIPROT "Ndc80 complex" complex SIGNOR-C361 SIGNOR "up-regulates activity" relocalization 9606 BTO:0000567 22869522 t lperfetto "Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites." SIGNOR-265224 RHOBTB3 protein O94955 UNIPROT CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 24145166 t miannu "Here we show that RhoBTB3, a Golgi-associated, Rho-related ATPase, regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitylation. Depletion of RhoBTB3 arrested cells in S phase, triggered Golgi fragmentation, and elevated cyclin E levels. On the Golgi, RhoBTB3 bound cyclin E as part of a Cullin3 (CUL3)-dependent RING-E3 ubiquitin ligase complex comprised of RhoBTB3, CUL3, and RBX1." SIGNOR-272131 HTR4 protein Q13639 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-257367 SNAP25 protein P60880 UNIPROT SNARE_complex complex SIGNOR-C346 SIGNOR "form complex" binding 9606 BTO:0000938 30267828 t 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-263967 PRKD1 protein Q15139 UNIPROT PKD2 protein Q13563 UNIPROT "up-regulates activity" phosphorylation Ser801 SSLPRPMsSRSFPRS 9606 BTO:0000007 20881056 t miannu "Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. Phosphorylation at this site was significantly increased in response to serum and epidermal growth factor stimulation.We confirmed previous studies showing that PC2 mediated Ca2+ release from the ER can be stimulated by ATP.Phosphorylation at Ser801 seems to be permissive for this activity without altering the subcellular localization nor homophilic and heterophilic (with PC1) interactions of wild-type PC2." SIGNOR-259829 HTATSF1 protein O43719 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-270652 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 DNMT3A protein Q9Y6K1 UNIPROT DPP6 protein P42658 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000596 23409053 t lperfetto "In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells." SIGNOR-268962 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr373 ASDTDSSyCIPTAGM 9606 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-236408 "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 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 N-[4-[2-ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide chemical CHEBI:91360 ChEBI MAPK11 protein Q15759 UNIPROT "down-regulates activity" "chemical inhibition" -1 16162000 t miannu "A novel structural class of 4-phenyl-5-pyridyl-1,3-thiazoles was optimized as inhibitors of p38 MAP kinase and the proinflammatory cytokine TNF-α. it only significantly inhibited p38α (IC50 = 7.1 nM) and p38β (IC50 = 200 nM) in a concentration-dependent manner and was approximately 28 times more selective for p38α over p38β." SIGNOR-262222 linifanib chemical CHEBI:91435 ChEBI FLT1 protein P17948 UNIPROT "down-regulates activity" "chemical inhibition" -1 16648571 t Gianni "ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families" SIGNOR-262206 MN1 protein Q10571 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 10090 17494859 f irozzo "MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment." SIGNOR-256016 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser366 PGGSRAHsSHLKSKK 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-75633 SAR1A protein Q9NR31 UNIPROT SEC24D protein O94855 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-265301 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 SAR1A protein Q9NR31 UNIPROT "COPII vesicle" complex SIGNOR-C370 SIGNOR "up-regulates quantity" binding 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-265304 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 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 BTO:0000130 14499342 t lperfetto "Mapk-activated protein kinase-2 (mk2) is activated by p38 mapk in human neutrophils." SIGNOR-118044 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 DCTN6 protein O00399 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 phosphorylation:Thr186 KTMKGSStPVKN 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-264798 CLASP1 protein Q7Z460 UNIPROT CLIP2 protein Q9UDT6 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15631994 t 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-265092 PBRM1 protein Q86U86 UNIPROT S100A13 protein Q99584 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000562 15601824 f miannu "We found that baf180 deficiency leads to a decreased expression of select target genes, such as s100a13 and ra targets rar_2 and crabpii in heart tissues." SIGNOR-132431 buprenorphine chemical CHEBI:3216 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-258940 Dihydromorphine chemical CHEBI:4575 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-258787 ARHGAP21 protein Q5T5U3 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-260475 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 "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 PTPN6 protein P29350 UNIPROT STAT6 protein P42226 UNIPROT down-regulates 9606 BTO:0000801 9852037 f gcesareni "Expression of an shp-1 transgene in nih 3t3 cells markedly reduces both il-4-dependent stat6 activation and stat6-mediated transcription of il-4-responsive genes" SIGNOR-62578 CSNK2A1 protein P68400 UNIPROT RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser358 AKVLASLsDDEDEEE 9606 16428860 t lperfetto "Phosphorylation of rangap1 stabilizes its interaction with ran and ranbp1. Serine-358 (358s) was identified as the major phosphorylation site. Experiments using purified recombinant kinase and specific inhibitors such as drb and apigenin strongly suggest that casein kinase ii (ck2) is the responsible kinase" SIGNOR-143948 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 18854157 t gcesareni "Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm" SIGNOR-181631 KAT2B protein Q92831 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-84032 KDM4C protein Q9H3R0 UNIPROT "Histone H2A" proteinfamily SIGNOR-PF70 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-265315 GRIK3 protein Q13003 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-268274 CTNNB1 protein P35222 UNIPROT CEBPA protein P49715 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-80589 lofexidine chemical CHEBI:51368 ChEBI ADRA2C protein P18825 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-258330 dopamine smallmolecule CHEBI:18243 ChEBI DRD3 protein P35462 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-258377 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 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 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 TRAF6 protein Q9Y4K3 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" binding 9606 10075662 t miannu "RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK." SIGNOR-253048 ADORA2B protein P29275 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-257307 CDC20 protein Q12834 UNIPROT MCC complex SIGNOR-C382 SIGNOR "form complex" binding 9606 BTO:0000567 25092294 t miannu "The mitotic (or spindle assembly) checkpoint system delays anaphase until all chromosomes are correctly attached to the mitotic spindle. When the checkpoint is active, a Mitotic Checkpoint Complex (MCC) assembles and inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C). MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3 associated with the APC/C activator Cdc20." SIGNOR-265976 CSNK2A1 protein P68400 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates activity" phosphorylation Thr391 TTHIRTHtGEKPFAC 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-250857 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 10490659 t "JNK bound to an NH2-terminal reagion of JIP1 (residues 283 to 660)." gcesareni "These experiments demonstrated that 10 different jnk isoforms bound to both jip proteins." SIGNOR-70851 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser353 VQNKRRRsVTPPEEQ 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-252781 TRAF2 protein Q12933 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates activity" binding 9606 8548810 t lperfetto "The c-iaps associate with traf1 and traf3" SIGNOR-39527 "precursor messenger RNA" smallmolecule CHEBI:139356 ChEBI SF3b complex SIGNOR-C442 SIGNOR "up-regulates activity" relocalization 9606 32140746 t lperfetto "The SF3b complex is an intrinsic component of the functional U2 small nuclear ribonucleoprotein (snRNP). As U2 snRNP enters nuclear pre-mRNA splicing, SF3b plays key roles in recognizing the branch point sequence (BPS) and facilitating spliceosome assembly and activation." SIGNOR-268413 "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 SGK2 protein Q9HBY8 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 BTO:0000007 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-252990 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MAPK1 protein P28482 UNIPROT "up-regulates activity" phosphorylation Thr185 HDHTGFLtEYVATRW 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-244792 Ub:E2 complex SIGNOR-C497 SIGNOR TRAF4 protein Q9BUZ4 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-271081 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 SMURF1 protein Q9HCE7 UNIPROT BMPR2 protein Q13873 UNIPROT down-regulates ubiquitination 9606 22298955 t 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-195654 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 9606 8119945 t gcesareni "Phosphorylation at thr-48, thr-67, ser-122, thr-130, ser-168 and ser-214 occurs at g2 and g2-m transition and is catalyzed by cdk1. Ser-168 phosphorylation levels are lower than those at the other 5 cdk1 sites. Phosphorylation by cdk1 leads to increased activity." SIGNOR-36271 KHSRP protein Q92945 UNIPROT SRC protein P12931 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" -1 9858532 t lperfetto "We show here that this component of the DCS complex is hnRNP H and that, like hnRNP F and KSRP, hnRNP H is needed for src N1 splicing in vitro." SIGNOR-261274 aclidinium chemical CHEBI:65346 ChEBI CHRM2 protein P08172 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000131 19653626 t Luana "This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects." SIGNOR-258049 MAP2K6 protein P52564 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates phosphorylation 9606 8663074 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily." SIGNOR-42390 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2Z protein Q9H832 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-271347 RPL8 protein P62917 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-262453 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR TTC3 protein P53804 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-271087 PIN1 protein Q13526 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" isomerization 9606 BTO:0000599 23720771 t lperfetto "In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events" SIGNOR-265757 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 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 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 "39S mitochondrial large ribosomal subunit" complex SIGNOR-C285 SIGNOR Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 25838379 f lperfetto "The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes." SIGNOR-262333 NFIL3 protein Q16649 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 10090 BTO:0003104 10082541 f lperfetto "NFIL3 inhibits apoptosis without affecting Bcl-xL expression." SIGNOR-256618 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 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 9606 BTO:0000887;BTO:0001260 14593115 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-118936 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 sapitinib chemical CHEBI:132986 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR down-regulates "chemical inhibition" 9606 BTO:0000551 20145185 t "AZD8931 has a unique pharmacologic profile providing equipotent EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models." 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-269874 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 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 GARS1 protein P41250 UNIPROT glycine smallmolecule CHEBI:15428 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-270478 RPS6KA4 protein O75676 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000782 17668895 t gcesareni "Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation." SIGNOR-157158 MAPK8 protein P45983 UNIPROT BCL2 protein P10415 UNIPROT down-regulates phosphorylation Thr69 SRDPVARtSPLQTPA 9606 10567572 t gcesareni "G(2)/m-phase cells proved more susceptible to death signals, and phosphorylation of bcl-2 appeared to be responsible, as a ser70ala substitution restored resistance to apoptosis. We noted that ask1 and jnk1 were normally activated at g(2)/m phase, and jnk was capable of phosphorylating bcl-2.." SIGNOR-72361 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 BAD protein Q92934 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0002552 17000778 t lperfetto "We also demonstrate that bad physically interacts with cytoplasmic p53. bad is able to direct p53 to the mitochondria and forms a p53/bad complex at the mitochondria. the mitochondrial p53/bad complex promotes apoptosis" SIGNOR-149815 "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 PI4K2A protein Q9BTU6 UNIPROT CLSPN protein Q9HAW4 UNIPROT down-regulates phosphorylation Ser984 ALALCSGsFPTDKEE 9606 18082599 t gcesareni "These results indicate that plx1 phosphorylates claspin on s934, which is relatively close to the plx1-docking site at t906. Human claspin also contains a serine at position 984 in a homologous sequence" SIGNOR-159937 ACTL6A protein O96019 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-132916 MAPK1 protein P28482 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 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-88720 NOXA1 protein Q86UR1 UNIPROT NOX1 protein Q9Y5S8 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-264710 Phagocytosis phenotype SIGNOR-PH97 SIGNOR IL1B protein P01584 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-255445 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 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 SOX6 protein P35712 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 26893351 t "We found that SOX6 regulates adipogenesis in vertebrate species by activating adipogenic regulators including PPARγ, C/EBPα and MEST" SIGNOR-255824 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 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 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 10973490 t gcesareni "Here we show that in vitro, atm phosphorylates the ser-gln/thr-gln (sq/tq) cluster domain (scd) on chk2, which contains seven sq/tq motifs, and thr68 is the major in vitro phosphorylation site by atm. Atm predominantly phosphorylates chk2 at thr68, promoting homodimerization and activation via intramolecular trans-autophosphorylation at thr383/387." SIGNOR-81438 MAPK3 protein P27361 UNIPROT RPS6KA3 protein P51812 UNIPROT up-regulates phosphorylation Thr577 AENGLLMtPCYTANF 9606 10980595 t llicata "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-81464 TRAF6 protein Q9Y4K3 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "down-regulates quantity" ubiquitination 9606 BTO:0000007 28980855 t "inferred from family member" "The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation." SIGNOR-270271 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 15208625 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-126055 BCL2 protein P10415 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" SIGNOR-256637 CHRM5 protein P08912 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-257009 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 MC5R protein P33032 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-257441 venlafaxine chemical CHEBI:9943 ChEBI SLC6A4 protein P31645 UNIPROT "down-regulates activity" "chemical inhibition" 9606 20378347 t Luana "The cycloalkanol ethylamine scaffold was successfully utilized in the discovery and development of dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitors (SNRIs).1 Drugs such as venlafaxine (1) and duloxetine (2) possessing norepinephrine reuptake inhibition, either selectively or in combination with serotonin reuptake inhibition were approved for major depressive disorder (MDD)." SIGNOR-257836 ATR protein Q13535 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-177809 ATM protein Q13315 UNIPROT MDM4 protein O15151 UNIPROT down-regulates phosphorylation 9606 16082221 t gcesareni "Atm directly and indirectly induces mdm2 and mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of mdm2 and mdmx by showing that atm-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme hausp." SIGNOR-139403 RINT1 protein Q6NUQ1 UNIPROT "NRZ complex" complex SIGNOR-C358 SIGNOR "form complex" binding 25364732 t lperfetto "NRZ complex, which comprises NAG, RINT1, and ZW10, is also involved in Golgi-to-ER retrograde transport, but each component of the complex has diverse cellular functions including endosome-to-Golgi transport, cytokinesis, cell cycle checkpoint, autophagy, and mRNA decay." SIGNOR-265025 CDK4 protein P11802 UNIPROT PRDX1 protein Q06830 UNIPROT down-regulates phosphorylation Thr90 CHLAWVNtPKKQGGL 9606 BTO:0000567 11986303 t lperfetto "Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown)." SIGNOR-87105 MAPK14 protein Q16539 UNIPROT ELK1 protein P19419 UNIPROT up-regulates phosphorylation Ser383 IHFWSTLsPIAPRSP 9606 BTO:0000150 20727996 t gcesareni "Elk-1 is a member of the e-twenty-six (ets) domain superfamily of transcription factors and has been traditionally associated with mitogen-induced immediate early gene transcription upon phosphorylation by mitogen activated protein kinases (erk/mapk)." SIGNOR-167539 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 DLK2 protein Q6UY11 UNIPROT NOTCH1 protein P46531 UNIPROT "down-regulates activity" binding 10090 BTO:0002572 21419176 t lperfetto "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-219377 LATS1 protein O95835 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser127 PQHVRAHsSPASLQL 9606 22658639 t milica "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-197647 MECP2 protein P51608 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "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-264680 CSNK2A1 protein P68400 UNIPROT SSB protein P05455 UNIPROT up-regulates phosphorylation Ser366 GKKTKFAsDDEHDEH 9606 18257391 t gcesareni "Prior studies indicate that hla is activated by phosphorylation of serine-366 by protein kinase ck2, neutralizing a negative effect of a short basic motif (sbm)" SIGNOR-160761 ABL1 protein P00519 UNIPROT CAT protein P04040 UNIPROT "up-regulates activity" phosphorylation Tyr231 NANGEAVyCKFHYKT 9606 BTO:0000093 12777400 t lperfetto "The SH3 domains of c-Abl and Arg bound directly to catalase at a P293FNP site. c-Abl and Arg phosphorylated catalase at Tyr231 and Tyr386 in vitro and in the response of cells to H2O2" SIGNOR-101298 PRKCB protein P05771 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 results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA." SIGNOR-168173 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 COL14A1 protein Q05707 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-254672 WDR24 protein Q96S15 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-255302 "Immunoglobulin kappa light chain" protein P0DOX7 UNIPROT BCR-Mk complex SIGNOR-C433 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-268186 H4C1 protein P62805 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-263877 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 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 PP1 proteinfamily SIGNOR-PF54 SIGNOR 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-264662 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 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1161 FGMTRDIyETDYYRK 9606 8940173 t lperfetto "Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor" SIGNOR-45122 PTEN protein P60484 UNIPROT GLI1 protein P08151 UNIPROT down-regulates 9606 17845852 f "PTEN is a suppressor of RAS-AKT function" gcesareni "Moreover, suppressors of ras akt function, such as the tumor-suppressor pten, and the attenuation of ras signaling involved in senescence, could be thus viewed as modulators of the gli code" SIGNOR-157776 ABL1 protein P00519 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-86585 WWC1 protein Q8IX03 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 21233212 t miannu "Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector." SIGNOR-263659 PTK2 protein Q05397 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 9606 BTO:0000671 15694384 t llicata "Once stimulated, fak undergoes autophosphorylation at tyrosine (y) 397, followed by phosphorylation of several sites including y576/y577 which increases fak's kinase activity, as well as at y407, y861, and y925." SIGNOR-133837 HTR3D protein Q70Z44 UNIPROT Excitatory_synaptic_transmission phenotype SIGNOR-PH133 SIGNOR up-regulates 9606 BTO:0000142 18761359 f miannu "The 5-hydroxytryptamine type-3 (5-HT3) receptor is a cation-selective ion channel of the Cys-loop superfamily. 5-HT3 receptor activation in the central and peripheral nervous systems evokes neuronal excitation and neurotransmitter release. " SIGNOR-264319 oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI citrate(3-) smallmolecule CHEBI:16947 ChEBI "up-regulates quantity" "precursor of" 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-266237 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MAPK6 protein Q16659 UNIPROT up-regulates phosphorylation Ser684 IGIPQFHsPVGSPLK 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-216797 JAK1 protein P23458 UNIPROT TYK2 protein P29597 UNIPROT up-regulates phosphorylation Tyr1054 AVPEGHEyYRVREDG 9606 8702790 t llicata "These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1." SIGNOR-43080 p38 proteinfamily SIGNOR-PF16 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Thr548 KKVAVVRtPPKSPSS 9606 21215781 t "The effect has been demonstrated using P10636-8" lperfetto "However, other kinases, such as cdk5, p38 and pka, also phosphorylate tau at t231tau phosphorylation at t231, s235 and s262 also contributes to the dissociation of tau from microtubules" SIGNOR-171062 2-[2-Amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl]-5-[(4-bromobenzyl)oxy]phenol smallmolecule CID:135651766 PUBCHEM GIPR protein P48546 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-257498 CTCF protein P49711 UNIPROT TERT protein O14746 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 1632686 f miannu "CTCF binds the proximal exonic region of hTERT and inhibits its transcription" SIGNOR-253832 "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 Ub:E2 complex SIGNOR-C497 SIGNOR HERC6 protein Q8IVU3 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-271295 "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 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 GRK6 protein P43250 UNIPROT GRK6 protein P43250 UNIPROT unknown phosphorylation Thr485 LDIEQFStVKGVELE 9534 BTO:0000298 10334944 t "GRK6 Is Autophosphorylated in COS-7 Cells. GRK6, like GRK5, is autophosphorylated on Ser484 and Thr485. Whether the autophosphorylation of GRK6 modulates its activity remains however to be established." SIGNOR-251212 TGFB1 protein P01137 UNIPROT ITGA3 protein P26006 UNIPROT "down-regulates quantity by repression" "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-253353 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 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 EPGN protein Q6UW88 UNIPROT ERBB4 protein Q15303 UNIPROT up-regulates binding 9606 16829981 t gcesareni "Areg (amphiregulin), btc (beta-cellulin), egf, epgn (epigen), ereg (epiregulin), hbegf, nrg1, nrg2, nrg3, nrg4 and tgfa (tgfalpha) constitute egf family ligands for erbb family receptors." SIGNOR-147835 CSNK2A2 protein P19784 UNIPROT SPIB protein Q01892 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser146 PALEVSDsESDEALV 9606 BTO:0000567 10618498 t llicata "Phosphorylation of the Spi-B transcription factor reduces its intrinsic stability. | 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" SIGNOR-251041 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 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 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-198547 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser634 ISQCGYSsTIVHVPP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250819 AMBRA1 protein Q9C0C7 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 BTO:0000459 20921139 t lperfetto "we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2." SIGNOR-168252 HTR2A protein P28223 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-257137 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 CRH protein P06850 UNIPROT KRT14 protein P02533 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 15468147 t Regulation miannu "CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels." SIGNOR-251899 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR METTL3 protein Q86U44 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser50 SPTFRSDsPVPTAPT 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-265951 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 RASSF1 protein Q9NS23 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 BTO:0002552 12024041 f Luana "RASSF1A expression dramatically inhibits native cyclin D1 accumulation | Regulation of cyclin D1 accumulation by RASSF1A is independent of the cyclin D1 promoter and likely occurs through inhibition of mRNA translation." SIGNOR-259455 PCC complex SIGNOR-C414 SIGNOR propionyl-CoA(4-) smallmolecule CHEBI:57392 ChEBI "down-regulates quantity" "chemical modification" 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-267184 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 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser93 RVPKDRPsLTVTPKR 9606 BTO:0000567 21658950 t miannu "Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis." SIGNOR-263139 "4-[6-[4-(methoxycarbonylamino)phenyl]-4-(4-morpholinyl)-1-pyrazolo[3,4-d]pyrimidinyl]-1-piperidinecarboxylic acid methyl ester" chemical CHEBI:94742 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t "Selleck;ATP-competitive inhibitor mTOR" gcesareni SIGNOR-207809 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 RPS6KB1 protein P23443 UNIPROT CAD protein P27708 UNIPROT up-regulates phosphorylation Ser1859 PPRIHRAsDPGLPAE 9606 23429703 t lperfetto "Mtorc1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein s6 kinase 1 (s6k1), which directly phosphorylates s1859 on cad, the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mtorc1 thus stimulates the production of new nucleotides to accommodate an increase in rna and dna synthesis." SIGNOR-201117 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 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1871 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-269337 ARRY-520 chemical CID:44224257 PUBCHEM KIF11 protein P52732 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189891 CSK protein P41240 UNIPROT ITCH protein Q96J02 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000007 16888620 t gcesareni "CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro." SIGNOR-245327 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 EGFR protein P00533 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates activity" phosphorylation Tyr1229 SSTDRSPyEKVSAGN 9606 BTO:0000150 11483589 t lperfetto "We also show that the activated egf-r phosphorylates the muc1 cytoplasmic tail on tyrosine at a yekv motif that functions as a binding site for the c-src sh2 domain. The results demonstrate that egf-r-mediated phosphorylation of muc1 induces binding of muc1 to c-src in cells" SIGNOR-109538 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 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 cortisone chemical CHEBI:16962 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 14817168 t allergy gcesareni SIGNOR-251691 MIOS protein Q9NXC5 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-255301 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 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-248517 DNAJC6 protein O75061 UNIPROT HSPA8 protein P11142 UNIPROT "up-regulates activity" relocalization 24789820 t lperfetto "Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane." SIGNOR-260719 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 DLG4 protein P78352 UNIPROT TANC1 protein Q9C0D5 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-266894 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 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT "up-regulates activity" phosphorylation Ser19 KRPQRATsNVFAMFD 9606 BTO:0000567 12185584 t miannu "Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies. we showed that the inhibition of Rho-kinase reduced diphosphorylated MRLC in the center of cells even in the presence of phosphatase inhibitor, suggesting that Rho-kinase directly diphosphorylates MRLC (red arrow in Figure 6). Taken together, we propose a model of diphosphorylation of MRLC through dual pathways of both the direct phosphorylation and the inhibition of myosin phosphatase by Rho-kinase (Figure 6)." SIGNOR-263073 VEPH1 protein Q14D04 UNIPROT YAP1 protein P46937 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000938 23989952 f "or inhibits the Hippo pathway to activate Yki" lperfetto "A double positive-feedback loop between melt and yki, wherein yki acti- vates melt expression, and melt promotes yki" SIGNOR-202540 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR HSD11B2 protein P80365 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15659537 f miannu "Overexpression of p50 inhibited HSD11B2 promoter activity and overexpression of Egr-1 inhibited transactivation of the HSD11B2 promoter by p65/p50." SIGNOR-253877 PDGFRB protein P09619 UNIPROT GRB2 protein P62993 UNIPROT up-regulates binding 9606 7935391 t fspada "A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo." SIGNOR-34765 levomethadone chemical CHEBI:136003 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-258807 "3-phenanthryl hydrogen sulfate" chemical CHEBI:37459 ChEBI DRD3 protein P35462 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-258438 CSNK2A1 protein P68400 UNIPROT HOXB7 protein P09629 UNIPROT "down-regulates activity" phosphorylation Ser133 IYPWMRSsGTDRKRG 10090 BTO:0002882 11290787 t llicata "Thus, we concluded that CKII can phosphorylate HOXB7 in vitro and that this phosphorylation occurs at both of the CKII target sites, S133 and T204. | Wild-type HOXB7 inhibited the differentiation of 32D cells, whereas mutations in the Pbx-binding pentapeptide motif or the DNA-binding homeodomain, as well as internal deletions of the N-terminal unique region, blocked this effect. Interestingly, mutations eliminating two target sites for casein kinase II, the glutamate-rich C terminus, or the first 14 amino acids of HOXB7, led to enhanced 32D differentiation." SIGNOR-250896 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates deubiquitination 9606 16027725 t gcesareni "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases" SIGNOR-138876 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-268107 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 linifanib chemical CHEBI:91435 ChEBI CSF1R protein P07333 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-258241 FGF2 protein P09038 UNIPROT ALPL protein P05186 UNIPROT "down-regulates quantity by repression" "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-252194 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 UBE2D1 protein P51668 UNIPROT TRIM2 protein Q9C040 UNIPROT "up-regulates activity" binding 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. Together, our results indicate that TRIM2 is an ubiquitin ligase that binds to and ubiquitinates NF-L and that TRIM2 deficiency leads to neurodegeneration in mice likely by altering NF-L metabolism with consequent NF-L accumulation in axons and impairment of axonal transport." SIGNOR-271775 "Melanin-concentrating hormone" smallmolecule CHEBI:80254 ChEBI MCHR1 protein Q99705 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-257540 IKBKG protein Q9Y6K9 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "form complex" binding 10090 SIGNOR-C14 SIGNOR-C14 19666475 t lperfetto "Proinflammatory NF-kappaB activation requires the IkappaB (inhibitor of NF-kappaB) kinase (IKK) complex that contains two catalytic subunits named IKKalpha and IKKbeta and a regulatory subunit named NF-kappaB essential modulator (NEMO)." SIGNOR-209762 NOX1 protein Q9Y5S8 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-264714 EPN1 protein Q9Y6I3 UNIPROT EGFR protein P00533 UNIPROT down-regulates relocalization 9606 19054389 t gcesareni "Epsin 1 is involved in recruitment of ubiquitinated egf receptors into clathrin-coated pits this supports the contention that epsin 1 promotes endocytosis of the ubiquitinated egfr." SIGNOR-182562 ABR protein Q12979 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-260525 ERG protein P11308 UNIPROT ICAM1 protein P05362 UNIPROT "down-regulates quantity by repression" "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-253917 ITCH protein Q96J02 UNIPROT ERBB4 protein Q15303 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 18334649 t miannu " Itch catalyzed ubiquitination of ErbB4 CYT-1, promoted its localization into intracellular vesicles, and stimulated degradation of ErbB4 CYT-1" SIGNOR-271416 PIM2 protein Q9P1W9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 16146838 f 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-256575 EPB41 protein P11171 UNIPROT DLG1 protein Q12959 UNIPROT "up-regulates activity" relocalization 9615 BTO:0000837 12807908 t lperfetto "Together, our results demonstrate that in addition to the N-terminal targeting domain, the alternatively spliced I3 insertion plays a critical role in recruiting hDlg to the lateral membrane in epithelial cells via its interaction with protein 4.1R." SIGNOR-266011 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ARF6 protein P62330 UNIPROT "down-regulates quantity by destabilization" 9534 BTO:0000298 18094045 t miannu "Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A)." SIGNOR-271766 NSL1 protein Q96IY1 UNIPROT "MIS12 complex" complex SIGNOR-C362 SIGNOR "form complex" binding -1 27881301 t lperfetto "Human MIS12C (also known as MIND complex or Mtw1 complex in Saccharomyces cerevisiae) contains the MIS12, PMF1, NSL1, and DSN1 subunits" SIGNOR-265191 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 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 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 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 TCL1B protein O95988 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t lperfetto "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-244452 OXGR1 protein Q96P68 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-257417 AMPK complex SIGNOR-C15 SIGNOR ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser317 SHLASPPsLGEMQQL 9606 19584320 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-216491 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser1217 SHHFRRRsFRGFWLT 9606 19144650 t llicata "We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade" SIGNOR-183445 SLC9A2 protein Q9UBY0 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-265592 STAT1 protein P42224 UNIPROT JAK1/STAT1/STAT3 complex SIGNOR-C120 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-235612 PTPRZ1 protein P23471 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT "down-regulates activity" dephosphorylation Tyr1105 RNEEENIySVPHDST 10090 BTO:0000601 16513268 t "Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo." SIGNOR-248451 RPS6KA1 protein Q15418 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL 9606 BTO:0000669 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-109708 PTPN6 protein P29350 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation Tyr1197 STAENAEyLRVAPQS 9606 9733788 t tpavlidou "The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation." SIGNOR-59965 FEZF2 protein Q8TBJ5 UNIPROT MDM2 protein Q00987 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 23677067 f lperfetto "FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma." SIGNOR-268974 KLHL12 protein Q53G59 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 32433973 t miannu "  Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC2" SIGNOR-272198 CSNK2A1 protein P68400 UNIPROT WASF2 protein Q9Y6W5 UNIPROT down-regulates phosphorylation Ser488 YSDSEDDsSEFDEDD 9606 19012317 t gcesareni "Here we identify five casein kinase 2 (ck2) phosphorylation sites within the vca domain of wave2, serines 482, 484, 488, 489, and 497. Phosphorylation of these sites is required for a high affinity interaction with the arp2/3 complex;we and show that their mutation to non-phosphorylatable alanine residues inhibits wave2 function in vivo." SIGNOR-182358 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 PRKCA protein P17252 UNIPROT GNAZ protein P19086 UNIPROT up-regulates phosphorylation Ser16 EKEAARRsRRIDRHL 9606 BTO:0000671 9166747 t gcesareni "Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling." SIGNOR-48677 COP1 protein Q8NHY2 UNIPROT "DCX DET1-COP1" complex SIGNOR-C24 SIGNOR "form complex" binding 9606 17452440 t lperfetto "Mammalian det1 regulates cul4a activity and forms stable complexes with e2 ubiquitin-conjugating enzymes" SIGNOR-154514 SUMO1 protein P63165 UNIPROT PML protein P29590 UNIPROT "up-regulates activity" sumoylation Lys65 QQCQAEAkCPKLLPC 9534 BTO:0000298 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. The PML mutant with Lys to Arg substitutions in all three sites is expressed normally, but cannot be sentrinized|Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies." SIGNOR-270542 HHIP protein Q96QV1 UNIPROT SHH protein Q15465 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-65078 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 clomipramine chemical CHEBI:47780 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-258874 STK4 protein Q13043 UNIPROT LATS2 protein Q9NRM7 UNIPROT up-regulates phosphorylation Thr1041 EHAFYEFtFRRFFDD 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-201302 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 BRSK1 protein Q8TDC3 UNIPROT WEE1 protein P30291 UNIPROT unknown phosphorylation Ser642 KKMNRSVsLTIY -1 15150265 t llicata "HsSAD1 protein produced in Sf9 cells phosphorylated the GST-fused human wild-type Wee1A fragment but not its S642A mutant produced inEscherichia coli (Fig. 2). The kinase-dead hsSAD1 mutant (K59A) failed to phosphorylate the wild-type Wee1A fragment." SIGNOR-250601 FHIT protein P49789 UNIPROT AKT1 protein P31749 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu "Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis" SIGNOR-252625 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF3 protein Q86UD3 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-271246 SSH3 protein Q8TE77 UNIPROT CFL1 protein P23528 UNIPROT "up-regulates activity" dephosphorylation Ser3 sGVAVSDG 9606 14531860 t "Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH)." SIGNOR-248759 MAPK3 protein P27361 UNIPROT 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-203480 gemcitabine chemical CHEBI:175901 ChEBI RRM1 protein P23921 UNIPROT "down-regulates activity" "chemical inhibition" -1 2233693 t miannu "Direct assays of partially purified ribonucleoside diphosphate reductase (EC 1.17.4.1) demonstrated 50% inhibition by 4 microM dFdC 5'-diphosphate; dFdC 5'-triphosphate was much less inhibitory. We conclude that dFdC 5'-diphosphate acts as an inhibitor of ribonucleoside diphosphate reductase." SIGNOR-258386 CSNK2A1 protein P68400 UNIPROT TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation Ser18 SPADDSLsNSEEEPD 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-173668 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" "precursor of" 9606 11863375 t miannu "Alanine aminotransferase (ALT) catalyzes the reversible transamination between alanine and 2-oxoglutarate to form pyruvate and glutamate, and thereby has a key role in the intermediary metabolism of glucose and amino acids. Two ALT isoenzymes are known to exist, but only one ALT gene has been cloned, GPT. In this study, we cloned a homolog of GPT and named it GPT2, and the corresponding protein ALT2" SIGNOR-266924 JUN protein P05412 UNIPROT CFI protein P05156 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10630630 f miannu "The production of CFI by Hep G2 cells was enhanced in a dose- and time-dependent fashion by 12-O-tetradecanoyl-1,2-phorbol 13-acetate (TPA), a potent PKC activator. The enhancement of the activity of transfected chimeric CAT constructs by TPA was abrogated by calphostin C and by pyrrolidine dithiocarbamate (an inhibitor of NF-kappaB and AP-1 transactivation). These results indicate that TPA regulation of CFI gene requires PKC signalling and is mediated by via a TPA response element (TRE) in the CFI promoter region located at -136/-130 and involves the transactivation of AP-1 and NF-kappaB transcription factors" SIGNOR-254787 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM63 protein Q969Q1 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-271117 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 EIF2AK4 protein Q9P2K8 UNIPROT EIF2S1 protein P05198 UNIPROT "down-regulates activity" phosphorylation Ser52 MILLSELsRRRIRSI 9606 32513922 t gcesareni "Translation initiation factor 2α [eukaryotic translation initiation factor 2α (eIF2α)] kinase phosphorylates serine51 (Ser51) of eIF2α and downregulates cellular protein synthesis." SIGNOR-246157 FYN protein P06241 UNIPROT CD300LB protein A8K4G0 UNIPROT "up-regulates activity" phosphorylation Tyr188 EPGEQPIyMNFSEPL 9534 16920917 t lperfetto "As CD300b phosphorylation was occurring only in the presence of both c-Fyn and DAP-12, we addressed whether tyrosine phosphorylation was required for association of CD300b and DAP-12. For this purpose, we generated a set of HA-tagged CD300b mutants affecting the transmembrane lysine (K158L), the cytoplasmic tyrosine (Y188F) or both residues.|As expected, the CD300b double mutant could neither recruit DAP-12 nor become phosphorylated in the presence of c-Fyn kinase (Fig. 5⇑C). Association between CD300b and DAP-12 was maintained in absence of the c-Fyn kinase, indicating that phosphorylation of the adaptor was not essential for the formation of the complex (data not shown)" SIGNOR-264771 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 EGFR protein P00533 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr659 VADERVDyVVVDQQK 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-236404 HTR2C protein P28335 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-257355 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 mTORC1 complex SIGNOR-C3 SIGNOR BTRC protein Q9Y297 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002572 33861966 t miannu "mTORC1 regulates the stability of CREB2. 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-267829 EIF4EBP1 protein Q13541 UNIPROT EIF4E protein P06730 UNIPROT "down-regulates activity" binding 9606 23584478 t lperfetto "The rate-limiting factor for translation is eukaryotic translation initiation factor 4E (eIF4E), which is negatively regulated by eIF4E-binding protein 1 (4E-BP1)." SIGNOR-167176 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 1,2-diacyl-sn-glycerol smallmolecule CHEBI:17815 ChEBI PRKCA protein P17252 UNIPROT "up-regulates activity" binding 9606 12629049 t "Activation of PKC depends on the availability of DAG,a signaling lipid that is tightly and dynamically regulated." SIGNOR-251559 MAPK14 protein Q16539 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 ((68)nqsllspl) and becomes phosphorylated in cultured cells and organs during mitosis, cell stress, and apoptosis. 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-114079 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 RAE1 protein P78406 UNIPROT NUP98 protein P52948 UNIPROT "up-regulates activity" binding 9606 16036565 t miannu "Nup98 is a major interacting partner of Rae1 and known to beinvolved in mRNA export." SIGNOR-260868 CDK1 protein P06493 UNIPROT KIF11 protein P52732 UNIPROT up-regulates phosphorylation Thr926 LDIPTGTtPQRKSYL 9606 9235942 t lperfetto "The kinesin-related motor hseg5 is essential for centrosome separation, and its association with centrosomes appears to be regulated by phosphorylation of tail residue threonine 927 by the p34(cdc2) protein kinase.Phosphorylation also enhanced the specific binding of p150(glued) to the tail domain of hseg5 in vitro" SIGNOR-50169 HTR1B protein P28222 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-256863 STAT3 protein P40763 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12565872 t "We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells" SIGNOR-253583 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 CARS1 protein P49589 UNIPROT cysteine smallmolecule CHEBI:15356 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-270470 IFNB1 protein P01574 UNIPROT IFNAR1 protein P17181 UNIPROT up-regulates binding 9606 11278538 t gcesareni "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-104663 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 21502402 t "inferred from 70% family members" 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-270209 IKK-complex complex SIGNOR-C14 SIGNOR NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 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-216341 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 10090 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-134477 NR4A3 protein Q92570 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 30455429 f miannu "Over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax." SIGNOR-259398 CDC25A protein P30304 UNIPROT CDK2 protein P24941 UNIPROT up-regulates dephosphorylation Thr14 VEKIGEGtYGVVYKA 9606 12411508 t gcesareni "Cell division cycle 25 a (cdc25a), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (cdks), such as cdk2, cdk4, and cdk6, and positively regulates the activities of cdks that lead to cell cycle progression." SIGNOR-95252 BRAF protein P15056 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser218 VSGQLIDsMANSFVG 10090 BTO:0000944 8131746 t lperfetto "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf." SIGNOR-235475 BRSK2 protein Q8IWQ3 UNIPROT 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-268482 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser285 NHTLAPAsPAPARPR -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250646 FLT3 protein P36888 UNIPROT SIRT1 protein Q96EB6 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 9606 26049753 f "SIRT1 protein but not mRNA expression is increased in CD34+ cells from FLT3-ITD positive AML patients compared to FLT3 wild-type AML patients" SIGNOR-261555 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 CSNK2A1 protein P68400 UNIPROT ARNT protein P27540 UNIPROT down-regulates phosphorylation Ser77 DKERFARsDDEQSSA 9606 16129408 t gcesareni "Here, we show that arnt and alt arnt proteins are differentially phosphorylated by protein kinase ckii in vitro. Phosphorylation had an inhibitory effect on dna-binding to an e-box probe by alt arnt, but not arnt, homodimers. This inhibitory phosphorylation occurs through ser77." SIGNOR-140034 "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 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 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser233 VSSQHRYsTPHAFTF 9606 12551925 t gcesareni "For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1." SIGNOR-37466 RICTOR protein Q6R327 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-205624 ACAT1 protein P24752 UNIPROT PDHA1 protein P08559 UNIPROT "down-regulates activity" acetylation 34289383 t lperfetto "We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)" SIGNOR-267633 CD40LG protein P29965 UNIPROT CD40 protein P25942 UNIPROT "up-regulates activity" binding 9606 BTO:0000782;BTO:0003076 19426221 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-185660 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 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 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 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 DOT1L protein Q8TEK3 UNIPROT MYC protein P01106 UNIPROT "up-regulates activity" binding 9606 BTO:0001939 26199140 t 1 miannu "Our data suggest that the c-Myc-dependent transcriptional switch is modulated by DOT1L, as in the presence of DOT1L c-Myc preferentially forms an active complex with p300 rather than a repressive complex containing HDAC1 and DNMT1" SIGNOR-239362 IGF1R protein P08069 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 21798082 t gcesareni "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-175665 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 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 19279133 t flangone "Here, we show that Smad2/3, the downstream effectors of Activin/Nodal signalling, bind and directly control the activity of the Nanog gene in hESCs." SIGNOR-242049 FOXO proteinfamily SIGNOR-PF27 SIGNOR 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-270252 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 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser315 ITATSPAsMVGGKPG 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-106578 EPHB2 protein P29323 UNIPROT EPHB2 protein P29323 UNIPROT "up-regulates activity" phosphorylation Tyr602 IYIDPFTyEDPNEAV -1 10572014 t "Our results demonstrate that autophosphorylation tyrosine 611 in the juxtamembrane region of chicken EphB2 is critical for the association of the Src SH2 domain." SIGNOR-251124 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 QRICH1 protein Q2TAL8 UNIPROT VARS2 protein Q5ST30 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-269409 CSNK2A1 protein P68400 UNIPROT EIF2S2 protein P20042 UNIPROT up-regulates phosphorylation Ser2 sGDEMIFD 9606 BTO:0000567 16225457 t lperfetto "The n-terminal domain of the human eif2beta subunit and the ck2 phosphorylation sites are required for its function. These results suggest that ser2 and ser67 contribute to the important role of the n-terminal region of eif2beta for its function in mammals." SIGNOR-140994 ECM stimulus SIGNOR-ST20 SIGNOR "AX/b2 integrin" complex SIGNOR-C171 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-259053 RCSD1 protein Q6JBY9 UNIPROT CAPZA1 protein P52907 UNIPROT up-regulates binding -1 15850461 t miannu "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-263088 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 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 22933625 f apalma "Recent findings have shown that IL-10 stimulation of macrophages isolated from skeletal muscles increases the phagocytic activity of macrophages" SIGNOR-255443 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2N protein P61088 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-271354 GATA3 protein P23771 UNIPROT CEBPA protein P49715 UNIPROT down-regulates binding 9606 17139329 t fferrentino "Whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBPα to inhibit its transcriptional activity on the Pparg2 promoter." SIGNOR-250569 AHCYL2 protein Q96HN2 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-268330 ADRB2 protein P07550 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-256952 PRKACA protein P17612 UNIPROT ARHGDIA protein P52565 UNIPROT down-regulates phosphorylation Ser174 KGMLARGsYSIKSRF 9606 18768928 t llicata "The results indicate that phosphorylation of gdi_ at ser174 by pka suppresses rhoa activity, providing a potential protective signaling mechanism for inflammatory injury." SIGNOR-180576 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Ser855 PKPKQFSsFEKRAKI 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-169404 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 22021368 f apalma "In normal hematopoiesis, AML1 suppresses NF-κB signaling and thus may contribute to inhibition of excessive proliferation of hematopoietic cells." SIGNOR-255692 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 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 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 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 "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 AKT proteinfamily SIGNOR-PF24 SIGNOR ARHGAP22 protein Q7Z5H3 UNIPROT "up-regulates activity" phosphorylation Ser16 ARRARSKsLVMGEQS 9606 BTO:0000007 21969604 t miannu "Akt phosphorylates RhoGAP22 at the 14-3-3 binding site and is required for insulin-stimulated 14-3-3 binding. we have demonstrated that Akt is the kinase responsible for phosphorylation of Ser16 in order to mediate 14-3-3 binding to RhoGAP22." SIGNOR-262613 TM4SF1 protein P30408 UNIPROT SDCBP2 protein Q9H190 UNIPROT "up-regulates activity" relocalization 33015133 t lperfetto "TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2." SIGNOR-272401 SMAD1/5/8/SMAD4 complex SIGNOR-C215 SIGNOR DLX5 protein P56178 UNIPROT up-regulates "transcriptional regulation" 10090 BTO:0000165 12815054 f ggiuliani "Over-expression of Smad1 or Smad5, mediators of BMP-signaling, also induced Dlx5 expression even in the absence of BMP-2 treatment concomitant with positive ALP staining" SIGNOR-255837 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 AURKA protein O14965 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 10090 12234980 t gcesareni "In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis." SIGNOR-265356 HDAC1 protein Q13547 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" deacetylation 10090 BTO:0000887 24463822 t "Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse." SIGNOR-256485 ZNF503 protein Q96F45 UNIPROT GATA3 protein P23771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 28258171 f Monia "Intriguingly, ZPO2/ZNF503 levels were higher in breast cancer samples with WT GATA3 than in those with mutated GATA3 (Fig. 1B). We found that Zpo2 down-regulated GATA3 levels, whereas shRNA-mediated Zpo2 knockdown enhanced GATA3 expression" SIGNOR-261189 SLC24A1 protein O60721 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-264400 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 testosterone smallmolecule CHEBI:17347 ChEBI SRD5A1 protein P18405 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-251532 ETS1 protein P14921 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-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-259869 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 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 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 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide chemical CHEBI:92223 ChEBI HDAC3 protein O15379 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-203476 PCDHA2 protein Q9Y5H9 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-265661 MAPK3 protein P27361 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation Ser715 YQSTIPQsPSPAPDD 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-77578 NR0B2 protein Q15466 UNIPROT HNF4A protein P41235 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 10594021 f gcesareni "Here we show that shp inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (hnf-4) and the retinoid x receptor (rxr) by at least two mechanisms shp also competes with coactivators for binding to ligand-activated rxr, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of shp-mediated repression." SIGNOR-73032 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 UFD1 protein Q92890 UNIPROT CD4 protein P01730 UNIPROT "down-regulates quantity by destabilization" 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." SIGNOR-252421 DNAJC11 protein Q9NVH1 UNIPROT Mitochondrial_biogenesis phenotype SIGNOR-PH32 SIGNOR up-regulates 10090 BTO:0000312 25111180 f "Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. T" SIGNOR-261147 ZSTK-474 chemical CHEBI:90545 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207935 MAPK3 protein P27361 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 t 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-58493 MAPK9 protein P45984 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 12151396 t gcesareni "Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro." SIGNOR-91071 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-141647 DIABLO protein Q9NR28 UNIPROT BIRC2 protein Q13490 UNIPROT "down-regulates quantity" binding 9606 BTO:0000567 14960576 t amattioni "Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells." SIGNOR-121883 "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 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT down-regulates dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000782 18840653 t gcesareni "Vegfr2 contains several critical tyrosine residues that are autophosphorylated following activation. Our phosphorylation assays showed that tcptp was able to target specific tyrosines in vegfr2. The autophosphorylation sites tyr1054/1059 and tyr1214 were dephosphorylated by tcptp. Tyr996 was a tcptp target as well." SIGNOR-181550 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR SALL4 protein Q9UJQ4 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-269252 EPAS1 protein Q99814 UNIPROT KDM2B protein Q8NHM5 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-271582 MAPK3 protein P27361 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-249463 GSK3B protein P49841 UNIPROT NR1D1 protein P20393 UNIPROT up-regulates phosphorylation Ser59 FPPSPTGsLTQDPAR 9606 16484495 t llicata "We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock." SIGNOR-144570 OXTR protein P30559 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-256936 MAPK14 protein Q16539 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 22975381 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-192057 DOT1L protein Q8TEK3 UNIPROT H3-3A protein P84243 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-267143 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 CNR1 protein P21554 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-257346 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 19130553 t gcesareni "Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna" SIGNOR-183158 NFIA protein Q12857 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 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-263982 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 CHEK1 protein O14757 UNIPROT TLK1 protein Q9UKI8 UNIPROT down-regulates phosphorylation Ser743 PHMRRSNsSGNLHMA 9606 12660173 t llicata "Chk1 phosphorylates tlk1 on serine 695 (s695) these findings identify an unprecedented functional co- operation between atm and chk1 in propagation of a checkpoint response during s phase and suggest that, through transient inhibition of tlk kinases, the atm_chk1_tlk pathway may regulate processes involved in chromatin assembly." SIGNOR-99653 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 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr231 NQDDVGVyTCLVVNG 9606 BTO:0000763 20861316 t lperfetto "Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-167989 RAB6A protein P20340 UNIPROT VPS13B protein Q7Z7G8 UNIPROT "up-regulates activity" binding 10116 BTO:0003102 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. We show that COH1 forms a physical and functional complex with RAB6. Our results point to a role of COH1 as a RAB6 effector protein. Depletion of COH1 leads to decreased neurite outgrowth in cultured primary hippocampal neurons. These results establish a critical role for RAB6-dependent function of COH1 in neuritogenesis by regulating Golgi complex organization." SIGNOR-266869 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244168 HIC1 protein Q14526 UNIPROT ACKR3 protein P25106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23340301 f miannu "we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression." SIGNOR-254238 MAML1 protein Q92585 UNIPROT CCNT1 protein O60563 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-130712 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 BTO:0000130 17217339 t lperfetto "Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.These results strongly support the observation that irak-4 is a kinase for p47phox in vivo. We also detected the signature of phosphorylation at ser320 and ser345" SIGNOR-152019 EZH2 protein Q15910 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 23239736 t miannu "This study demonstrates that phosphorylation of EZH2 at Ser21, mediated directly or indirectly by the PI3K-Akt pathway, can switch its function from a Polycomb repressor to a transcriptional coactivator of AR (and potentially other factors)." SIGNOR-251542 ERG protein P11308 UNIPROT CLDN5 protein O00501 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22235125 t Luana "ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene." SIGNOR-261596 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 EGFR protein P00533 UNIPROT ERRFI1 protein Q9UJM3 UNIPROT "up-regulates activity" phosphorylation Tyr394 KKVSSTHyYLLPERP 10090 BTO:0000944 phosphorylation:Tyr395 KVSSTHYyLLPERPP 26280531 t """here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.""" SIGNOR-252091 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 RAC1 protein P63000 UNIPROT PAK2 protein Q13177 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-248250 PRKCD protein Q05655 UNIPROT HDAC5 protein Q9UQL6 UNIPROT "down-regulates activity" phosphorylation Ser259 FPLRKTAsEPNLKVR 9606 18332134 t Manara "In this report, we show that VEGF stimulates PKD-dependent phosphorylation of HDAC5 at Ser259/498residues in ECs, which leads to HDAC5 nuclear exclusion and myocyte enhancer factor-2 (MEF2) transcriptional activation." SIGNOR-260875 SHC1 protein P29353 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR "up-regulates activity" 10090 BTO:0000944 17673906 f "inferred from 70% of family members" lperfetto "We report that upon TGF__ stimulation, the activated TGF__ type I receptor (T_RI) recruits and directly phosphorylates ShcA proteins on tyrosine and serine. This dual phosphorylation results from an intrinsic T_RI tyrosine kinase activity that complements its well_defined serine_threonine kinase function. TGF___induced ShcA phosphorylation induces ShcA association with Grb2 and Sos, thereby initiating the well_characterised pathway linking receptor tyrosine kinases with Erk MAP kinases." SIGNOR-269903 PRKACA protein P17612 UNIPROT SOX9 protein P48436 UNIPROT up-regulates phosphorylation Ser64 EPDLKKEsEEDKFPV 9606 15889150 t llicata "We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta." SIGNOR-137089 TAOK2 protein Q9UL54 UNIPROT MAP2K6 protein P52564 UNIPROT "up-regulates activity" binding 9606 10497253 t lperfetto "Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7." SIGNOR-70950 "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR CDKN2A protein P42771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22469984 t irozzo "The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a" SIGNOR-256122 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 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-271326 PRKAA1 protein Q13131 UNIPROT ZNF692 protein Q9BU19 UNIPROT down-regulates phosphorylation Ser470 VAAHRSKsHPALLLA 9606 SIGNOR-C15 17097062 t gcesareni "Arebp is phosphorylated at ser(470) by ampk. Phosphorylation reduces the dna-binding activity of arebp." SIGNOR-150590 estriol smallmolecule CHEBI:27974 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-258585 MRPL10 protein Q7Z7H8 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-262383 MAPKAPK2 protein P49137 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 20626350 t lperfetto "Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2." SIGNOR-166619 AURKB protein Q96GD4 UNIPROT VIM protein P08670 UNIPROT down-regulates phosphorylation Ser73 SAVRLRSsVPGVRLL 9606 12458200 t llicata "By identifying eight aurora-b phosphorylation sites on vimentin in vitro, we have demonstrated that vimentin-ser-72 is an in vitrophosphorylation site of aurora-b. in vitro analyses revealed that aurora-b phosphorylates vimentin at approximately 2 mol phosphate/mol of substrate for 30 min and that this phosphorylation dramatically inhibits vimentin filament formation." SIGNOR-96057 CCNA1 protein P78396 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 15829981 f lperfetto "Cyclin A1 contributes to G1 to S cell cycle progression in somatic cells. Cyclin A1 overexpression enhances S phase entry consistent with an oncogenic function. Finally, cyclin A1 might be a therapeutic target since its silencing inhibited leukemia cell growth." SIGNOR-249637 WNT11 protein O96014 UNIPROT FZD3 protein Q9NPG1 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-141428 MET protein P08581 UNIPROT GLMN protein Q92990 UNIPROT down-regulates relocalization 9606 11571281 t gcesareni "Significantly, nonphosphorylated hgf receptor prevents fap68 from stimulating p70s6k. fap68 binding to met requires the last 30 amino acids of the c-terminal tail, which are unique to the hgf receptor." SIGNOR-110726 YAP1 protein P46937 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-199214 NF90-NF45 complex SIGNOR-C443 SIGNOR CDKN1A protein P38936 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 BTO:0001221 25566957 t 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 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM3 protein Q14832 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-264075 PPARA protein Q07869 UNIPROT Fatty_acid_oxidation phenotype SIGNOR-PH129 SIGNOR up-regulates 9606 BTO:0001103;BTO:0000671 18836859 f miannu "PPAR-α is predominantly expressed in the liver and skeletal muscles, participating in fatty-acids catabolism. PPAR-α also activates fatty-acid oxidation in the kidney, skeletal muscles, and heart" SIGNOR-268027 GNGT1 protein P63211 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 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-145128 RXRB protein P28702 UNIPROT RARB protein P10826 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 1310351 f gcesareni "Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins" SIGNOR-16680 Corticotropin protein P01189-PRO_0000024969 UNIPROT MC5R protein P33032 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-268716 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 EML4-ALK "fusion protein" SIGNOR-FP8 SIGNOR HIF1A protein Q16665 UNIPROT "up-regulates quantity by stabilization" 9606 27141364 f irozzo "EML4-ALK enhanced HIF-1Œ± expression through increasing transcription and decreasing ubiquitination of HIF-1Œ±." SIGNOR-259173 MMP23B protein O75900 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-272367 EIF6 protein P56537 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "up-regulates quantity" binding 9606 10085284 t lperfetto "The beta4 integrin interactor p27(BBP/eIF6) is an essential nuclear matrix protein involved in 60S ribosomal subunit assembly." SIGNOR-269151 KDM2A protein Q9Y2K7 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-217415 MTHFR protein P42898 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 ChEBI "down-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-268228 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 Laminin-5 complex SIGNOR-C184 SIGNOR "A3/b1 integrin" complex SIGNOR-C161 SIGNOR "up-regulates activity" binding 2032285 t lperfetto "Epiligrin, a new cell adhesion ligand for integrin alpha 3 beta 1 in epithelial basement membranes." SIGNOR-253252 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 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 L-arginine chemical CHEBI:16467 ChEBI ARG1 protein P05089 UNIPROT up-regulates BTO:0000801 BTO:0001103 25386178 f apalma "In mammalian cells, arginine can be catabolized by four classes of enzymes (Figure ​(Figure1):1): NOS, arginase, arginine decarboxylase (ADC), and arginine:glycine amidinotransferase (AGAT)" SIGNOR-255555 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 MAP4K4 protein O95819 UNIPROT MAP3K7 protein O43318 UNIPROT up-regulates binding 9606 10807933 t gcesareni "The existence of an at least trimolecular complex consisting of nik, tak1, and ikk2, although the precise sequence of activation as well as the possible location of the kinases within the signalosome remains to be elucidated." SIGNOR-77404 Ub:E2 complex SIGNOR-C497 SIGNOR RFPL3 protein O75679 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-271148 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 SF3B6 protein Q9Y3B4 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-270675 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 P300/PCAF complex SIGNOR-C7 SIGNOR SMAD3 protein P84022 UNIPROT up-regulates binding 9606 BTO:0000150 15009097 t lperfetto "Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo." SIGNOR-217233 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 CSNK2A1 protein P68400 UNIPROT CDK1 protein P06493 UNIPROT up-regulates phosphorylation Ser39 MKKIRLEsEEEGVPS 9606 15788687 t lperfetto "Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment." SIGNOR-134846 PTPN2 protein P17706 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 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-75914 GP5 protein P40197 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-261849 ASAP2 protein O43150 UNIPROT ARF5 protein P84085 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-269707 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 AKT proteinfamily SIGNOR-PF24 SIGNOR BRAF protein P15056 UNIPROT down-regulates phosphorylation Thr440 EDRNRMKtLGRRDSS 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-244156 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 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 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 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 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 MAPK1 protein P28482 UNIPROT ARHGEF2 protein Q92974 UNIPROT up-regulates phosphorylation Thr679 PGVELLLtPREPALP 9606 BTO:0000671 19261619 t gcesareni "Importantly tnf-alpha enhanced the erk pathway-dependent phosphorylation of thr-678 of gef-h1 that was key for activation." SIGNOR-184469 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 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 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 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 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 "NuA4 complex" complex SIGNOR-C459 SIGNOR "Histone H2A" proteinfamily SIGNOR-PF70 SIGNOR "down-regulates activity" acetylation 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-269287 MYC protein P01106 UNIPROT HK2 protein P52789 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 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-259986 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 ARHGEF10 protein O15013 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-260537 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 ELANE protein P08246 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Val72 GLTEYRLvSINKSSP -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-263567 AGTR1 protein P30556 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 11313903 t gcesareni "These neuropeptide gpcrs are coupled to the activation of phospholipase c, and therefore to calcium ele- vation and protein kinase c (pkc) activation, through g proteins of the alfaq family." SIGNOR-106932 TNFRSF21 protein O75509 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni "Dr6 interacts with tradd" SIGNOR-100184 EGR1 protein P18146 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-253881 DYNLL2 protein Q96FJ2 UNIPROT AMBRA1 protein Q9C0C7 UNIPROT down-regulates binding 9606 20921139 t gcesareni "The beclin 1 vps34 complex is tethered to the cytoskeleton through an interaction between the beclin 1 interacting protein ambra1 and dynein light chains 1/2" SIGNOR-168289 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 prazosin chemical CHEBI:8364 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-258468 CNOT3 protein O75175 UNIPROT TNFRSF11A protein Q9Y6Q6 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0003292 24550297 t Luana "Our results reveal that CNOT3 is a critical regulator of bone mass acting on bone resorption through posttranscriptional down-regulation of RANK mRNA stability, at least in part, even in aging-induced osteoporosis." SIGNOR-261572 FIZ1 protein Q96SL8 UNIPROT NRL protein P54845 UNIPROT "up-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-223796 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 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 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 TP53RK protein Q96S44 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17712528 t gcesareni "The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15." SIGNOR-157471 PHLPP2 protein Q6ZVD8 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 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-248729 MAP2K4 protein P45985 UNIPROT MAPK8 protein P45983 UNIPROT "up-regulates activity" phosphorylation Tyr185 TSFMMTPyVVTRYYR -1 11062067 t "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. 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-251419 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 CBFbeta-MYH11 "fusion protein" SIGNOR-FP3 SIGNOR TP53 protein P04637 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 9834241 f miannu "CBFbeta-SMMHC, Expressed in M4eo Acute Myeloid Leukemia, Reduces p53 Induction and Slows Apoptosis in Hematopoietic Cells Exposed to DNA-damaging Agents Reduced p53 induction may be caused in part by direct inhibition of p53 gene transcription, because p53 mRNA levels were reduced by CBFβ-SMMHC. Attenuated p53 induction and slowed apoptosis may contribute to leukemogenesis by CBFβ-SMMHC." SIGNOR-256132 AKT proteinfamily SIGNOR-PF24 SIGNOR HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto "Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212" SIGNOR-153323 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 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 "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 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 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 DIO1 protein P49895 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-266954 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 EGR1 protein P18146 UNIPROT COL11A1 protein P12107 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-251919 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 MTMR1 protein Q13613 UNIPROT "1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-)" smallmolecule CHEBI:57923 ChEBI "down-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-269804 IFNW1 protein P05000 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni "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-105982 "RNA Polymerase III" complex SIGNOR-C389 SIGNOR tRNA(Asp) smallmolecule CHEBI:29186 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-269483 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 COX5B protein P10606 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-253102 ABL1 protein P00519 UNIPROT PSMA7 protein O14818 UNIPROT down-regulates phosphorylation Tyr153 QTDPSGTyHAWKANA 9606 16678104 t lperfetto "Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised" SIGNOR-146585 FZD1 protein Q9UP38 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-258953 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 IKK-complex complex SIGNOR-C14 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser644 GLDFNFDsLISTQNV 9606 BTO:0000150 15084260 t lperfetto "Ikappab kinase promotes tumorigenesis through inhibition of forkhead foxo3a. The tnf treatment of ht-29 cells increased ikk-dependent foxo3 ser644 phosphorylation." SIGNOR-252950 GRK6 protein P43250 UNIPROT SLC9A3R1 protein O14745 UNIPROT "down-regulates activity" phosphorylation Ser290 PALVRSAsSDTSEEL 9606 10446210 t "GRK6A phosphorylates NHERF on Ser289, the primary site of constitutive phosphorylation of NHERF in HEK-293 cells. The interaction of NHERF and NHE3 is mediated by the region of NHERF encompassing the second PDZ domain and the tail (25), and it is therefore reasonable that phosphorylation of the serine-rich stretch in the center of this region (including Ser289) might affect the physical interaction of NHERF with NHE3." SIGNOR-251214 PLK3 protein Q9H4B4 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser370 TSVTPDVsDNEPDHY 9606 20940307 t gcesareni "Plk3 phosphorylates pten on thr-366 and ser-370. Plk3-mediated phosphorylation facilitates pten stabilization, thereby negatively regulating the pi3k/pdk1/akt1 signaling axis" SIGNOR-168469 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 CASP3 protein P42574 UNIPROT GORASP1 protein Q9BQQ3 UNIPROT "down-regulates quantity by destabilization" cleavage Asp317 VSGISLLdNSNASVW 9606 BTO:0000567 11815631 t Giulio "Together, our results strongly suggest GRASP65 is a specific substrate for caspase-3.|This suggests that GRASP65 cleavage is required for fragmentation of the Golgi ribbon during apoptosis.| we analyzed the sequence in this region and identified three potential cleavage sites as SLLD320S, SFPD375S, and TLPD393G|mutation of all three aspartic acid residues completely blocked cleavage" SIGNOR-260602 "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 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 "WRC complex" complex SIGNOR-C191 SIGNOR F-actin_assembly phenotype SIGNOR-PH18 SIGNOR up-regulates 9606 20332100 f miannu "The activated WAVE complex at the leading edge of lamellipodia promotes actin polymerization at the plasma membrane by activating the Arp2/3 complex." SIGNOR-253578 PTEN protein P60484 UNIPROT NDRG1 protein Q92597 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-260054 EPHB2 protein P29323 UNIPROT NRCAM protein Q92823 UNIPROT "up-regulates activity" phosphorylation Tyr1276 DGSFIGQySGKKEKE 9606 BTO:0000007 24023801 t miannu "EphB receptors were found to induce phosphorylation of NrCAM on the tyrosine residue within the FIGQY ankyrin binding motif, inhibiting ankyrin recruitment. Furthermore, NrCAM phospho-FIGQY levels in the SC were decreased in EphB1/3 and EphB1/2/3 null mice and increased in mutant mice overexpressing constitutively active EphB2 kinase. " SIGNOR-262863 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 ZNF217 protein O75362 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-222118 CD70 protein P32970 UNIPROT CD27 protein P26842 UNIPROT up-regulates binding 9606 BTO:0001103;BTO:0000142;BTO:0000562;BTO:0000672 8120384 t gcesareni "The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. 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." SIGNOR-36357 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 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 Degranulation phenotype SIGNOR-PH92 SIGNOR IL5 protein P05113 UNIPROT "up-regulates quantity" 9606 BTO:0000830 17259966 f apalma "The array of mediators released by human mast cells is enormous and explains how mast cells can be involved in so many different physiological and pathophysiological functions. Of particular relevance [...] cytokines, such as IL-3 -basophil recruitment and activation-, IL-5 -eosinophil recruitment and activation- and IL-13 -induction of IgE synthesis by B cells." SIGNOR-255346 LIMS4 protein P0CW20 UNIPROT "IPP complex" complex SIGNOR-C380 SIGNOR "form complex" binding 16493410 t lperfetto "Integrin-linked kinase (ILK), PINCH and parvin form a ternary complex (the IPP complex) that binds to ECM-ligated integrins. This complex regulates signalling pathways and connects the ECM with the actin cytoskeleton." SIGNOR-265766 SOX2 protein P48431 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-242002 F2RL1 protein P55085 UNIPROT TSPAN15 protein O95858 UNIPROT "down-regulates quantity by repression" "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-254862 PARD6A protein Q9NPB6 UNIPROT PRKCA protein P17252 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 22544755 t lperfetto "The Par complex member Par-6, previously thought to inhibit aPKC, is a potent activator of aPKC in our assays. Par-6 and aPKC interact via PB1 domain heterodimerization, and this interaction activates aPKC by displacing the pseudosubstrate, although full activity requires the Par-6 CRIB-PDZ domains." SIGNOR-227489 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 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 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT up-regulates phosphorylation Tyr1166 DIYETDYyRKGGKGL 9606 8940173 t lperfetto "Src phosphorylates the insulin-like growth factor type i receptor on the autophosphorylation sites. Requirement for transformation by srcsrc kinase can substitute for the receptor kinase in phosphorylating and activating the igf-i receptor" SIGNOR-45130 DYRK2 protein Q92630 UNIPROT CARHSP1 protein Q9Y2V2 UNIPROT unknown phosphorylation Ser41 LRGNVVPsPLPTRRT 9606 21177848 t gcesareni "Ser41 is known to be phosphorylated by a dyrk isoform in serum-fed or -starved cells (21). A phosphomimetic mutation of ser41 to asp resulted in complete loss of human crhsp-24 binding ability whether in the oxidative state or not" SIGNOR-170781 SIN3A protein Q96ST3 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-267737 "Vps34 Complex I" complex SIGNOR-C242 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-260325 TCF4 protein P15884 UNIPROT CNTNAP2 protein Q9UHC6 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22777675 f miannu "we show that TCF4 can transactivate the NRXN1β and CNTNAP2 promoters in luciferase assays." SIGNOR-255390 UBA52 protein P62987 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-262459 "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 MMP13 protein P45452 UNIPROT FGB protein P02675 UNIPROT "down-regulates quantity by destabilization" cleavage Arg124 LQQERPIrNSVDELN -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-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain" SIGNOR-263615 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 ANGPT1 protein Q15389 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 9204896 t gcesareni "Angiopoietin-1 (ang1) is an angiogenic factor that signals through the endothelial cell-specific tie2 receptor tyrosine kinase." SIGNOR-49355 fulvestrant chemical CHEBI:31638 ChEBI ESR1 protein P03372 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000150 12113237 t miannu "Fulvestrant (Faslodex, formerly ICI 182,780) is a potent steroidal antiestrogen that mediates its effects by estrogen receptor downregulation." SIGNOR-259305 CCL2 protein P13500 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32446778 f Luana "In this scenario,the release by immune effector cells of large amounts of pro-in-flammatory cytokines (IFNŒ±, IFNŒ≥, IL-1Œ≤, IL-6, IL-12, IL-18, IL-33,TNFŒ±, TGFŒ≤) and chemokines (CXCL10, CXCL8, CXCL9, CCL2, CCL3,CCL5) precipitates and sustains the aberrant systemic inflammatory response." SIGNOR-261317 TBX2 protein Q13207 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 24470334 f "TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells" SIGNOR-251562 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI CSF1R protein P07333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-199527 PRKACB protein P22694 UNIPROT MYBPC3 protein Q14896 UNIPROT up-regulates phosphorylation Ser311 SFRTPRDsKLEAPAE 9606 20151718 t miannu "Phosphorylation of cmybp-c by pka speeds actomyosin interactions and contributes to increased cardiac contractility following _-adrenergic stimulation./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-163780 TTI1 protein O43156 UNIPROT mTORC2 complex SIGNOR-C2 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-272004 "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 PRKCZ protein Q05513 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser558 VPTYESAsIRRFQEG 9606 BTO:0000938 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-129336 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 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 CDH2 protein P19022 UNIPROT CDON protein Q4KMG0 UNIPROT up-regulates binding 9606 SIGNOR-C21 20160094 t gcesareni "We report here that n-cadherin ligation activates p38alpha/beta in myoblasts in a cdo-, bnip-2-, and jlp-dependent manner" SIGNOR-163844 KIT protein P10721 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000830 15526160 t miannu "Activation of PI3-kinase by c-Kit has been linked to mitogenesis, differentiation, survival, adhesion, secretion and actin cytoskeletal reorganization. In c-Kit, Y721 has been found to directly interact with PI3-kinase" SIGNOR-254949 ATM protein Q13315 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0000887 18534819 f lperfetto "The decreased atm expression suggests that atm is involved in the development of insulin resistance through down-regulation of akt activity." SIGNOR-244392 HECW2 protein Q9P2P5 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 BTO:0000093 27119228 t miannu "NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains" SIGNOR-269458 HOXB8 protein P17481 UNIPROT ACTA2 protein P62736 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-261641 PTPN2 protein P17706 UNIPROT GHR protein P10912 UNIPROT "down-regulates activity" dephosphorylation Tyr566 SLNQEDIyITTESLT 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-248394 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 Ub:E2 complex SIGNOR-C497 SIGNOR NEURL1 protein O76050 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-271043 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT up-regulates 9606 BTO:0000887;BTO:0001103 12782654 f lperfetto "It was shown recently that akt activates mtor through direct phosphorylation of tsc2 the serine/threonine kinase akt is an upstream positive regulator of the mammalian target of rapamycin (mtor). However, the mechanism by which akt activates mtor is not fully understood. The known pathway by which akt activates mtor is via direct phosphorylation and tuberous sclerosis complex 2 (tsc2), which is a negative regulator of mtor." SIGNOR-244314 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 MMP7 protein P09237 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-256351 SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11689553 f irozzo "To identify this pathway, we analyzed TGF-β-responsive elements in the human c-myc promoter and found that Smad proteins directly bound to an element in the c-myc promoter and suppressed c-myc promoter activity." SIGNOR-256291 Tocilizumab antibody DB06273 DRUGBANK IL6R protein P08887 UNIPROT "down-regulates activity" binding 9606 32446778 t "doi: 10.1016/j.cytogfr.2020.05.003" miannu "Tocilizumab is a humanized anti-IL-6 receptor IgG1 monoclonal antibody used for the treatment of rheumatoid arthritis and other chronic inflammatory diseases [14]. By blocking the IL-6-receptor interaction, Tocilizumab inhibits the IL-6-mediated signal transduction. Although clinical data on the use of Tocilizumab in COVID-19 patients derive from small series, some authors recommend its use in critically ill COVID-19 patients with significantly elevated IL-6 levels." SIGNOR-260857 CSNK2A1 protein P68400 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Thr16 DVSVSVEtQGDDWDT 9606 10806407 t llicata "The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2." SIGNOR-250885 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 NUP155 protein O75694 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-262082 MAP3K10 protein Q02779 UNIPROT TCF3 protein P15923 UNIPROT down-regulates phosphorylation Thr355 NFSSSPStPVGSPQG 9606 19801649 t llicata "Mlk2 inhibits e47 transactivation activity on the trkb promote" SIGNOR-161544 ANXA1 protein P04083 UNIPROT FPR1 protein P21462 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-259439 CLASP2 protein O75122 UNIPROT MAPRE1 protein Q15691 UNIPROT "up-regulates activity" binding 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-264829 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 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1336 RFMDGSPyAHMFEMS 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-251173 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 PRKCA protein P17252 UNIPROT PLD1 protein Q13393 UNIPROT up-regulates phosphorylation Ser2 sLKNEPRV 9606 10441128 t gcesareni "Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells." SIGNOR-69930 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 propranolol chemical CHEBI:8499 ChEBI ADRB2 protein P07550 UNIPROT "down-regulates activity" "chemical inhibition" 10030 10079020 t Luana "Similarly, the binding affinities of ICI 118–551, CGP 20712A, propranolol, bupranolol and CGP 12177 for human β1-, β2- and β3-adrenoceptors correlate with their affinities at human β1- (P=0.04), β2- (P=0.01)" SIGNOR-258334 Ub:E2 complex SIGNOR-C497 SIGNOR MKRN3 protein Q13064 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-271132 TLR5 protein O60602 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24709011 f miannu "These studies demonstrate a novel function of Toll-like receptor-5 (TLR5) in a human multiple myeloma (MM) cell line, KMS28BM. These cells express high levels of both TLR5 mRNA and protein. When cells were treated with the specific TLR5 ligand flagellin, proliferation was increased, and the secretion of IgG λ antibody and the expression of the pro-inflammatory cytokine IL-6 were increased via NF-κB activation through PI3K/AKT and p38 signaling." SIGNOR-259868 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 STAT1 protein P42224 UNIPROT TLR3 protein O15455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-255230 RPLP0 protein P05388 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-262451 FLT3 protein P36888 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14592841 f "This data confirms that PU.1 is a downstream target of activated C/EBPα and is suppressed in FLT3/ITD-expressing cells as a result of C/EBPα suppression." SIGNOR-261530 TTK protein P33981 UNIPROT HSPA9 protein P38646 UNIPROT up-regulates phosphorylation Ser65 IDLGTTNsCVAVMEG 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-156181 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 PLK1 protein P53350 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-125666 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 PTK6 protein Q13882 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-166506 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000552 9736735 t lperfetto "Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins|These data suggest that the human p19(SKP1)/p45(SKP2)/CUL-1 complex is likely to function as an E3 ligase to selectively target cyclin D and p21 for the ubiquitin-dependent protein degradation." SIGNOR-267556 Ub:E2 complex SIGNOR-C497 SIGNOR PDZRN4 protein Q6ZMN7 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-271036 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 IFNGR1 protein P15260 UNIPROT JAK2 protein O60674 UNIPROT up-regulates binding 9606 17063185 t flangone "Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively" SIGNOR-150197 DLGAP5 protein Q15398 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-264213 GFs stimulus SIGNOR-ST12 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR up-regulates 9606 23863153 f lperfetto "Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease." SIGNOR-219382 PTPRJ protein Q12913 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-76100 CCNK protein O75909 UNIPROT CyclinK/CDK12 complex SIGNOR-C37 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-176783 CAMK2D protein Q13557 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Thr594 LHGKKNStVDCNGVV 9606 22514276 t miannu "A stable interaction between ?(C)-camkii and the intracellular loop between domains 1 and 2 of na(v)1.5 was observed. This region was also phosphorylated by ?(C)-camkii, specifically at the ser-516 and thr-594 sites.Wild-type (wt) and phosphomutant hna(v)1.5 were co-expressed with gfp-?(C)-camkii in hek293 cells, and i(na) was recorded. As observed in myocytes, camkii shifted wt i(na) availability to a more negative membrane potential and enhanced accumulation of i(na) into an intermediate inactivated state, but these effects were abolished by mutating either of these sites to non-phosphorylatable ala residues." SIGNOR-197067 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 paliperidone chemical CHEBI:82978 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-258562 PEBP1 protein P30086 UNIPROT RAF1 protein P04049 UNIPROT down-regulates binding 9606 10490027 t gcesareni "Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras." SIGNOR-70838 PPP2CA protein P67775 UNIPROT MAPK1 protein P28482 UNIPROT down-regulates dephosphorylation Thr185 HDHTGFLtEYVATRW 9606 phosphorylation:Thr185 HDHTGFLtEYVATRW 16456541 t gcesareni "B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk" SIGNOR-143052 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 PAX7 protein P23759 UNIPROT KMT2D protein O14686 UNIPROT up-regulates binding 9606 SIGNOR-C88 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-198629 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 ATP13A1 protein Q9HD20 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0004093 29650961 f doi.org/10.1101/185272 francesca "Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions" SIGNOR-261216 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 CHUK protein O15111 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser432 KMPNTNGsIGHSPLS 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-204696 CYTH2 protein Q99418 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0003102 14565977 f miannu "ARNO and ARF6 regulate axonal elongation and branching through downstream activation of phosphatidylinositol 4-phosphate 5-kinase alpha" SIGNOR-264909 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 LYN protein P07948 UNIPROT PPP1R8 protein Q12972 UNIPROT "down-regulates activity" phosphorylation Tyr335 NEPKKKKyAKEAWPG -1 11104670 t "Lyn phosphorylates both Tyr-264 and Tyr-335, but that the phosphorylation of Tyr-335 is dependent on the association of NIPP1 with RNA. The inhibitory potency of the C-terminal site of NIPP1 was decreased by phosphorylation of Tyr-335 and by the addition of RNA." SIGNOR-251406 PLG protein P00747 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Arg70 ESGLTEYrLVSINKS -1 10978167 t lperfetto "Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site." SIGNOR-263572 CTDSPL2 protein Q05D32 UNIPROT HBG2 protein P69892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664 20932329 f "Indirect: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-251777 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 PRKCA protein P17252 UNIPROT ITPKB protein P27987 UNIPROT "down-regulates activity" -1 9374536 t lperfetto "However, when assayed in the presence of calcium/calmodulin, the activity of the B isoform was decreased following phosphorylation by either protein kinase." SIGNOR-248990 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 ADRB1 protein P08588 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-256901 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 glycogen smallmolecule CHEBI:28087 ChEBI PYGB protein P11216 UNIPROT "up-regulates activity" "chemical activation" 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 […] 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-267951 SOSTDC1 protein Q6X4U4 UNIPROT WNT10A protein Q9GZT5 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-242695 CSNK2A1 protein P68400 UNIPROT AKT1 protein P31749 UNIPROT up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni "CK2 hyperactivates AKT by phosphorylation at Ser129" SIGNOR-252595 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 PRKCA protein P17252 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-249004 85375-15-1 chemical CID:6917797 PUBCHEM SLC6A13 protein Q9NSD5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207066 FN1 protein P02751 UNIPROT "Av/b6 integrin" complex SIGNOR-C179 SIGNOR up-regulates binding 9606 1532572 t gcesareni "Integrin alpha v beta 6 binds to fibronectin, but not to vitronectin or collagen i. cell adhesion assays show that fg-2 cell attachment to fibronectin is only partially inhibited by anti-beta 1 integrin antibodies, implying that other fibronectin receptors may be involved." SIGNOR-19793 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 BRD4 protein O60885 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr58 KKFELLPtPPLSPSR 9606 32482868 t lperfetto "We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes." SIGNOR-262046 STK39 protein Q9UEW8 UNIPROT SLC4A4 protein Q9Y6R1 UNIPROT "down-regulates activity" phosphorylation 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-264644 ERG protein P11308 UNIPROT PIM proteinfamily SIGNOR-PF34 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002398 22140532 t 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-259408 "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 SNAI1 protein O95863 UNIPROT SNAIL/RELA/PARP1 complex SIGNOR-C198 SIGNOR "form complex" binding 9606 BTO:0000452;BTO:0002625 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-254526 WNT10B protein O00744 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 9606 21872687 f fspada "We show that knockdown of Beta-catenin completely prevents the inhibition of adipogenesis and stimulation of osteoblast differentiation by wnt6, wnt10a or wnt10b" SIGNOR-176190 MAP2K7 protein O14733 UNIPROT MAPK10 protein P53779 UNIPROT up-regulates phosphorylation 9606 11062067 t "Phosphorylation of a threonine and a tyrosine residue in a Thr-Pro-Tyr motif" gcesareni "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)these results indicate that hgk, a novel activator of the jnk pathway, may function through tak1, and that the hgk --> tak1 --> mkk4, mkk7 --> jnk kinase cascade may mediate the TNF-alphalpha signaling pathway." SIGNOR-83732 RALGAPA1 protein Q6GYQ0 UNIPROT RalGAP1 complex SIGNOR-C468 SIGNOR "form complex" binding 10090 BTO:0000011 21148297 t miannu "Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA." SIGNOR-269791 "NSL histone acetyltransferase" complex SIGNOR-C413 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys6 kGGKGLGK 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-267167 DMC1 protein Q14565 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "up-regulates activity" binding 10090 BTO:0001275 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-264208 NR2F2 protein P24468 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-79446 CHEK2 protein O96017 UNIPROT AATF protein Q9NY61 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser510 KKVDRKAsKGRKLRF 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-264418 EGFR protein P00533 UNIPROT STAT5A protein P42229 UNIPROT up-regulates binding 9606 BTO:0000017 10358079 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-68159 SHMT2 protein P34897 UNIPROT (6R)-5,10-methylenetetrahydrofolate(2-) smallmolecule CHEBI:15636 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-268227 CSNK2A1 protein P68400 UNIPROT DDIT3 protein P35638 UNIPROT "down-regulates activity" phosphorylation Ser30 EDLQEVLsSDENGGT 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-250852 CSNK2A1 protein P68400 UNIPROT RRN3 protein Q9NYV6 UNIPROT down-regulates phosphorylation Ser172 GDVDVSDsDDEDDNL 9606 18559419 t llicata "Here we show that ck2 phosphorylates the transcription initiation factor tif-ia at serines 170 and 172 (ser170/172), and this phosphorylation triggers the release of tif-ia from pol i after transcription initiation." SIGNOR-178943 CDK5 protein Q00535 UNIPROT STMN3 protein Q9NZ72 UNIPROT unknown phosphorylation Ser73 PESPMLSsPPKKKDT -1 22577147 t lperfetto "Altogether, these results indicate that CDK5 phosphorylates similarly serines 68 and 73, whereas ERK2 targets mostly serine 68 and GSK-3beta mostly serine 60.|This observation may support the hypothesis of a specific localization of stathmin 3 depending on its phosphorylation by GSK-3beta" SIGNOR-264894 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 GCG protein P01275 UNIPROT GLP1R protein P43220 UNIPROT up-regulates binding 9606 BTO:0000776 7937318 t gcesareni "In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin" SIGNOR-34855 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 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 EGR3 protein Q06889 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-253882 PELI1 protein Q96FA3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates quantity by expression" ubiquitination 9606 17997719 t lperfetto "These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells." SIGNOR-159055 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR TAL1 protein P17542 UNIPROT down-regulates phosphorylation Ser122 DGRMVQLsPPALAAP 9606 11904294 t lperfetto "We found that hypoxia greatly accelerated tal1 turnover in these cells through mitogen-activated protein kinase (mapk)2-mediated phosphorylation, ubiquitination, and proteasomal degradation." SIGNOR-244975 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 GSK3B protein P49841 UNIPROT MAFA protein Q8NHW3 UNIPROT "down-regulates quantity by destabilization" 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-159458 (R)-carnitine smallmolecule CHEBI:16347 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-267119 PTGER3 protein P43115 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-257111 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 MTOR protein P42345 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser639 YMPMSPKsVSAPQQI 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-106590 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 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 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 CAMK1 protein Q14012 UNIPROT PPME1 protein Q9Y570 UNIPROT "down-regulates activity" phosphorylation Ser15 MHLGRLPsRPPLPGS 9606 BTO:0000007 24841198 t lperfetto "CaMKI Is the Upstream Kinase for Phosphorylation of PME-1/Ser15|Our results also demonstrated that the phosphorylated levels of PME-1/Ser15 and CaMKI/Thr177 are inversely correlated with the phosphatase activity of SIK2·PP2A complex, further implying that the demethylase activity of phosphorylated PME-1/Ser15 may be higher than that of its unphosphorylated state." SIGNOR-265747 OMG protein P23515 UNIPROT LINGO1 protein Q96FE5 UNIPROT up-regulates binding 9606 BTO:0000938 15694321 t flangone "Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1..." SIGNOR-133640 KIF5C protein O60282 UNIPROT TRAK2 protein O60296 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 24161670 t miannu "Trafficking kinesin proteins (TRAKs) are kinesin adaptors. They bind the cargo binding domain of kinesin-1 motor proteins forming a link between the motor and their cargoes. This supports the idea that the KIF5A–TRAK2 interaction is multivalent and could act to ensure stable motor-cargo interaction during intracellular trafficking; dimerization of both motor and adaptor molecules further enhances this stability (Fig. 6). A similar multivalent profile was found for the TRAK2 binding site within the kinesin-1 isoform, KIF5C." SIGNOR-264064 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 GOLGB1 protein Q14789 UNIPROT GOLGA2 protein Q08379 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-261238 FURIN protein P09958 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates binding 9606 22479394 t "Cleavage in Golgi" gcesareni "The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling." SIGNOR-196914 SPRY2 protein O43597 UNIPROT PTPN1 protein P18031 UNIPROT up-regulates 9606 12414790 f gcesareni "Therefore, we conclude that an increase in soluble ptp1b activity contributes to the anti-migratory, but not anti-mitogenic, actions of hspry2." SIGNOR-95313 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 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 IRAK3 protein Q9Y616 UNIPROT IRAK4 protein Q9NWZ3 UNIPROT down-regulates binding 9606 25290089 t flangone "Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation" SIGNOR-205434 MTOR protein P42345 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 BTO:0000527 16740698 t miannu "Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor" SIGNOR-146915 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 CAMK2B protein Q13554 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Thr472 ICALRHLtSRHQEAE 9606 BTO:0000938 24117889 t lperfetto "Camkii represses transcriptionally active _-catenin to mediate acute ethanol neurodegeneration and can phosphorylate _-catenincamkii can directly phosphorylate _-catenin. Using targeted mutagenesis we identified camkii phosphorylation sites within human _-catenin at t332, t472, and s552." SIGNOR-202833 RBBP4 protein Q09028 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-241906 8-hydroxy-5-[1-hydroxy-2-(propan-2-ylamino)butyl]-1H-quinolin-2-one chemical CHEBI:91585 ChEBI ADRB2 protein P07550 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-257857 CASP6 protein P55212 UNIPROT LMNA protein P02545 UNIPROT down-regulates cleavage 9606 11058599 t amattioni "Lamin a breakdown is largely mediated by caspase-6 during the execution phase of apoptosis." SIGNOR-83611 MAPK3 protein P27361 UNIPROT HDAC6 protein Q9UBN7 UNIPROT up-regulates phosphorylation Ser1035 DHQTPPTsPVQGTTP 9606 24089523 t lperfetto "Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1" SIGNOR-202698 G8RGG88B68 smallmolecule SID:135317436 ChEBI IFNAR2 protein P48551 UNIPROT "up-regulates activity" "chemical activation" -1 15898717 t miannu "To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a)." SIGNOR-259391 miR-29b mirna URS0000150A7D_9606 RNAcentral TET2 protein Q6N021 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 18568019 t miannu "In leukaemic cell lines PLZF overexpression downmodulated miR-146a and upregulated CXCR4 protein, whereas PLZF knockdown induced the opposite effects. Our data indicate that megakaryopoiesis is controlled by a cascade pathway, in which PLZF suppresses miR-146a transcription and thereby activates CXCR4 translation." SIGNOR-256310 MTNR1A protein P48039 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-256706 RAF1 protein P04049 UNIPROT BAD protein Q92934 UNIPROT down-regulates phosphorylation Ser118 GRELRRMsDEFVDSF 9606 17535812 t lperfetto "The activation of several major anti-apoptotic signaling pathways correlates with an increase in the phosphorylation of bad on ser-112, ser-136, and ser-155. These phosphorylation events result in bad inactivation through sequestration by 14-3-3 proteins" SIGNOR-155293 EIF5 protein P55010 UNIPROT EIF5B protein O60841 UNIPROT "up-regulates activity" relocalization 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-269122 "tacrolimus (anhydrous)" chemical CHEBI:61049 ChEBI PPP3CC protein P48454 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127245 MAPK7 protein Q13164 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates phosphorylation Ser387 LSLPSTQsLNIKSEP 9606 9384584 t lperfetto "Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor." SIGNOR-53545 PGS1 protein Q32NB8 UNIPROT "1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-)" smallmolecule CHEBI:60110 ChEBI up-regulates "chemical modification" 9606 29034233 t lperfetto "After activation of PA by the CDP-DAG synthase TAMM41 (Kutik et al., 2008), the phosphatidylglycerol phosphate synthase (PGS1) catalyzes the committed step by converting CDP-DAG to phosphatidylglycerol phosphate (PGP)" SIGNOR-267023 ING1 protein Q9UK53 UNIPROT SIRT2 protein Q8IXJ6 UNIPROT "down-regulates activity" binding 9606 14522900 t miannu "We found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382)." SIGNOR-254486 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 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR tRNA(Met) smallmolecule CHEBI:29173 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-270395 CAMK2D protein Q13557 UNIPROT HDAC4 protein P56524 UNIPROT up-regulates phosphorylation Ser210 YGKTQHSsLDQSSPP 9606 17179159 t lperfetto "These results demonstrate that camkiideltab preferentially targets hdac4, and this involves serine 210overexpression of camkiideltab in primary neonatal cardiomyocytes increases the activity of the mef2 transcription factor and completely rescues hdac4-mediated repression of mef2" SIGNOR-151418 HTR1B protein P28222 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-257115 AREL1 protein O15033 UNIPROT MTX2 protein O75431 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 34584540 t lperfetto "Therefore, these results implied that AREL1 ubiquitinates and promotes the degradation of MTX2." SIGNOR-267674 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 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 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 "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 FGFR2 protein P21802 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-258080 antigen smallmolecule CHEBI:59132 ChEBI BCR-Dk complex SIGNOR-C435 SIGNOR "up-regulates activity" binding 9606 BTO:0000776 32323266 t scontino "The recognition of antigen by the BCR initiates BCR signaling cascade." SIGNOR-268204 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr846 DGGGSDRyGSLRPGW 9606 BTO:0000763 20861316 t lperfetto "Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-168001 PPP2CA protein P67775 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248616 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-192260 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 "NMDA receptor_2C" complex SIGNOR-C349 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-264220 MMP19 protein Q99542 UNIPROT ACAN protein P16112 UNIPROT "down-regulates quantity by destabilization" cleavage -1 10922468 t lperfetto "Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|It has been suggested that MMPs play a role in the hydrolysis of COMP and, therefore, compromise the integrity of the cartilage ECM structure leading to the ultimate loss of joint function" SIGNOR-266980 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 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 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 MAPK3 protein P27361 UNIPROT GAB2 protein Q9UQC2 UNIPROT up-regulates phosphorylation Ser623 ALDFQPSsPSPHRKP 9606 15356145 t lperfetto "Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623." SIGNOR-128731 TNF protein P01375 UNIPROT LPL protein P06858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 3063839 f "Regulation of expression" miannu "Cytokines, notably TNF and IL-1, suppress synthesis of lipoprotein lipase which decreases the rate of TGFA clearance." SIGNOR-251853 "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 TP53INP1 protein Q96A56 UNIPROT GABARAPL2 protein P60520 UNIPROT up-regulates binding 9606 22421968 t gcesareni "In this work, we show that tp53inp1 is also able to interact with atg8-family proteins and to induce autophagy-dependent cell death. mammalian cells contain multiple atg8 orthologs belonging to three subfamilies: microtubule-associated protein 1 light chain 3, -aminobutyric acid receptor-associated protein (gabarap) and -aminobutyric acid receptor-associated protein like 2 (gabarapl2)." SIGNOR-196667 WWTR1 protein Q9GZV5 UNIPROT BAX protein Q07812 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001615 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-255606 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252833 HIF1A protein Q16665 UNIPROT STC2 protein O76061 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18394600 t Giorgia "With the ChIP assay, we demonstrated the direct binding of HIF-1alpha to STC2 promoter. These findings support the notion that HIF-1 is a potent stimulator of STC2 expression. Collectively, this is the first report to show that STC2 was aberrantly hypermethylated in human cancer cells. The findings demonstrated that STC2 epigenetic inactivation may interfere with HIF-1 mediated activation of STC2 expression." SIGNOR-260389 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 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser170 SFKLSGFsFKKNKKE -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-249670 TRIM5 protein Q9C035 UNIPROT TRIM5 protein Q9C035 UNIPROT "up-regulates quantity" monoubiquitination 9606 BTO:0000567 18312418 t miannu "Here, we show that TRIM5alpha functions as a RING-finger-type E3 ubiquitin ligase both in vitro and in vivo and ubiquitinates itself in cooperation with the E2 ubiquitin-conjugating enzyme UbcH5B. Thus, the ubiquitination of TRIM5alpha is catalyzed by itself and Ro52. Unexpectedly, although TRIM5alpha is ubiquitinated, our results have revealed that the proteasome inhibitors MG115 and MG132 do not stabilize it in HeLa cells, suggesting that the ubiquitination of TRIM5alpha does not lead to proteasomal degradation. Importantly, TRIM5alpha is clearly conjugated by a single ubiquitin molecule (monoubiquitination). Our monoubiquitin-fusion assay suggests that monoubiquitination is a signal for TRIM5alpha to translocate from cytoplasmic bodies to the cytoplasm." SIGNOR-271671 MIF protein P14174 UNIPROT CD74 protein P04233 UNIPROT up-regulates binding 9606 12782713 t miannu "Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production." SIGNOR-101526 SRC protein P12931 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr246 LCFSPNRyWLCAATG 9606 12400005 t gcesareni "We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246" SIGNOR-94800 ABL1 protein P00519 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr556 LNGQPIQyARSTCEA 9606 BTO:0000763 20861316 t lperfetto "Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity" SIGNOR-167997 Ub:E2 complex SIGNOR-C497 SIGNOR TRAIP protein Q9BWF2 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-270982 ABL1 protein P00519 UNIPROT LGALS3 protein P17931 UNIPROT unknown phosphorylation Tyr79 GAPAPGVyPGPPSGP 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-166501 ATM protein Q13315 UNIPROT BUB1 protein O43683 UNIPROT up-regulates phosphorylation Ser314 SHEDLPAsQERSEVN 9606 22099307 t lperfetto "We also demonstrate that mitotically activated atm phosphorylates bub1, a critical kinetochore protein, on ser314. Atm-mediated bub1 ser314 phosphorylation is required for bub1 activity and is essential for the activation of the spindle checkpoint" SIGNOR-177276 CSNK2A1 protein P68400 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation Ser129 SGSPSDNsGAEEMEV 9606 BTO:0000007 21735093 t gcesareni "CK2 hyperactivates AKT by phosphorylation at Ser129" SIGNOR-174691 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 ASTN1 protein O14525 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-269815 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 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 SRGAP3 protein O43295 UNIPROT RAC2 protein P15153 UNIPROT down-regulates 9606 12447388 f miannu "Wrp binds directly to wave-1 through its src homology domain 3 and specifically inhibits rac function in vivo." SIGNOR-95921 MAPK3 protein P27361 UNIPROT SREBF1 protein P36956 UNIPROT "up-regulates activity" phosphorylation Ser117 YPSMPAFsPGPGIKE 9606 BTO:0000599 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-80096 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 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 CSNK2B protein P67870 UNIPROT USO1 protein O60763 UNIPROT "up-regulates activity" phosphorylation Ser942 EEEDELEsGDQEDED -1 10931861 t llicata "Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae" SIGNOR-251082 Nalorphine chemical CHEBI:7458 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-258815 PRKAA1 protein Q13131 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates activity" phosphorylation Thr178 NHNHRIRtNPAIVKT 9606 BTO:0000887;BTO:0001103 SIGNOR-C15 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-156780 IL10 protein P22301 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10116 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-253502 N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide chemical CHEBI:91409 ChEBI MET protein P08581 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190404 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 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 dothiepin chemical CHEBI:36798 ChEBI CHRM4 protein P08173 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-258698 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 KATNAL2 protein Q8IYT4 UNIPROT TUBD1 protein Q9UJT1 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0001363 29136647 t miannu "Here we show that KATNAL2 is critical for numerous aspects of this developmental process, including the initiation of the axoneme from the basal body, suppression of the spermatid centriole duplication cycle, sperm nuclear sculpting via the manchette, the attachment of the acrosome to the nucleus and the tethering of elongated spermatids to Sertoli cells via the tubulobulbar complex and ultimately sperm release via spermiation. KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin" SIGNOR-267175 nilotinib chemical CHEBI:52172 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-258258 IFNL2 protein Q8IZJ0 UNIPROT IL10RB protein Q08334 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-96209 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 DZIP3 protein Q86Y13 UNIPROT H2AZ2 protein Q71UI9 UNIPROT "up-regulates activity" monoubiquitination Lys121 IHKSLIGkKGQQKTA 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-271756 IL10 protein P22301 UNIPROT SCN8A protein Q9UQD0 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-253501 MFN2 protein O95140 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-272985 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 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 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr200 LPLLVQRtIARTIVL -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-255962 PNMT protein P11086 UNIPROT adrenaline smallmolecule CHEBI:33568 ChEBI "up-regulates quantity" "chemical modification" 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-264007 RORA protein P35398 UNIPROT NPAS2 protein Q99743 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 20817722 t miannu "Direct Regulation of the NPAS2 Promoter by 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-267980 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 ABL1 protein P00519 UNIPROT RAD52 protein P43351 UNIPROT "up-regulates activity" phosphorylation Tyr104 DLNNGKFyVGVCAFV 9606 BTO:0000007 12379650 t "C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR." SIGNOR-251435 "MSH release-inhibiting hormone" smallmolecule CID:56842142 PUBCHEM MC3R protein P41968 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-257537 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 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 IRF4 protein Q15306 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-249561 GUCY1A1 protein Q02108 UNIPROT GUCY1A3-B3 complex SIGNOR-C140 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-243983 KANSL3 protein Q9P2N6 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-267171 MTOR protein P42345 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser83 PTIPGVTsPSSDEPP 9606 9204908 t miannu "MTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E." SIGNOR-250292 CCNY protein Q8ND76 UNIPROT CyclinY/CDK16 complex SIGNOR-C540 SIGNOR "form complex" binding 30992425 t lperfetto "CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that forms an active complex with cyclin Y (CCNY)." SIGNOR-273002 NFE2L1 protein Q14494 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8962164 f irozzo "These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2." SIGNOR-256280 MAPK10 protein P53779 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 20395206 t gcesareni "With epidermal growth factor treatment, overexpression of erk8 in jb6 cl41 cells caused an increased phosphorylation of c-jun at ser(63) and ser(73), resulting in increased activator protein-1 transactivation." SIGNOR-164800 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 NFY complex SIGNOR-C1 SIGNOR CCNB1 protein P14635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 BTO:0000887;BTO:0001103 10362252 f lperfetto "In conclusion, our data demonstrate that nf-y is required for cyclin b1 promoter activity." SIGNOR-235834 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 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 FZD8 protein Q9H461 UNIPROT LRP5 protein O75197 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-169635 DLL1 protein O00548 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 23111325 t gcesareni "In this study, we demonstrate that dll1 can activate notch signaling mostly through notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human mm cells." SIGNOR-199320 "Condensin II" complex SIGNOR-C342 SIGNOR Chromatine_condensation phenotype SIGNOR-PH21 SIGNOR up-regulates 9606 32445620 f miannu "Human Condensin I and II Drive Extensive ATP-Dependent Compaction of Nucleosome-Bound DNA. the combined actions of both condensins contribute to formation of a nested-loop architecture necessary to achieve the highest level of chromosome compaction." SIGNOR-263913 TWIST2 protein Q8WVJ9 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255517 PRKCA protein P17252 UNIPROT DLX3 protein O60479 UNIPROT "down-regulates activity" phosphorylation Ser138 KPRTIYSsYQLAALQ -1 11343707 t lperfetto "Dlx3 is primarily phosphorylated by PKC alpha. By deletion and mutational analysis, we show that the serine residue S(138), located in the homeodomain of Dlx3 protein, was specifically phosphorylated by PKC. The phosphorylation of purified Dlx3 proteins by PKC partially inhibited formation of complexes between Dlx3 protein and DNA. These results suggest that Dlx3 protein can be directly phosphorylated by PKC and this affects the DNA binding activity of Dlx3." SIGNOR-249096 RPE protein Q96AT9 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-267065 PRKACA protein P17612 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser276 SMQLRRPsDRELSEP 9606 SIGNOR-C13 9660950 t llicata "The transcriptional activity of nf-kappa b is stimulated upon phosphorylation of its p65 subunit on serine 276 by protein kinase a (pka)." SIGNOR-58972 MPO-ANCA complex SIGNOR-C474 SIGNOR thiocyanate smallmolecule CHEBI:18022 ChEBI "up-regulates quantity by expression" oxidation 9606 BTO:0000133 9922160 t 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-270591 ITCH protein Q96J02 UNIPROT BCL10 protein O95999 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000661 15082780 t miannu "The HECT domain ubiquitin ligases NEDD4 and Itch promote ubiquitination and degradation of Bcl10, thus downmodulating NF-kappa B activation. " SIGNOR-271414 FOXO3 protein O43524 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates quantity" "transcriptional regulation" 22848740 t "We show that FOXO3 binds and activates its own promoter via a positive autoregulatory feedback loop" SIGNOR-255757 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Ser1403 AGREEFYsTHPHFMT 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." SIGNOR-188429 CEBPD protein P49716 UNIPROT IL23A protein Q9NPF7 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-254061 AKT proteinfamily SIGNOR-PF24 SIGNOR GRIN2C protein Q14957 UNIPROT "up-regulates activity" phosphorylation Ser1081 GSRPRHAsLPSSVAE 10090 BTO:0004278 19477150 t miannu "Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells." SIGNOR-262620 TP53 protein P04637 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR up-regulates binding 9606 10207072 t gcesareni "Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo." SIGNOR-66956 "Chaperone-mediated autophagy" phenotype SIGNOR-PH118 SIGNOR HK2 protein P52789 UNIPROT "down-regulates quantity by destabilization" 9606 BTO:0004424 26323688 t "Our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability." SIGNOR-261247 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 Ub:E2 complex SIGNOR-C497 SIGNOR HECTD1 protein Q9ULT8 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-271294 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 Ub:E2 complex SIGNOR-C497 SIGNOR DTX3 protein Q8N9I9 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-271107 KLK3 protein P07288 UNIPROT PTHLH protein P12272 UNIPROT "down-regulates activity" cleavage Ser22 LLSYAVPsCGRSVEG -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-270547 SF3B3 protein Q15393 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-268405 SHMT1 protein P34896 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI "down-regulates quantity" "chemical modification" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269687 PDYN protein P01213 UNIPROT OPRK1 protein P41145 UNIPROT "up-regulates activity" binding 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-258411 RIPK1 protein Q13546 UNIPROT TAB3 protein Q8N5C8 UNIPROT "up-regulates activity" binding 9606 19927120 t lperfetto "Tab2 and tab3 activate the jun n-terminal kinase and nuclear factor-kappab pathways through the specific recognition of lys 63-linked polyubiquitin chains by its npl4 zinc-finger (nzf) domain." SIGNOR-161787 MTOR protein P42345 UNIPROT ULK2 protein Q8IYT8 UNIPROT down-regulates phosphorylation 9606 19211836 t gcesareni "Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2" SIGNOR-183961 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 MAPK3 protein P27361 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "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-252963 SIRT3 protein Q9NTG7 UNIPROT IDH2 protein P48735 UNIPROT up-regulates deacetylation Lys413 VESGAMTkDLAGCIH 9606 22416140 t miannu "Site-specific, genetic incorporation of n(_)-acetyllysine into position 413 of idh2 revealed that acetylated idh2 displays a dramatic 44-fold loss in activity. Deacetylation by sirt3 fully restored maximum idh2 activity." SIGNOR-196617 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 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 CDC73 protein Q6P1J9 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates binding 9606 16630820 t gcesareni "Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo" SIGNOR-146282 CLTC protein Q00610 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-260665 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 RPL10 protein P27635 UNIPROT JUN protein P05412 UNIPROT down-regulates binding 9606 12138090 t miannu "The qm gene encodes a 24.5 kda ribosomal protein l10 known to be highly homologous to a jun-binding protein (jif-1), which inhibits the formation of jun-jun dimers." SIGNOR-90750 SMARCA2 protein P51531 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-270610 HDAC1 protein Q13547 UNIPROT EGR1 protein P18146 UNIPROT "down-regulates quantity by repression" "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." SIGNOR-254257 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-263830 RIPK3 protein Q9Y572 UNIPROT MLKL protein Q8NB16 UNIPROT "up-regulates activity" phosphorylation Thr357 FELRKTQtSMSLGTT 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-266429 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CEP76 protein Q8TAP6 UNIPROT "down-regulates activity" phosphorylation Ser83 VEQELPSsPKQPICF 9606 BTO:0001938 27065328 t miannu "Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. we conclude that Cep76 inhibits centriole disengagement and consequently amplification by blocking Plk1 activation at the centrosome." SIGNOR-262730 SP1 protein P08047 UNIPROT TBXA2R protein P21731 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000565 19747485 f "Collectively, data establish that regulated WT1 followed by sequential Egr1 and Sp1 binding to elements within Prm1 mediate repression and subsequent induction of TPα during differentiation into the megakaryocytic phenotype, shedding significant insights into factors regulating TPα expression therein." SIGNOR-254254 BECN1 protein Q14457 UNIPROT ZWINT protein O95229 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 23478334 t lperfetto "We show that Beclin-1 interacts directly with Zwint-1-a component of the KMN (KNL-1/Mis12/Ndc80) complex-which is essential for kinetochore-microtubule interactions. This suggests that Beclin-1 acts downstream of the KMN complex to influence the recruitment of outer kinetochore proteins and promotes accurate kinetochore anchoring to the spindle during mitosis." SIGNOR-265027 FZD4 protein Q9ULV1 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-258967 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 entinostat chemical CHEBI:132082 ChEBI HDAC3 protein O15379 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191481 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 PIM proteinfamily SIGNOR-PF34 SIGNOR MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser166 SSRRRAIsETEENSD 9606 BTO:0000785 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-259433 POLR2H protein P52434 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-266172 PSMD3 protein O43242 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-263353 heme smallmolecule CHEBI:30413 ChEBI HBB protein P68871 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-251908 CSNK2A1 protein P68400 UNIPROT AMPH protein P49418 UNIPROT down-regulates phosphorylation Thr350 PEVKKEEtLLDLDFD 9606 BTO:0000567 16945112 t lperfetto "Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin." SIGNOR-149314 MASTL protein Q96GX5 UNIPROT ENSA protein O43768 UNIPROT "up-regulates activity" phosphorylation Ser67 KGQKYFDsGDYNMAK -1 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-243690 ADORA2A protein P29274 UNIPROT GNAS protein Q5JWF2 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-256766 MEF2C protein Q06413 UNIPROT CTNNA3 protein Q9UI47 UNIPROT "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-265491 UQCRH protein P07919 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-262195 BUB1 protein O43683 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" relocalization 11402067 t lperfetto "Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity" SIGNOR-252018 DAD1 protein P61803 UNIPROT "OST-B complex" complex SIGNOR-C536 SIGNOR "form complex" binding 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-272067 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Ser451 STSTPAPsRTASFSE 10653665 t "Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3)" SIGNOR-251218 FYN protein P06241 UNIPROT GRIN2B protein Q13224 UNIPROT unknown phosphorylation Tyr1252 CKKAGNLyDISEDNS 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-251172 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 MBTPS1 protein Q14703 UNIPROT SREBF2 protein Q12772 UNIPROT "up-regulates activity" cleavage 10029 BTO:0000246 10644685 t "We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2" SIGNOR-267496 RAD21 protein O60216 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR "up-regulates activity" 10090 20711430 f "Rad21-cohesin haploinsufficiency impedes DNA repair and enhances gastrointestinal radiosensitivity in mice" SIGNOR-259975 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser400 SRDESTDsGLSMSSY 9606 phosphorylation:Ser127 PQHVRAHsSPASLQL 23431053 t milica "Phosphorylation of YAP (S381) and TAZ (S311) by Lats1/2 primes subsequent phosphorylation events by casein kinase 1 (CK1d/e); this sequential phosphorylation results in recruitment of b-transducin repeat-containing proteins (b-TRCP; a subunit of the SCF ubiquitin E3 ligase) and consequently leads to degradation of YAP/TAZ" SIGNOR-201165 AKT3 protein Q9Y243 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-217466 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser221 PRTSPIMsPRTSLAE 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-248687 KLHL15 protein Q96M94 UNIPROT PPP2R5B protein Q15173 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23135275 t miannu "Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β." SIGNOR-272017 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 PDPK1 protein O15530 UNIPROT SGK1 protein O00141 UNIPROT "up-regulates activity" phosphorylation Thr256 EHNSTTStFCGTPEY -1 10191262 t miannu "PDK1 activates SGK in vitro by phosphorylating Thr256." SIGNOR-250275 S1PR5 protein Q9H228 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-256819 F2RL3 protein Q96RI0 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-257419 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 PER2 protein O15055 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-267973 PAMPs stimulus SIGNOR-ST11 SIGNOR AIM2 protein O14862 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-256423 phosphatidylinositol chemical CHEBI:28874 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition." SIGNOR-267001 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 TBK1 protein Q9UHD2 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser398 VDLHISNsHPLSLTS -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-178403 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI SH2B3 protein Q9UQQ2 UNIPROT "down-regulates activity" "chemical inhibition" -1 17620431 t miannu "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-259169 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 MARK2 protein Q7KZI7 UNIPROT ARHGEF2 protein Q92974 UNIPROT down-regulates phosphorylation Ser886 PVDPRRRsLPAGDAL 9606 22072711 t "The effect has been demonstrated using Q92974-2" gcesareni "We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation" SIGNOR-177096 SUV39H1 protein O43463 UNIPROT MYOG protein P15173 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002267 23435416 f lperfetto "The methyl marks H3K9me3 on the myoD promoter and H3K27me3 on the myogenin promoter have been shown to be under the control of the histone methyl transferase KMT1A and the HDM KDM4A, respectively, during normal myogenesis. In addition, KMT1A has recently been shown to play a role in ARMS by inhibiting myogenic differentiation" SIGNOR-249601 GUCA2B protein Q16661 UNIPROT GUCY2C protein P25092 UNIPROT up-regulates binding 9606 10845107 t gcesareni "Guanylins activate two receptors, gc-c and ok-gc, which are expressed in intestine and/or kidney." SIGNOR-78120 WNT3A protein P56704 UNIPROT Frizzled proteinfamily SIGNOR-PF11 SIGNOR "up-regulates activity" binding 18697834 t "Simone Vumbaca" "Wnt1, Wnt3a and Wnt5a all induced a statistically greater degree of proliferation than control cells" SIGNOR-255650 PYGL protein P06737 UNIPROT 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-267949 olanzapine chemical CHEBI:7735 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-258834 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 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 ORC2 protein Q13416 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-267566 CDK5 protein Q00535 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" phosphorylation Ser242 IPNGFGTsPLTPSAR 10090 BTO:0000142 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-250677 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser15 PSVEPPLsQETFSDL 9606 17108107 t gcesareni "We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392" SIGNOR-150830 CyclinD3/CDK11B complex SIGNOR-C543 SIGNOR AR protein P10275 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser310 TEDTAEYsPFKGGYT 9534 17698582 t "phosphorylation site remapping based on Fig 7D" lperfetto "We found that AR was phosphorylated at Ser-308 by cyclin D3/CDK11p58 in vitro and in vivo, leading to the repressed activity of AR transcriptional activation unit 1 (TAU1)." SIGNOR-273130 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 PRKDC protein P78527 UNIPROT PRKDC protein P78527 UNIPROT "up-regulates activity" phosphorylation Thr2647 QQHDFTLtQTADGRS 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-249160 Ub:E2 complex SIGNOR-C497 SIGNOR PJA1 protein Q8NG27 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-270990 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 ADSS2 protein P30520 UNIPROT GDP smallmolecule CHEBI:17552 ChEBI "up-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-267349 HNF4A protein P41235 UNIPROT ABCG5 protein Q9H222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000398 21123766 f miannu "these results indicate that HMG-CoAR inhibition with atorvastatin stimulates intestinal expression of NPC1L1 and PCSK9, increases cholesterol absorption, and reduces ABCG5/8 expression; these effects are mediated most likely by stimulation of the transcription factors SREBP-2 and HNF-4α." SIGNOR-254457 IL10RA protein Q13651 UNIPROT Phagocytosis phenotype SIGNOR-PH97 SIGNOR up-regulates 19837374 f apalma "Treatment of monocytes with IL-10 as compared to IL-15 resulted in a two-fold greater level of phagocytosis and binding of latex beads. In summary, IL-10, in comparison to IL-15, induces greater macrophage endocytic function" SIGNOR-255442 NPFFR1 protein Q9GZQ6 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-256987 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 TNF protein P01375 UNIPROT SCN10A protein Q9Y5Y9 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-253493 ATP5PB protein P24539 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-261401 PER1 protein O15534 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-267974 TAL1 protein P17542 UNIPROT MEF2C protein Q06413 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000661 21261500 f miannu "TAL1 and LYL1 are two leukemic members of the bHLH family of transcription factors. TAL1 and LYL1 activate expression of MEF2C" SIGNOR-254209 "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 PPP2CA protein P67775 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-243442 PROK1 protein P58294 UNIPROT PROKR1 protein Q8TCW9 UNIPROT up-regulates binding 9606 12054613 t gcesareni "The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2)" SIGNOR-89084 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 LNX2 protein Q8N448 UNIPROT NUMB protein P49757 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 26451611 t miannu "Polyubiquitination of Human Numb by LNX2. The Zn-RING-Zn domain of LNX2 is a dimer and assumes a rigid elongated structure that undergoes autoubiquitination and undergoes N-terminal polyubiquitination. LNX2 can bind numb and induce its ubiquitination and subsequent proteasomal degradation" SIGNOR-272423 BDKRB2 protein P30411 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-257281 IRX1 protein P78414 UNIPROT NPTX1 protein Q15818 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-261655 RPS6KA2 protein Q15349 UNIPROT NR4A1 protein P22736 UNIPROT "down-regulates activity" phosphorylation Ser351 GRRGRLPsKPKQPPD 10116 11883936 t "From PMID 9395454: We have shown that the in vitro phosphorylation of Ser350 located within the ""A-box,"" a motif necessary for DNA binding by NGFI-B, results in a decrease in the binding of NGFI-B to its response element" lperfetto "Phosphorylation of a residue in the DNA-binding region (Ser-350 of NGFI-B and 354 of Nur77) has been described in detail to have effect on the transcriptional function of the protein [11, 24]. Growth-related kinase pp90rsk, but not ERK1 (pp44mapk), was shown to phosphorylate recombinant Nur77 in vitro in the DNA binding domain, but not the amino-terminus, using an immune complex kinase as- say [11]." SIGNOR-249429 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 RXRB protein P28702 UNIPROT NR1H2 protein P55055 UNIPROT up-regulates binding 9606 14993927 t gcesareni "We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active." SIGNOR-123094 LUBAC complex SIGNOR-C527 SIGNOR DDX58 protein O95786 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 21292167 t miannu "HOIL-1L/HOIP LUBAC induces TRIM25 ubiquitination and degradation Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner." SIGNOR-271860 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15964798 f gcesareni "Reduction in p53 expression also blocks p65 binding to the intronic region of the dr5 gene, indicating cooperation between p53 and p65 in dr5 expression. (articolo-abstract)" SIGNOR-138293 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 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 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 CDK5 protein Q00535 UNIPROT AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250648 GSK3B protein P49841 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-249350 ruxolitinib chemical CHEBI:66919 ChEBI JAK3 protein P52333 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-258278 PRKCA protein P17252 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser109 KERRRTEsINSAFAE 9606 14636580 t lperfetto "In vitro and in vivo phosphorylation studies show that both PKA and PKC can phosphorylate HAND1 and -2. In addition, phosphopeptide mapping analysis of wild-type and mutant forms of HAND1 shows that three of these conserved residues, T107; S109 within helix I and S98 within the basic domain, are the phosphorylated residues. " SIGNOR-249242 ANGPTL1 protein O95841 UNIPROT TEK protein Q02763 UNIPROT up-regulates binding 9606 10051567 t gcesareni "Ang3 and ang4 are agonists of tie2, but mouse ang3 has strong activity only on endothelial cells of its own species." SIGNOR-65110 HDAC2 protein Q92769 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001939 23836662 f miannu "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-254154 "Non-structural protein 10" protein P0C6X7-PRO_0000037317 UNIPROT IFTAP protein Q86VG3 UNIPROT unknown binding 4932 18433331 t lperfetto "In our previous work, we isolated a gene from a cDNA library of human embryo lung tissue, which en- coded a novel protein that specifically interacted with nsp-10 of SARS-CoV in a yeast trap experiment.|Since nsp- 10 of SARS-CoV is involved in viral genomic replica- tion and was observed to interact with ATF5, the cellular initiation factor of the RNA pol II complex (13), we in- ferred that HEPIS may also be involved in cellular gene transcription. Therefore, the significance of HEPIS ex- pression in cells needed to be further investigated. The work we describe here suggests that HEPIS represses cel- lular transcription initiation through interaction with a component of the RNA pol II complex" SIGNOR-260251 ACAT1 protein P24752 UNIPROT IDH2 protein P48735 UNIPROT "down-regulates activity" acetylation Lys413 VESGAMTkDLAGCIH 9606 BTO:0001545 34289383 t lperfetto "Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers" SIGNOR-267627 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 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 MDK protein P21741 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18469519 t gcesareni "We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2" SIGNOR-161427 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser166 EPRSRHLsVSSQNPG 9606 12761204 t lperfetto "Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 1" SIGNOR-101211 ELP1 protein O95163 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-269708 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 Tosedostat chemical CID:15547703 PUBCHEM ANPEP protein P15144 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207372 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA12 protein O60330 UNIPROT "up-regulates activity" binding 9606 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-265676 BBOX1 protein O75936 UNIPROT carnitine smallmolecule CHEBI:17126 ChEBI "up-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-269699 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM11 protein Q96F44 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-271083 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 KANSL3 protein Q9P2N6 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 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-267169 ADAM10 protein O14672 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "up-regulates activity" cleavage 9606 28624438 t miannu "One of the most important and best characterized ADAM10 substrates is the Notch receptor [16]. After ligand binding to the Notch receptor, ADAM10 liberates the ectodomain and the membrane remaining part is processed by the γ-secretase complex, which releases a Notch Intracellular Domain (NICD)." SIGNOR-259836 EIF2AK2 protein P19525 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 16179259 t lperfetto "The antiviral protein kinase pkr inhibits protein synthesis by phosphorylating the translation initiation factor eif2alpha on ser51the protein kinases pkr, hri, perk, and gcn2 specifically phosphorylate ser51 on the _ subunit of the translation initiation factor eif2, a gtp binding protein that delivers the initiator methionyl-trna to the small ribosomal subunit in the first step of translation initiation. Phosphorylation of eif2_ converts eif2 from a substrate to an inhibitor of its gdp-gtp exchange factor eif2b, thereby blocking protein synthesis" SIGNOR-140656 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 calcium(2+) smallmolecule CHEBI:29108 ChEBI PLA2G4A protein P47712 UNIPROT up-regulates relocalization 9606 8027085 t gcesareni "Cytosolic phospholipase a2 (cpla2) is a calcium-sensitive 85-kda enzyme that hydrolyzes arachidonic acid-containing membrane phospholipids to initiate the biosynthesis of eicosanoids and platelet-activating factor, potent inflammatory mediators. The calcium-dependent activation of the enzyme is mediated by an n-terminal c2 domain, which is responsible for calcium-dependent translocation of the enzyme to membranes and that enables the intact enzyme to hydrolyze membrane-resident substrates. cytosolic phospholipase a2 (cpla2) associates with natural membranes in response to physiological increases in ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids." SIGNOR-35874 "prostaglandin F2alpha(1-)" smallmolecule CHEBI:57404 ChEBI PTGFR protein P43088 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-257573 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 PTPN11 protein Q06124 UNIPROT MPZL1 protein O95297 UNIPROT down-regulates dephosphorylation Tyr263 NKSESVVyADIRKN 9606 10681522 t gcesareni "In vitro, tyrosine-phosphorylated pzr was efficiently dephosphorylated by the full-length form of shp-2 but not by its sh2 domain-truncated form. The coexisting binding and dephosphorylation of pzr by shp-2 may function to terminate signal transduction initiated by pzr and shp-2 and to set a threshold for the signal transduction to be initiated." SIGNOR-75220 TP53 protein P04637 UNIPROT OGG1 protein O15527 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16293709 t miannu "Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1." SIGNOR-255440 "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 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-263790 "AMG 900" chemical CID:24856041 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189492 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 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 PDPK1 protein O15530 UNIPROT PKN1 protein Q16512 UNIPROT up-regulates phosphorylation Thr774 GYGDRTStFCGTPEF 9606 10753910 t miannu "It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)" SIGNOR-76640 SYK protein P43405 UNIPROT BLNK protein Q8WV28 UNIPROT up-regulates phosphorylation Tyr178 LLEDEADyVVPVEDN 9606 BTO:0000776 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-96040 adenosine smallmolecule CHEBI:16335 ChEBI ADORA1 protein P30542 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-257446 DAPK3 protein O43293 UNIPROT DAPK3 protein O43293 UNIPROT up-regulates phosphorylation Thr265 KDPKRRMtIAQSLEH 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-132467 KDM4C protein Q9H3R0 UNIPROT JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23698634 f miannu "The expression of KDM4C gene was increased in spheres from colorectal cancer (CRC) cells and the knockdown (KD) of KDM4C eliminated colonosphere formation. KDM4C KD decreased the expression of JAG1 gene, and the downregulation of JAG1 gene recapitulated the impaired colonosphere formation." SIGNOR-254542 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser567 DSSRFPMsPRPDSVH 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-249462 lurasidone chemical CHEBI:70735 ChEBI ADRA2A protein P08913 UNIPROT "down-regulates activity" "chemical inhibition" 10030 BTO:0000246 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-257842 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 NEK8 protein Q86SG6 UNIPROT NEK8 protein Q86SG6 UNIPROT "up-regulates activity" phosphorylation Thr162 SSKSKAYtVVGTPCY -1 11864968 t miannu "Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop." SIGNOR-250298 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 JWOGUUIOCYMBPV-GMFLJSBRSA-N chemical CID:6918328 PUBCHEM 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-257976 DRD1 protein P21728 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-256939 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 SH3RF1 protein Q7Z6J0 UNIPROT MAPK8IP1 protein Q9UQF2 UNIPROT up-regulates binding 9606 16571722 t gcesareni "We find that posh and jips directly associate with one another to form a multiprotein complex, pjac (posh-jip apoptotic complex), that includes all of the known kinase components of the pathway. Our observations indicate that this complex is required for jnk activation and cell death in response to apoptotic stimuli." SIGNOR-145393 NCOA2 protein Q15596 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 10090 BTO:0000801 29170386 t "Here we report that GRIP1 loss in macrophages attenuates glucocorticoid induction of several anti-inflammatory targets, and that GC treatment of quiescent macrophages globally directs GRIP1 toward GR binding sites dominated by palindromic GC response elements (GRE), suggesting a non-redundant GRIP1 function as a GR coactivator." SIGNOR-256095 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR TERT protein O14746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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-253280 ARID2 protein Q68CP9 UNIPROT "SWI/SNF complex" complex SIGNOR-C92 SIGNOR "form complex" binding 9606 15627498 t lperfetto "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-241756 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 AP2B1 protein P63010 UNIPROT "AP-2 complex" complex SIGNOR-C245 SIGNOR "form complex" binding 31671891 t lperfetto "The most important endocytic adaptor is the heterotetrameric AP-2 complex made up of the large alpha- and beta2-adaptin subunits, the medium-sized mu2-subunit and a small sigma2-subunit" SIGNOR-260422 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001412 8394219 f "We expressed the PML-RARa protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin Ds and transforming growth factor pl), acquired enhanced sensitivity to retinoic acid, and exhibited a higher growth rate consequent to diminished apoptotic cell death." SIGNOR-255723 SYCE1 protein Q8N0S2 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "form complex" binding 9606 22394509 t miannu "The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region." SIGNOR-264201 NPM1 protein P06748 UNIPROT FBXW7 protein Q969H0 UNIPROT "up-regulates quantity" binding 10090 BTO:0002572 18625840 t gcesareni "We report here that NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7 , a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc. NPM was required for nucleolar localization and stabili- zation of Fbw7" SIGNOR-245084 LAS1L protein Q9Y4W2 UNIPROT "Rix1 complex" complex SIGNOR-C373 SIGNOR "up-regulates activity" 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-265467 GABRB1 protein P18505 UNIPROT "GABA-A (a4-b1-g2) receptor" complex SIGNOR-C333 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-263760 gamma-secretase complex SIGNOR-C98 SIGNOR NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates cleavage 23729744 t apalma "Receptor–ligand engagement triggers a second NECD cleavage (S2 cleavage) by a metalloproteinase ADAM (known as Kuzbanian in Drosophila melanogaster), which in turn facilitates a further crucial signaling cleavage within the Notch transmembrane domain by a γ-secretase complex that contains Presenilin (S3 cleavage)" SIGNOR-255372 SLC20A2 protein Q08357 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI "up-regulates quantity" relocalization 9606 11009570 t lperfetto SIGNOR-270580 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser250 TGSPAELsPTTLSPV 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-182992 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 CDK1 protein P06493 UNIPROT RAB1A protein P62820 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000567 1902553 t Giulio "We now present biochemical evidence for a mitosis-specific p34cdc2 phosphorylation of RablAp and Rab4p.We also show that the distribution of RablAp and Rab4p between cytosolic and membrane-bound forms is different in interphase and mitotic cells." SIGNOR-261284 (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 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr457 YVSPRIStPQTNTVP 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-265035 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 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 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 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000150 22418700 t gcesareni "Afatinib is an oral, erbb family blocker, which covalently binds and irreversibly blocks all kinase-competent erbb family members." SIGNOR-259442 propan-2-ol smallmolecule CHEBI:17824 ChEBI TLCD3B protein Q71RH2 UNIPROT "up-regulates activity" binding 9606 BTO:0000140 30010626 t lperfetto "Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2" SIGNOR-270575 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Ser332 STPKSKQsPISTPTS 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-250667 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 BAIAP2 protein Q9UQB8 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 BTO:0001909 19171758 f miannu "Ectopic expression of IRSp53 in mouse neuroblastoma N1E115 cells induces neurite outgrowth . Kank inhibits IRSp53-mediated neurite outgrowth in N1E115 cells" SIGNOR-265555 TBX21 protein Q9UL17 UNIPROT IFNG protein P01579 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0003432 10761931 t Luana "T-bet Transactivates the IFNγ Gene and Represses the IL-2 Gene in EL4 Cells" SIGNOR-266234 "sedoheptulose 7-phosphate" smallmolecule CHEBI:15721 ChEBI "D-erythrose 4-phosphate(2-)" smallmolecule CHEBI:16897 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-268135 PCM1 protein Q15154 UNIPROT CETN2 protein P41208 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-94990 RBPJ protein Q06330 UNIPROT DUSP1 protein P28562 UNIPROT up-regulates binding 10090 17158101 t gcesareni "Notch induction of mkp-1 depends on an rbp-j-dependent mechanism." SIGNOR-236851 FFAR1 protein O14842 UNIPROT GNAS protein Q5JWF2 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-256799 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 PRKCE protein Q02156 UNIPROT CTNND1 protein O60716 UNIPROT down-regulates phosphorylation Ser268 PQVRVGGsSVDLHRF 9606 21251911 t lperfetto "We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation" SIGNOR-171712 S100A9 protein P06702 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 BTO:0001545 28137827 f miannu "S100A9 induces differentiation of acute myeloid leukemia cells through TLR4." SIGNOR-261922 MLL-ENL "fusion protein" SIGNOR-FP7 SIGNOR RUNX1 protein Q01196 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-255853 MRPL23 protein Q16540 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-262370 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation Ser246 DSVSDQFsVEFEVES 9606 20708156 t gcesareni "Cki phosphorylates mdm2 at multiple sites to trigger mdm2/beta-trcp1 interactionbeta-trcp promotes mdm2 turnover and ubiquitination" SIGNOR-167509 JAG1 protein P78504 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 10551863 t "Binding Calcium-dependent." gcesareni "Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch." SIGNOR-269936 NLK protein Q9UBE8 UNIPROT TCF4 protein P15884 UNIPROT down-regulates phosphorylation 9606 2861485 t gcesareni "Whereas lef-1 and tcf-4 phosphorylation by nlk (nemo-like kinase) leads to less lef/tcf/beta-catenin complex binding to dna and to lef-1/tcf-4 degradation" SIGNOR-24147 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine chemical CID:11617559 PUBCHEM CSF1R protein P07333 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-259743 ponatinib chemical CHEBI:78543 ChEBI KIT protein P10721 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001669 23539538 t miannu "Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells" SIGNOR-259272 PRSS21 protein Q9Y6M0 UNIPROT RAD21 protein O60216 UNIPROT up-regulates cleavage 9606 11875078 t miannu "Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation." SIGNOR-115426 "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 PRKCB protein P05771 UNIPROT EEF1A2 protein Q05639 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-263166 CTNNB1 protein P35222 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 18316399 t "Simone Vumbaca" "Together, these results suggest that B-Cat increases MyoD binding to E box elements" SIGNOR-255653 ABCC4 protein O15439 UNIPROT BLOC-1 complex SIGNOR-C381 SIGNOR "up-regulates activity" binding 9606 BTO:0000132 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). " SIGNOR-265996 sirolimus chemical CHEBI:9168 ChEBI AKT proteinfamily SIGNOR-PF24 SIGNOR 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-144156 CSNK2B protein P67870 UNIPROT EIF5 protein P55010 UNIPROT "up-regulates activity" phosphorylation Ser390 KEAEEESsGGEEEDE 9606 BTO:0001938 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-251070 GATA1 protein P15976 UNIPROT ZNF268 protein Q14587 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001271 22235304 f miannu "Here we found that gata-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of znf268" SIGNOR-195410 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 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 TRHR protein P34981 UNIPROT GNAQ protein P50148 UNIPROT "up-regulates activity" binding 9606 BTO:0001379 23248581 t scontino "TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ)." SIGNOR-267202 ASCL1 protein P50553 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000938 BTO:0000142 24243019 f lperfetto "Here we reveal a hierarchical mechanism in the direct conversion of fibroblasts into induced neuronal (iN) cells mediated by the transcription factors Ascl1|Accordingly, Ascl1-mutant mice show severe defects in neurogenesis" SIGNOR-265174 "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR TWIST1 protein Q15672 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272190 nafadotride chemical CHEBI:64191 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-258854 MAPK1 protein P28482 UNIPROT APBB1 protein O00213 UNIPROT unknown phosphorylation Ser347 TFPAQSLsPEPLPQE 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-120459 WNT7B protein P56706 UNIPROT FZD10 protein Q9ULW2 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 t gcesareni "Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling" SIGNOR-137934 NR1I3 protein Q14994 UNIPROT CYP2B6 protein P20813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19702527 f miannu "Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding." SIGNOR-254863 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 GLI1 protein P08151 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 9606 3563490 f gcesareni "The gli gene is a member of a select group of cellular genes that are genetically altered in primary human tumors." SIGNOR-235196 S1PR1 protein P21453 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-257108 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 BCL2L11 protein O43521 UNIPROT BAX protein Q07812 UNIPROT "up-regulates activity" binding 9606 17289999 t lperfetto "Contrary to the direct-activation model, we show that Bax and Bak can mediate apoptosis without discernable association with the putative BH3-only activators (Bim, Bid, and Puma), even in cells with no Bim or Bid and reduced Puma. Our results indicate that BH3-only proteins induce apoptosis at least primarily by engaging the multiple pro-survival relatives guarding Bax and Bak" SIGNOR-152986 SUFU protein Q9UMX1 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates binding 9606 BTO:0001130;BTO:0000848;BTO:0000527 10564661 t miannu "Hsu(fu) associated with itself / homo- or heterodimers of hsu(fu) might function to bring together other effector proteins" SIGNOR-72311 LRRK2 protein Q5S007 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR up-regulates phosphorylation 9606 BTO:0000938 21658387 t lperfetto "Lrrk2 directly phosphorylates akt1 as a possible physiological substrate. These data establish that lrrk2 can protect neurons from apoptotic insult through a survival pathway in which lrrk2 signals to activate akt. Lrrk2-mediated phosphorylation of akt1 (ser473)" SIGNOR-244410 PLK1 protein P53350 UNIPROT BRCA2 protein P51587 UNIPROT unknown phosphorylation Thr207 TPPTLSStVLIVRNE 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-249221 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 PRKCA protein P17252 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Thr63 LSSAWPGtLRSGMVP 9606 22721717 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-197949 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 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 CDC25B protein P30305 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR up-regulates dephosphorylation 9606 7880537 t lperfetto "Cdc25 dephosphorylates cdc2/cdk1 within the activation loop of the kinase domain to achieve full activity of the cyclin-cdk complex" SIGNOR-217511 CSNK2A1 protein P68400 UNIPROT ARRB2 protein P32121 UNIPROT unknown phosphorylation Thr382 EFDTNYAtDDDIVFE -1 11877451 t llicata "We found that arrestin-3 is constitutively phosphorylated at Thr-382 and becomes dephosphorylated upon beta(2)-adrenergic receptor activation in COS-1 cells. Casein kinase II (CKII) appears to be the major kinase mediating arrestin-3 phosphorylation, since 1) Thr-382 is contained within a canonical consensus sequence for CKII phosphorylation and 2) wild type arrestin-3 but not a T382A mutant is phosphorylated by CKII in vitro. | However, additional analysis reveals that arrestin-3 phosphorylation may regulate formation of a large arrestin-3-containing protein complex." SIGNOR-250829 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 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 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-257974 LMNA protein P02545 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000944 16415042 f "Cleaved by CASP6" amattioni "Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy.|We conclude that A-type lamins act as inhibitors of adipocyte differentiation, possibly by affecting PPARgamma2 and insulin signaling." SIGNOR-45455 NEXMIF protein Q5QGS0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10116 BTO:0000938 27822498 f miannu "The X-Linked Autism Protein KIAA2022/KIDLIA Regulates Neurite Outgrowth via N-Cadherin and δ-Catenin Signaling. We found that KIDLIA is distributed exclusively in the nucleus" SIGNOR-269659 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Thr575 SNSCRSStTTCPEQD 9606 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-249299 MEF2A protein Q02078 UNIPROT MYF6 protein P23409 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 7739551 t lperfetto "Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis." SIGNOR-238709 MAP2K6 protein P52564 UNIPROT STAT4 protein Q14765 UNIPROT "up-regulates activity" phosphorylation Ser721 PSDLLPMsPSVYAVL 10090 BTO:0000944 10961885 t "MKK6, phosphorylate STAT4 on serine 721. IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity." SIGNOR-251425 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1672 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-203528 HLX protein Q14774 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20008130 f 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-261624 CSNK2A1 protein P68400 UNIPROT SNCA protein P37840 UNIPROT up-regulates phosphorylation Ser87 KTVEGAGsIAAATGF 9606 BTO:0000938 10617630 t lperfetto "In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes." SIGNOR-73807 Ub:E2 complex SIGNOR-C497 SIGNOR RNF39 protein Q9H2S5 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-271223 PEX1 protein O43933 UNIPROT Protein_localization_to_peroxisome phenotype SIGNOR-PH86 SIGNOR up-regulates 9606 26476099 f "The Pex1 and Pex6 proteins are members of the AAA family of ATPases and are involved in peroxisome biogenesis." SIGNOR-253616 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 PRKACA protein P17612 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-134605 CASP3 protein P42574 UNIPROT DFFB protein O76075 UNIPROT up-regulates cleavage 9606 9108473 t gcesareni "Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation" SIGNOR-47419 AKT3 protein Q9Y243 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-249643 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR2 protein Q9GZQ4 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-257592 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 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." SIGNOR-253001 RPRD1B protein Q9NQG5 UNIPROT CCNB1 protein P14635 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004953 30518842 t lperfetto "These results indicated that CREPT regulates the Cyclin B1 expression via directly targeting its promoter region during transcription." SIGNOR-265500 RPS6KB1 protein P23443 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-180771 "MECP2/SIN3A/HDAC complex" complex SIGNOR-C360 SIGNOR BDNF protein P23560 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0004102 14593184 t Luana "Moreover, increased Bdnf transcription involves dissociation of the MeCP2–histone deacetylase–mSin3A repression complex from its promoter." SIGNOR-265071 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 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr336 SKQSPIStPTSPGSL 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-250660 PRKCG protein P05129 UNIPROT ARHGEF7 protein Q14155 UNIPROT up-regulates phosphorylation Ser761 DSLGRRSsLSRLEPS 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-205238 CSNK2A1 protein P68400 UNIPROT HES6 protein Q96HZ4 UNIPROT "up-regulates activity" phosphorylation Ser183 GPGDDLCsDLEEAPE -1 12972610 t llicata "Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2. " SIGNOR-250890 GOT1 protein P17174 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 9606 26003525 t miannu "Glutamate oxaloacetate transaminase (GOT) catalyzes the reversible reaction of l-aspartate and Œ±-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-267510 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 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR tRNA(Leu) smallmolecule CHEBI:29169 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-270411 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 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 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 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 GNGT1 protein P63211 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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-252686 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 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 triptorelin chemical CHEBI:63633 ChEBI GNRH1 protein P01148 UNIPROT "up-regulates activity" "chemical activation" 9606 22416801 t miannu "The comparative effects of degarelix and GnRH agonists were assessed in two studies in a rat model of prostate cancer.14 In a 2‐month study, rats receiving the GnRH agonist, triptorelin (0.5 mg/kg daily), experienced an initial testosterone surge, followed by suppression to castration levels by day 28, which was maintained for the remainder of the study." SIGNOR-259158 GLI1/GLI2 complex SIGNOR-C450 SIGNOR MYCN protein P04198 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-269212 "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 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 HTR2A protein P28223 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-257021 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 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 DLL3 protein Q9NYJ7 UNIPROT NOTCH proteinfamily SIGNOR-PF30 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-254316 NMBR protein P28336 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-257315 ITK protein Q08881 UNIPROT BMX protein P51813 UNIPROT "up-regulates activity" phosphorylation Tyr216 SSTSLAQyDSNSKKI -1 12573241 t "Itk phosphorylated Bmx-SH3 to a low extent. pY positions correspond to the residues Y215 and Y223 in Bmx. 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." SIGNOR-251331 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 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 MAPK3 protein P27361 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-249474 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 PIK3C3 protein Q8NEB9 UNIPROT AKT1 protein P31749 UNIPROT up-regulates 9606 10698680 f acerquone "Pkb is activated through recruitment to cellular membranes by pi3k lipid products and phosphorylation by 3h-phosphoinositide-dependent kinase-1 (pdk1)" SIGNOR-252633 afatinib chemical CHEBI:61390 ChEBI "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR "down-regulates activity" "chemical inhibition" 9606 BTO:0000551 22452896 t "Like lapatinib and neratinib, afatinib is a next generation tyrosine kinase inhibitor (TKI) that irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and epidermal growth factor receptor (EGFR) kinases." gcesareni "Afatinib, an irreversible erbb-family blocker, has shown preclinical activity when tested in egfr mutant models with mutations that confer resistance to egfr tyrosine-kinase inhibitors." SIGNOR-259440 NBN protein O60934 UNIPROT ATM protein Q13315 UNIPROT up-regulates binding 9606 15758953 t gcesareni "Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm" SIGNOR-134508 SLA protein Q13239 UNIPROT KIT protein P10721 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0001538 24284075 t miannu "In this report, we show that SLAP associates with both wild-type and oncogenic c-Kit (c-Kit-D816V). The association involves the SLAP SH2 domain and receptor phosphotyrosine residues different from those mediating Src interaction. Association of SLAP triggers c-Kit ubiquitylation which, in turn, is followed by receptor degradation" SIGNOR-263143 CTTNBP2NL protein Q9P2B4 UNIPROT CTTN protein Q14247 UNIPROT "up-regulates activity" binding 10116 23015759 t miannu "CTTNBP2NL interacts with cortactin and targets cortactin to stress fibers." SIGNOR-261695 TNK2 protein Q07912 UNIPROT TNK2 protein Q07912 UNIPROT "up-regulates activity" phosphorylation Tyr284 LPQNDDHyVMQEHRK -1 16472662 t "Purified ACK1 undergoes autophosphorylation at Tyr284, and autophosphorylation increases kinase activity" SIGNOR-251184 PHC1 protein P78364 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-266809 OTULIN protein Q96BN8 UNIPROT UBB protein P0CG47 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-270819 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 GSK1292263 chemical CID:24996872 PUBCHEM GPR119 protein Q8TDV5 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-257500 AT9283 chemical CID:11696609 PUBCHEM JAK3 protein P52333 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190020 SLC4A10 protein Q6U841 UNIPROT hydrogencarbonate smallmolecule CHEBI:17544 ChEBI "up-regulates quantity" relocalization 9606 26136660 t miannu "Slc4a10 is a Na+-coupled Cl−-HCO3− exchanger, which is expressed in principal and inhibitory neurons as well as in choroid plexus epithelial cells of the brain. In neurons, bicarbonate transport is mainly mediated by members of the SLC4A family of proteins. While the Na+-independent anion-exchanger SLC4A3 lowers the intraneuronal bicarbonate concentration, the Na+-dependent anion exchangers SLC4A8 (NDCBE) and SLC4A10 (NCBE) use the sodium gradient to accumulate bicarbonate in exchange of chloride" SIGNOR-264919 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 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 RPS6KA4 protein O75676 UNIPROT RPS6KA4 protein O75676 UNIPROT up-regulates phosphorylation Ser196 EEKERTFsFCGTIEY 9606 BTO:0001253 17429437 t gcesareni "Ser-343 and ser-196 are autophosphorylated by the c-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the n-terminal kinase domain." SIGNOR-154324 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 N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide chemical CHEBI:91399 ChEBI CDK7 protein P50613 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207087 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 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 PPP3CA protein Q08209 UNIPROT NFATC1 protein O95644 UNIPROT up-regulates dephosphorylation 9606 BTO:0000782 14722106 t gcesareni "Once activated, calcineurin directly dephosphorylates NFAT proteins that are present in a hyperphosphorylated latent form in the cytoplasm and induces their rapid translocation into the nucleus, where in concert with nuclear partner proteins such as the AP-1 transcription factor complex, they are able to bind cooperatively to their target promoter elements and activate the transcription of specific NFAT target genes" SIGNOR-84038 ID1 protein P41134 UNIPROT MYOD/E2-2 complex SIGNOR-C129 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-241125 AURKB protein Q96GD4 UNIPROT HASPIN protein Q8TF76 UNIPROT "up-regulates activity" phosphorylation Ser108 WKLRARPsLTVTPRR 9606 BTO:0000567 21658950 t miannu "Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis." SIGNOR-263137 PP121 chemical CHEBI:50915 ChEBI PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206304 MAPK1 protein P28482 UNIPROT UBAP2L protein Q14157 UNIPROT unknown phosphorylation Thr844 IPFPTPTtPLTGRDG 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-262774 PPM1D protein O15297 UNIPROT ATM protein Q13315 UNIPROT down-regulates dephosphorylation 9606 19360021 t gcesareni "The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity." SIGNOR-185135 COL3A1 protein P02461 UNIPROT ECM_synthesis phenotype SIGNOR-PH8 SIGNOR up-regulates 9606 21949456 t "Collagen is the major structural protein in skeletal muscle ECM;... type III collagen appears to be more evenly distributed between endomysium and epimysium" SIGNOR-254664 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 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR Interferon-type-I proteinfamily SIGNOR-PF50 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 10090 20610653 f miannu "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-260329 HBA1 protein P69905 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-251755 RAI1 protein Q7Z5J4 UNIPROT CLOCK protein O15516 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 22578325 t miannu "RAI1 Transcriptionally Activates CLOCK via an Intron 1 Enhancer Element. data suggest that RAI1 binds, directly or in a complex, to the first intron of CLOCK and enhances its transcriptional activity in vitro, supporting RAI1 as a positive regulator of CLOCK and an important part of the circadian loop of transcription. 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-266839 doxepin chemical CHEBI:4710 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-258879 CCND1 protein P24385 UNIPROT CyclinD/CDK4 complex SIGNOR-C18 SIGNOR "form complex" 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-32298 PRKDC protein P78527 UNIPROT DCLRE1C protein Q96SD1 UNIPROT up-regulates phosphorylation Ser516 SSTVAGGsQSPKLFS 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-145837 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 MRPS24 protein Q96EL2 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-261436 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr242 FFQQQMIyDSPPSRA 10090 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251310 BCL2L11 protein O43521 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18498746 t lperfetto "We show that mutation of the phosphorylation site Thr-112 causes decreased binding of Bim to the antiapoptotic protein Bcl2 and can increase cell survival." SIGNOR-178676 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0001593 BTO:0000140 22298955 t lperfetto "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-153420 miR-199a mirna URS0000759977_9606 RNAcentral MTOR protein P42345 UNIPROT "up-regulates activity" 9606 26055960 t miannu "Our results suggest that activating mutation of FLT3 in AML can lead, to increased expression of miR-155, which then causes down-regulation of SPI1 and CEBPB and consequently causes block of myeloid differentiation." SIGNOR-255803 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 CAMK2G protein Q13555 UNIPROT SYN1 protein P17600 UNIPROT unknown phosphorylation Ser605 AGPTRQAsQAGPVPR 3118371 t llicata "Sites 2 and 3 are serine residues phosphorylated by calcium/calmodulin-dependent protein kinase II." SIGNOR-250708 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 "perfluorooctanoic acid" chemical CHEBI:35549 ChEBI ESR2 protein Q92731 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-268765 WNT9A protein O14904 UNIPROT CHRNA1 protein P02708 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000887 22309736 t 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-195972 SNRPA protein P09012 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-270627 NAA20 protein P61599 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-267230 PKN1 protein Q16512 UNIPROT PKN1 protein Q16512 UNIPROT "up-regulates activity" phosphorylation Thr531 PNATGTGtFSPGASP -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-249020 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 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-257964 GATAD2A protein Q86YP4 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-263846 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "up-regulates quantity" "precursor of" 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-267553 MDH1 protein P40925 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI "down-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-268099 DLX3 protein O60479 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17060321 f gcesareni "Here we show that bmp2 induces dlx3, a homeodomain protein that activates runx2 gene transcription. Small interfering rna knockdown studies in osteoblasts validate that dlx3 is a potent regulator of runx2." SIGNOR-150177 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 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser26 GTASRPSsSRSYVTT -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-248882 ITGA4 protein P13612 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-253175 "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 PDP2 protein Q9P2J9 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates dephosphorylation 9606 16510868 t lpetrilli "We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1." SIGNOR-144909 RFXAP protein O00287 UNIPROT "RFX complex" complex SIGNOR-C104 SIGNOR "form complex" binding -1 10825209 t miannu "RFXANK and RFXAP bind to each other and form a heterodimer (step 1) that subsequently interacts with RFX5 Upon binding, the conformation of RFX5 changes (step 2) in a way that enables the RFX complex to bind to DNA (step 3) and to recruit other proteins that are required for the transcription of MHC II genes" SIGNOR-221568 buspirone chemical CHEBI:3223 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-258837 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 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 DACT1 protein Q9NYF0 UNIPROT DVL2 protein O14641 UNIPROT down-regulates binding 9606 16446366 t gcesareni "Dapper 1 antagonizes wnt signaling by promoting dishevelled degradation" SIGNOR-144053 Ub:E2 complex SIGNOR-C497 SIGNOR RNF151 protein Q2KHN1 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-271158 metaproterenol chemical CHEBI:6792 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-257874 PRDM14 protein Q9GZV8 UNIPROT Pluripotency phenotype SIGNOR-PH43 SIGNOR up-regulates 31583686 f SimoneGraziosi "SOX17 regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and suppressing somatic differentiation." SIGNOR-269261 Helicase protein P0DTD1-PRO_0000449630 UNIPROT TBK1 protein Q9UHD2 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 32979938 t miannu "We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F)." SIGNOR-262511 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 FYN protein P06241 UNIPROT FYN protein P06241 UNIPROT "up-regulates activity" phosphorylation Tyr28 SLNQSSGyRYGTDPT -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-251168 MAPK1 protein P28482 UNIPROT BCL6 protein P41182 UNIPROT down-regulates phosphorylation Ser343 KSDCQPNsPTESCSS 9606 BTO:0000782;BTO:0000785 9649500 t 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-58485 PLK1 protein P53350 UNIPROT RACGAP1 protein Q9H0H5 UNIPROT up-regulates phosphorylation Ser170 ESLDWDSsLVKTFKL 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-185750 TRAF2 protein Q12933 UNIPROT TICAM1 protein Q8IUC6 UNIPROT up-regulates polyubiquitination 9606 20047764 t miannu "Here, we show that the TRAF family proteins directly bind TICAM-1 and demonstrate that TRAF2 and TRAF6 bind different sites of the N-terminal TICAM-1 and accelerate its polyubiquitination. we speculate that polyubiquitination of TICAM-1 by TRAF2 and TRAF6 is required for TICAM-1 to induce IRF-3 and NF-κB activation. This is supported by the observation that polyubiquitination of TICAM-1 was required for TRAF3-binding to TICAM-1" SIGNOR-271427 TRIM47 protein Q96LD4 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates quantity" ubiquitination 10090 BTO:0000575 29291351 t gianni "CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity" SIGNOR-266443 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 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 STOML2 protein Q9UJZ1 UNIPROT CD3E protein P07766 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 18641330 t Giorgia "We observed that SLP-2 steadily associated with the CD3-epsilon chain of the TCR complex under resting conditions and during the 60 min of stimulation|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-260375 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 LBX1 protein P52954 UNIPROT ZEB1 protein P37275 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002181 19651985 t Luana "Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively " SIGNOR-266054 MAGED1 protein Q9Y5V3 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 BTO:0000222 BTO:0000887 20646279 f gcesareni "These data demonstrate for the first time that maged1 is an important factor required for proper skeletal myoblast differentiation and muscle healing." SIGNOR-166896 MEST protein Q5EB52 UNIPROT LRP6 protein O75581 UNIPROT "down-regulates activity" 9606 21375506 f "Mest/Peg1 inhibited maturation of LRP6 by controlling the glycosylation of LRP6. Knockdown of Mest/Peg1, which might enhance Wnt signalling, blocked adipogenic differentiation of 3T3-L1 cells" SIGNOR-255826 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 CREB1 protein P16220 UNIPROT PLAT protein P00750 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001282 8647095 f lperfetto "We suggest that the mechanism for the transcriptional down-regulation of t-PA by PMA in HT-1080 cells requires CREB-1 binding to the t-PACRE while ATF-2, by associating with the same site, plays a role in PMA-mediated induction of t-PA in HeLa cells." SIGNOR-253732 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT "up-regulates activity" "transcriptional regulation" 10090 PMC3619734 f areggio "Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1induction." SIGNOR-254990 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR AP1 complex SIGNOR-C154 SIGNOR up-regulates phosphorylation Thr232 GGLPEVAtPESEEAF 9606 7816602 t 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-252359 ADORA2B protein P29275 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-257039 PPP1CC protein P36873 UNIPROT EIF2S1 protein P05198 UNIPROT "up-regulates activity" dephosphorylation 9606 27629041 t miannu "Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning. 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-254119 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 PRKCD protein Q05655 UNIPROT CREBBP protein Q92793 UNIPROT unknown phosphorylation Ser437 CLPLKNAsDKRNQQT 11463380 t lperfetto "This study demonstrates that transcriptional control of mitogen-responsive genes by AP-1 and Pit-1 response elements involves direct phosphorylation of CBP and that growth factor€“dependent phosphorylation of CBP within the GF box is indispensable for signaling via these sites. " SIGNOR-249104 ABL1 protein P00519 UNIPROT GMFG protein O60234 UNIPROT "down-regulates activity" phosphorylation Tyr104 KPEQQMMyAGSKNRL 9606 BTO:0001660 24818551 t miannu "Acetylcholine stimulation also increased GMF-γ phosphorylation at Tyr-104. GMF-γ phosphorylation at this residue was mediated by c-Abl tyrosine kinase. The GMF-γ mutant Y104F (phenylalanine substitution at Tyr-104) had higher association with Arp2 in HASM cells upon contractile activation.Furthermore, expression of mutant Y104F GMF-γ attenuated actin polymerization and contraction in smooth muscle." SIGNOR-273536 SRC protein P12931 UNIPROT PLEKHG2 protein Q9H7P9 UNIPROT unknown phosphorylation Tyr489 SEPVKDPyVMFPQNA 9606 BTO:0000007 24378532 t miannu "Through deletion and base substitution mutagenesis we have identified Tyr489 of PLEKHG2 as the site phosphorylated by cSrc.Furthermore, PLEKHG2 is tyrosine phosphorylated at Tyr489 by ephrinB2 receptor signaling via cSrc. Investigation of the physiological function of tyrosine phosphorylation at Tyr489 in PLEKHG2 remains a subject for future studies." SIGNOR-273537 NR3C1 protein P04150 UNIPROT PPARG protein P37231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 10649448 f gcesareni "The dose of DEX required to promote maximal expression of PPARg mRNA is approximately 10 nM, which is within the range of the Kd for the association of DEX with the glucocorticoid receptor in 3T3-L1 cells" SIGNOR-255753 ABL1 protein P00519 UNIPROT STX17 protein P56962 UNIPROT "down-regulates activity" phosphorylation Tyr157 SQSLTQIyALPEIPQ 9534 BTO:0001538 23006999 t miannu "C-Abl was identified as one of the kinases, which phosphorylates syntaxin 17.Western blot shows phosphorylation of syntaxin 17 on Tyr-156 by overexpression and activation of c-Abl. A phospho-mimicking mutant (Y156E) of syntaxin 17 showed reduced interaction with COPI vesicles. These results suggest that tyrosine phosphorylation of syntaxin 17 is likely to have a role in regulating syntaxin 17 dependent membrane trafficking in the early secretory pathway." SIGNOR-273538 AKT proteinfamily SIGNOR-PF24 SIGNOR LARP6 protein Q9BRS8 UNIPROT "up-regulates activity" phosphorylation Ser451 QEKSPGTsPLLSRKM 9606 BTO:0000007 26932461 t miannu "This strongly suggested that Akt dependent phosphorylation of LARP6 targets S451.S451A mutant of LARP6 acts as dominant negative protein in collagen synthesis. these results support the hypothesis that phosphorylation of S451 by Akt is a necessary step to activate productive synthesis type I collagen and suggests that secretion and modifications of type I collagen are impaired if LARP6 is not phosphorylated on S451." SIGNOR-273539 AKT1 protein P31749 UNIPROT SYTL1 protein Q8IYJ3 UNIPROT "down-regulates quantity" phosphorylation Ser241 RMLSSSSsVSSLNSS 9606 BTO:0001321 15998322 t miannu "By mutagenesis analysis and subsequent immunoprecipitation (IP), we established that Akt phosphorylates JFC1 at serine 241. Phosphorylation did not alter the ability of JFC1 to bind to Rab27a. Instead, phosphorylation by Akt dramatically decreased when JFC1 was bound to Rab27a. Finally, we show that as a consequence of in vivo phosphorylation, JFC1 dissociates from the membrane, promoting JFC1 redistribution to the cytosol." SIGNOR-273540 AKT proteinfamily SIGNOR-PF24 SIGNOR TBC1D7 protein Q9P0N9 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser124 GKLPRSPsFPLEPDD 9606 BTO:0000007 30143532 t miannu " Sequence analysis identified a putative site for both Akt-mediated phosphorylation and 14-3-3 binding at Ser-124, and we found that Akt phosphorylates TBC1D7 at Ser-124. However, this phosphorylation had no effect on the binding of TBC1D7 to TSC1, but stabilized TBC1D7." SIGNOR-273541 AKT1 protein P31749 UNIPROT TIFA protein Q96CG3 UNIPROT "up-regulates activity" phosphorylation Thr9 TSFEDADtEETVTCL 9606 BTO:0000007 27965388 t miannu "For the activation of signal 2, Akt is involved in TIFA Thr9 phosphorylation, which is essential for TIFA-TIFA homophilic oligomerization. Thr9 phosphorylation-dependent TIFA oligomerization facilitates the higher-order assembly of NLRP3 inflammasome, as indicated by the interaction between TIFA and caspase-1 in the activated ECs." SIGNOR-273542 ALPK1 protein Q96QP1 UNIPROT TIFA protein Q96CG3 UNIPROT "up-regulates activity" phosphorylation Thr9 TSFEDADtEETVTCL -1 30111836 t miannu "Infection-induced activation of NF-κB and formation of eGFP–TIFA foci required ALPK1-dependent phosphorylation of TIFA at T9 (Extended Data Fig. 3a–e). Upon phosphorylation at T9, TIFA forms foci to activate TRAF6-dependent NF-κB signalling" SIGNOR-273543 AURKA protein O14965 UNIPROT KCTD12 protein Q96CX2 UNIPROT "up-regulates activity" phosphorylation Ser243 ITVCGKTsLAKEVFG 9606 BTO:0000567 28869606 t miannu " In addition, Aurora A phosphorylated KCTD12 at serine 243, thereby initiating a positive feedback loop necessary for KCTD12 to exert its cancer-promoting effects." SIGNOR-273544 AURKA protein O14965 UNIPROT PHLDA1 protein Q8WV24 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser95 PLCLLRVsLLCALRA 9606 BTO:0006218 21807936 t miannu "Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98." SIGNOR-273545 AURKA protein O14965 UNIPROT POU6F1 protein Q14863 UNIPROT "down-regulates activity" phosphorylation Ser197 KLDITPKsAQKLKPV -1 31665313 t miannu " Here, we report that Aurora kinase A phosphorylates mPOU at Ser197 and inhibit its DNA-binding ability. " SIGNOR-273546 AURKA protein O14965 UNIPROT SECISBP2L protein Q93073 UNIPROT "up-regulates quantity" phosphorylation Thr573 IAKLKRPtALKKVIL 9606 BTO:0000007 31314582 t miannu "To explore the underlying mechanisms, we found that SLAN, a potential tumor suppressor, served as a substrate of Aurora-A and knockdown of SLAN induced immature cytokinesis. Aurora-A phosphorylates SLAN at T573 under the help of the scaffold protein 14-3-3η. Intriguingly, SLAN T573D or T573E inactivated and T573A activated the key cytokinesis regulator RhoA." SIGNOR-273547 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 AURKA protein O14965 UNIPROT SPIN1 protein Q9Y657 UNIPROT "up-regulates activity" phosphorylation Ser109 LNKDERVsALEVLPD 9606 BTO:0000567 22258766 t miannu "The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function." SIGNOR-273549 AURKA protein O14965 UNIPROT SPIN1 protein Q9Y657 UNIPROT "up-regulates activity" phosphorylation Ser124 RVATSRIsDAHLADT 9606 BTO:0000567 22258766 t miannu "The Ser84 and Ser99 amino acids within SPINDLIN1 were further identified as the key functional sites in WNT/TCF-4 signaling activation. Mutation of these two sites of SPINDLIN1 abolished its effects on promoting WNT/TCF-4 signaling and cancer cell proliferation. We further found that Aurora-A could interact with and phosphorylate SPINDLIN1 at its key functional sites, Ser84 and Ser99, suggesting that phosphorylation of SPINDLIN1 is involved in its oncogenic function." SIGNOR-273550 ROCK1 protein Q13464 UNIPROT Membrane_blebbing phenotype SIGNOR-PH24 SIGNOR up-regulates 9606 11283607 f "Cleaved by CASP3" amattioni "Activation of rock i by caspase-3 seems to be responsible for bleb formation in apoptotic cells." SIGNOR-106549 AURKA protein O14965 UNIPROT TIFA protein Q96CG3 UNIPROT "up-regulates activity" phosphorylation Thr9 TSFEDADtEETVTCL 9606 BTO:0001545 28069801 t miannu "Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. " SIGNOR-273551 AURKB protein Q96GD4 UNIPROT SHCBP1 protein Q8NEM2 UNIPROT "up-regulates activity" phosphorylation Ser634 QIKKKRLsELGITQA 9606 BTO:0000567 23704356 t miannu "AurB phosphorylates Ser634 of SHCBP1 during mitosis. We generated a phosphorylation site mutant, S634A-SHCBP1, which was prematurely recruited to the central spindle during anaphase and inhibited furrowing. " SIGNOR-273552 CAMK2A protein Q9UQM7 UNIPROT GLO1 protein Q04760 UNIPROT "up-regulates activity" phosphorylation Thr107 ELTHNWGtEDDETQS -1 32966793 t miannu "This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax)." SIGNOR-273553 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 CDK1 protein P06493 UNIPROT FMNL2 protein Q96PY5 UNIPROT "up-regulates activity" phosphorylation Ser1016 MEQQDPKsPSHKSKR 9606 BTO:0000567 29930204 t miannu "In this study we have identified the formin FMNL2 as a novel substrate for CDK1 that plays a role in maintaining adhesion complexes and facilitates cell cycle–dependent changes in adhesion complexes. Knockdown of FMNL2 or expression of a nonphosphorylatable S1016A mutant resulted in the loss of adhesion complexes and stress fibers within the cell body, with peripheral structures being maintained. " SIGNOR-273555 AKT1 protein P31749 UNIPROT KHSRP protein Q92945 UNIPROT "down-regulates activity" phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto "Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome." SIGNOR-252497 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr106 SGNSAEEyYENVPCK -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273556 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr107 GNSAEEYyENVPCKA -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273557 CHEK1 protein O14757 UNIPROT E2F6 protein O75461 UNIPROT "down-regulates activity" phosphorylation Ser12 RPARKLPsLLLDPTE -1 23954429 t miannu "the checkpoint kinase Chk1 phosphorylates E2F6 leading to its dissociation from promoters." SIGNOR-266370 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr80 QDNVDQTySEELCYT -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273558 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr128 LGGTETEySLLHMPS -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273559 LYN protein P07948 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr86 TYSEELCyTLINHRV -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273560 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr171 RGTLRKGtLGSKGQK -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-273488 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 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 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 AKT2 protein P31751 UNIPROT PKP1 protein Q13835 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr166 LYCDPRGtLRKGTLG -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-273491 PRKACA protein P17612 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT "up-regulates activity" phosphorylation Ser686 LGRSIVSsPQGKSGP -1 29230552 t miannu "PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation." SIGNOR-273561 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 ATM protein Q13315 UNIPROT KHDC3L protein Q587J8 UNIPROT "up-regulates activity" phosphorylation Thr145 IEVREAGtQRSVEVR 9606 BTO:0001086 31609975 t miannu "Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. " SIGNOR-273505 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser233 ARLHTKPsQAPAVEV 9606 BTO:0000007 27829214 t miannu "PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1. " SIGNOR-273506 ATM protein Q13315 UNIPROT NOP53 protein Q9NZM5 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr289 PATEQAAtQESTFQE 9606 BTO:0000007 27829214 t miannu "PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1. " SIGNOR-273507 "ER stress" stimulus SIGNOR-ST9 SIGNOR BBC3 protein Q9BXH1 UNIPROT up-regulates 9606 22492984 f miannu "Exposure to stress results in the induction of bh3-only proteins, which neutralise the pro-survival proteins" SIGNOR-196938 ATM protein Q13315 UNIPROT PAN2 protein Q504Q3 UNIPROT "up-regulates activity" phosphorylation Ser1003 TKSTIKPsQMSVARI 9606 BTO:0000007 33097710 t miannu "Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52. " SIGNOR-273508 CTSD protein P07339 UNIPROT APP protein P05067 UNIPROT "up-regulates activity" cleavage Phe635 HHQKLVFfAEDVGSN -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-261774 PPP2CB protein P62714 UNIPROT AKT1 protein P31749 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-252636 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 PRKACA protein P17612 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT "up-regulates activity" phosphorylation Ser685 KLGRSIVsSPQGKSG -1 29230552 t miannu "PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation." SIGNOR-273562 PRKACA protein P17612 UNIPROT PKD2L1 protein Q9P0L9 UNIPROT "up-regulates activity" phosphorylation Ser682 EIEKLGRsIVSSPQG -1 29230552 t miannu "PKD2L1 channel activation by PKA phosphorylation. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of β2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser-686 that are significant in the channel regulation by phosphorylation." SIGNOR-273563 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT "up-regulates activity" phosphorylation Thr417 RRLKKKKtTIKKNTL 9606 BTO:0001277 16111671 t miannu "We have previously reported that synaptotagmin VI is present in human sperm cells and that a recombinant protein containing the C2A and C2B domains abrogates acrosomal exocytosis in permeabilized spermatozoa, an effect that was regulated by phosphorylation. We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain." SIGNOR-273564 AKT proteinfamily SIGNOR-PF24 SIGNOR NUAK1 protein O60285 UNIPROT up-regulates phosphorylation Ser600 PARQRIRsCVSAENF 9606 12409306 t esanto "Ser(600) in ark5 was found to be phosphorylated by active akt resulting in the activation of kinase activity." SIGNOR-95247 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT "up-regulates activity" phosphorylation Thr283 DRKCKLQtRVHRKTL 9606 BTO:0001277 16111671 t miannu "We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain." SIGNOR-273565 PRKCB protein P05771 UNIPROT protein Q5T7P8 UNIPROT "up-regulates activity" phosphorylation Thr418 RLKKKKTtIKKNTLN 9606 BTO:0001277 16111671 t miannu "We found by site-directed mutagenesis that Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain--a key region for the function of synaptotagmins--are the PKC target that regulates its inhibitory effect on acrosomal exocytosis. Similarly, we showed that Thr284 in the polybasic region of C2A (KCKLQTR) is the target for PKC-mediated phosphorylation in this domain." SIGNOR-273566 PAN2 protein Q504Q3 UNIPROT RBBP8 protein Q99708 UNIPROT "up-regulates activity" deubiquitination 9606 BTO:0000007 33097710 t miannu "Here, we identify that USP52 directly interacts with and deubiquitinates CtIP, thereby promoting DNA end resection and HR. Mechanistically, USP52 removes the ubiquitination of CtIP to facilitate the phosphorylation and activation of CtIP at Thr-847. In addition, USP52 is phosphorylated by ATM at Ser-1003 after DNA damage, which enhances the catalytic activity of USP52. " SIGNOR-273509 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 LEF1 protein Q9UJU2 UNIPROT ALX4 protein Q9H161 UNIPROT "up-regulates quantity by expression" binding 10090 BTO:0003952 11696550 t miannu "Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter." SIGNOR-254547 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 MAML1 protein Q92585 UNIPROT TP53 protein P04637 UNIPROT up-regulates binding 9606 BTO:0000887 18758483 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-180136 RALA protein P11233 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Thr451 PIPKALGtPVLTPPT 10090 11689711 t gcesareni "We conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT." SIGNOR-252984 IL4R protein P24394 UNIPROT JAK1 protein P23458 UNIPROT up-regulates 9606 7538655 f lperfetto "We demonstrate that il4r triggering induced the tyrosine phosphorylation of jak3" SIGNOR-34756 SEC24C protein P53992 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-265294 FYN protein P06241 UNIPROT FCGR2A protein P12318 UNIPROT "up-regulates activity" phosphorylation Tyr288 YETADGGyMTLNPRA -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-249336 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 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr133 HGNRPSTtVRVHRSS 9606 BTO:0000007 19287380 t miannu "DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d)." SIGNOR-262849 PIK3CA protein P42336 UNIPROT 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-236353 "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 MYF5 protein P13349 UNIPROT MIR1-1 mirna URS000075CF56_9606 RNAcentral "up-regulates quantity" "transcriptional regulation" 10090 21730352 f miannu "We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. We conclude that PU.1 bound to open chromatin near 4 of its induced miR loci with 2 types of kinetics: (1) permanent (miR-146a, miR-342, and miR-338) and (2) transient (miR-155) during myeloid differentiation." SIGNOR-256241 Ub:E2 complex SIGNOR-C497 SIGNOR HLTF protein Q14527 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-271131 VDR protein P11473 UNIPROT CYP3A4 protein P08684 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12147248 f miannu "Expression of cytochrome P450 3A4 (CYP3A4) is induced by 1,25-dihydroxyvitamin D(3)(1,25(OH)(2)D(3)) in Caco-2 cells. However, since a typical vitamin D responsive element has not been found in the 5(')-flanking region of the CYP3A4 gene, the mechanism of 1,25(OH)(2)D(3)-induced CYP3A4 mRNA expression is poorly understood. In the present study, we demonstrated that vitamin D receptor (VDR) is a critical factor for the induction using the antisense oligonucleotide technique." SIGNOR-255600 SRC protein P12931 UNIPROT WBP2 protein Q969T9 UNIPROT "up-regulates activity" phosphorylation Tyr192 MMDGAMGyVQPPPPP 9606 BTO:0000093 21642474 t miannu "Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα." SIGNOR-273567 SRC protein P12931 UNIPROT WBP2 protein Q969T9 UNIPROT "up-regulates activity" phosphorylation Tyr231 AEAAASAyYNPGNPH 9606 BTO:0000093 21642474 t miannu "Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα." SIGNOR-273568 SRPK2 protein P78362 UNIPROT LGMN protein Q99538 UNIPROT "up-regulates activity" phosphorylation Ser226 CYYDEKRsTYLGDWY 10116 BTO:0000938 28826672 t miannu "Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. " SIGNOR-273569 ATM protein Q13315 UNIPROT WRAP53 protein Q9BUR4 UNIPROT "up-regulates activity" phosphorylation Ser64 PVAGSAVsQELREGD 9606 BTO:0001938 27715493 t done miannu "Here, we show that in response to various types of DNA damage, including IR and UV, WRAP53β is phosphorylated on serine residue 64 by ATM with a time-course that parallels its accumulation at DNA lesions. Interestingly, recruitment of phosphorylated WRAP53β (pWRAP53βS64) to sites of such DNA damage promotes its interaction with γH2AX at these locations. " SIGNOR-273511 ZNF420 protein Q8TAQ5 UNIPROT TP53BP1 protein Q12888 UNIPROT "down-regulates activity" binding 9606 BTO:0001109 19377469 t done miannu "These results indicate that Apak is a genuine substrate of ATM kinase. Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis. in response to DNA damage, ATM is rapidly activated by autophosphorylation and mediates p53 activation through disruption of the Apak–p53 complex by phosphorylating Apak on Ser 68." SIGNOR-273512 FHIT protein P49789 UNIPROT AKT3 protein Q9Y243 UNIPROT down-regulates 9606 BTO:0000551 16407838 f miannu "Fhit inhibited activity of akt, a key effector in the phosphatidylinositol 3-oh kinase (pi3k) pathway;loss of endogenous fhit expression caused increased akt activity in vitro and in vivo, and overexpression of constitutively active akt inhibited fhit-induced apoptosis" SIGNOR-143706 ATM protein Q13315 UNIPROT ZNF420 protein Q8TAQ5 UNIPROT "down-regulates activity" phosphorylation Ser68 NTYETELsQWEMSDR 9606 BTO:0001109 19377469 t done miannu "These results indicate that Apak is a genuine substrate of ATM kinase. Apak phosphorylation on Ser 68 is critical for p53-mediated apoptosis. in response to DNA damage, ATM is rapidly activated by autophosphorylation and mediates p53 activation through disruption of the Apak–p53 complex by phosphorylating Apak on Ser 68." SIGNOR-273513 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 TRAF1 protein Q13077 UNIPROT TRAF2 protein Q12933 UNIPROT up-regulates binding 9606 8069916 t gcesareni "Traf1 and traf2 can form homo- and heterotypic dimers." SIGNOR-34768 HOXA9 protein P31269 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-254211 FZD5 protein Q13467 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-258963 RAC1 protein P63000 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 "BTO:0003009; BTO:0000018" 22549160 f irozzo "The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. We found that silencing of Rac1 expression decreases NSCLC migration and proliferation [.]" SIGNOR-259088 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Ser370 TSVTPDVsDNEPDHY -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-251025 Ub:E2 complex SIGNOR-C497 SIGNOR SIAH3 protein Q8IW03 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-271264 "Camostat mesylate" chemical CID:5284360 PUBCHEM TMPRSS2 protein O15393 UNIPROT "down-regulates activity" "chemical inhibition" 9606 32142651 t Monia "Ndeed, the clinically proven serine protease inhibitor camostat mesylate, which is active against TMPRSS2 (Kawase et al., 2012), partially blocked SARS-2-S-driven entry into Caco-2 (Figure S3 B) and Vero-TMPRSS2 cells, efficiently blocked 2019-nCoV-S-driven entry into Caco-2 (TMPRSS2+) but not 293T (TMPRSS2- 110 ) cells while the CatB/L inhibitor E64d had the opposite effect" SIGNOR-261098 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 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 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr106 SGNSAEEyYENVPCK -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273570 FOXE1 protein O00358 UNIPROT MSX1 protein P28360 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 21177256 f miannu "The MSX1 and TGF-β3 up-regulation in response to FOXE1 at both transcriptional and translational levels and the recruitment of FOXE1 to specific binding motifs, together with the transactivation of the promoters of these genes, indicate that MSX1 and TGF-β3 are direct FOXE1 targets." SIGNOR-254173 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr107 GNSAEEYyENVPCKA -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273571 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr80 QDNVDQTySEELCYT -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273572 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr128 LGGTETEySLLHMPS -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273573 SYK protein P43405 UNIPROT GCSAM protein Q8N6F7 UNIPROT "up-regulates activity" phosphorylation Tyr86 TYSEELCyTLINHRV -1 31362927 t miannu "Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148.  Y148 (in black) was already phosphorylated before the addition of kinases. We demonstrate that Grb2 facilitates HGAL and Syk binding following BCR stimulation but does not affect the HGAL-mediated increase in Syk kinase activity. Previous studies showed that Grb2 inhibits BCR signaling by decreasing the activation of Syk by Lyn.11 Thus, while HGAL and Grb2 oppositely affect Syk kinase activity, this is not due to direct Grb2 effects on HGAL-mediated Syk kinase activation." SIGNOR-273574 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT "up-regulates activity" phosphorylation Tyr193 EDEESEDyQNSASIH 10090 BTO:0001930 14722116 t miannu "Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases." SIGNOR-273575 PHA-848125 chemical CID:16718576 PUBCHEM CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206151 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT "up-regulates activity" phosphorylation Tyr136 EDDDANSyENVLICK 10090 BTO:0001930 14722116 t miannu "Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases." SIGNOR-273576 SYK protein P43405 UNIPROT LAT2 protein Q9GZY6 UNIPROT "up-regulates activity" phosphorylation Tyr233 EEDGEPDyVNGEVAA 10090 BTO:0001930 14722116 t miannu "Our results indicated that human LAB was primarily phosphorylated on three membrane-distal tyrosines, Tyr(136), Tyr(193), and Tyr(233). Mutation of these three tyrosines abolished Grb2 binding and LAB function. Our data suggested that these tyrosines are the most important tyrosines for LAB function.The dramatic reduction in phosphorylation of the LAB Y233F mutant suggested that Tyr233 is a primary target of the Syk family kinases." SIGNOR-273577 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT "down-regulates activity" phosphorylation Thr727 QKLRESEtSVTTAQA 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273578 AS-605240 chemical CID:5289247 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189921 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT "down-regulates activity" phosphorylation Ser745 PEYLEQPsRSDFSKH 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273579 VRK2 protein Q86Y07 UNIPROT USP25 protein Q9UHP3 UNIPROT "down-regulates activity" phosphorylation Thr680 QPLVGIEtLPPDLRD 9606 BTO:0000007 25755282 t miannu "Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues. " SIGNOR-273580 WNT4 protein P56705 UNIPROT MYOD1 protein P15172 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-60373 YES1 protein P07947 UNIPROT WBP2 protein Q969T9 UNIPROT "up-regulates activity" phosphorylation Tyr192 MMDGAMGyVQPPPPP 9606 BTO:0000093 21642474 t miannu "Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα." SIGNOR-273581 YES1 protein P07947 UNIPROT WBP2 protein Q969T9 UNIPROT "up-regulates activity" phosphorylation Tyr231 AEAAASAyYNPGNPH 9606 BTO:0000093 21642474 t miannu "Using dominant-negative, constitutively active mutants, RNAi, and pharmacological studies, we demonstrated that phosphorylation of WBP2 at Tyr192 and Tyr231 could be regulated by c-Src and c-Yes kinases.We further showed that abrogating WBP2 phosphorylation impaired >60% of ERα reporter activity, putatively by blocking nuclear entry of WBP2 and its interaction with ERα." SIGNOR-273582 "A5/b1 integrin" complex SIGNOR-C163 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-269012 VKORC1 protein Q9BQB6 UNIPROT "vitamin K" smallmolecule CHEBI:28384 ChEBI "down-regulates quantity" "chemical modification" 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-265904 CDK1 protein P06493 UNIPROT ODF2 protein Q5BJF6 UNIPROT "up-regulates activity" phosphorylation Ser796 S-->Y 9606 BTO:0000567 19386263 t miannu "Phosphorylation of hCenexin1 at S796 is critical for the hCenexin1-Plk1 interaction.Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits Plk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and Plk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles." SIGNOR-273584 NR4A3 protein Q92570 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 9606 30455429 t miannu "NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis." SIGNOR-259399 CDK1 protein P06493 UNIPROT PPP1R13L protein Q8WUF5 UNIPROT "up-regulates activity" phosphorylation Ser84 EPFGSRGsPRKAATD 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-273585 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 CDK1 protein P06493 UNIPROT PPP6R2 protein O75170 UNIPROT "down-regulates activity" phosphorylation Ser771 ESGPRCSsPVDTECS -1 29764989 t done miannu "We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit." SIGNOR-273587 CDK1 protein P06493 UNIPROT RAB11FIP3 protein O75154 UNIPROT "up-regulates quantity" phosphorylation Ser102 GPRGQLAsPDAPGPG 9606 BTO:0000567 22401586 t done miannu "FIP3 is phosphorylated on S102 in a cell cycle-dependent manner. We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase." SIGNOR-273588 CDK1 protein P06493 UNIPROT PLK1 protein P53350 UNIPROT "up-regulates activity" phosphorylation Ser1375 S>1374 9606 BTO:0000567 26259146 t done 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 PLK1 protein P53350 UNIPROT RSF1 protein Q96T23 UNIPROT "up-regulates activity" phosphorylation Ser1359 ENVGKVGsPLDYSLV 9606 BTO:0000567 26259146 t done 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-273590 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 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 F2RL1 protein P55085 UNIPROT F2RL1 protein P55085 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 21072196 f miannu "PAR2 expression is up-regulated following PAR2 activation. This is logical for PAR2, as endogenous activators for the receptor are serine proteases, which irreversibly activate PAR2 through N-terminal cleavage." SIGNOR-254840 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-259465 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT "up-regulates activity" phosphorylation Tyr294 AFQCCRDyENVPAAD 9606 BTO:0000007 12359715 t miannu "Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. " SIGNOR-273534 ERG protein P11308 UNIPROT WNT1 protein P04628 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-261597 PINK1 protein Q9BXM7 UNIPROT Ubiquitin proteinfamily SIGNOR-PF89 SIGNOR up-regulates phosphorylation Ser65 DYNIQKEsTLHLVLR 24784582 t "Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential." SIGNOR-270341 MSH2 protein P43246 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "form complex" binding 9606 15064730 t miannu "The human msh2/6 complex is essential for mismatch recognition during the repair of replication errors." SIGNOR-123702 HOXD3 protein P31249 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002828 14610084 t Luana "The homeobox transcription factor Hox D3 promotes integrin alpha5beta1 expression and function during angiogenesis." SIGNOR-261650 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 imiquimod chemical CHEBI:36704 ChEBI TLR7 protein Q9NYK1 UNIPROT "up-regulates activity" "chemical activation" 9606 15661881 t miannu "Imiquimod and resiquimod can tentatively be defined as human TLR7 or TLR7/8 agonists, respectively." SIGNOR-259244 CBP/p300 complex SIGNOR-C6 SIGNOR DDX5 protein P17844 UNIPROT up-regulates binding 9606 12527917 t miannu "Cbp/p300 interact with p68 rna helicase / the atpase activity of p68 is required for the specific transcriptional activation of cbp" SIGNOR-97274 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-268341 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 CSNK1A1 protein P48729 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser321 NSNASTVsGRLSPIM 9606 20110348 t lperfetto "Casein kinase (ck) 1 mediates the hierarchical phosphorylation of foxo3a at s318 and s321, which like foxo1 (rena et al., 2002 blue right-pointing triangle, 2004 blue right-pointing triangle), is probably to enhance its rate of nuclear export" SIGNOR-252900 N protein P0DTC9 UNIPROT G3BP1 protein Q13283 UNIPROT "down-regulates activity" binding 9606 32353859 t miannu "N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms" SIGNOR-260749 PPARGC1A protein Q9UBK2 UNIPROT SOD2 protein P04179 UNIPROT up-regulates 10090 18074631 f lperfetto "In fact, experiments with either genetic knockouts or RNAi for the PGC1s show that the ability of ROS to induce a ROS scavenging programme depends entirely on the PGC1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins such as catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat." SIGNOR-253395 PRKACA protein P17612 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser17 DASQRRRsLEPAENV 9606 11804588 t llicata "Pka activated src both in vitro and in vivo by phosphorylating src on serine 17" SIGNOR-114277 FANCM protein Q8IYD8 UNIPROT TOPBP1 protein Q92547 UNIPROT up-regulates relocalization 9606 20372056 t gcesareni "The enzymatic activity of fan cm is then required to remodel and stabilize the fork to allow topbp1 access to activate atr , in a 9-1-1-independent manner." SIGNOR-164765 (R)-noradrenaline smallmolecule CHEBI:18357 ChEBI ADRA2A protein P08913 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-257453 GSK3B protein P49841 UNIPROT MACF1 protein Q9UPN3 UNIPROT "down-regulates activity" phosphorylation Ser7310 ADPKKSAsRPGSRAG 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-264430 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 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 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val48 KVDGTSHvTGKGVTV -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-263598 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 PDGFRB protein P09619 UNIPROT PDGFRB protein P09619 UNIPROT "up-regulates activity" phosphorylation Tyr716 RPPSAELySNALPVG -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-250256 DRD3 protein P35462 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-257097 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT unknown phosphorylation Ser213 SGAPVKPsPQAAAVE 9606 11110801 t llicata "In vitro phosphorylation of pr with cdk2 has revealed five additional in vitro cdk2 phosphorylation sites: ser(25), ser(213), thr(430), ser(554), and ser(676)." SIGNOR-84984 F2RL3 protein Q96RI0 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-256915 TRIM27 protein P14373 UNIPROT Cell_death phenotype SIGNOR-PH109 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-256667 "alvocidib hydrochloride" chemical CHEBI:90998 ChEBI CDK9 protein P50750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192480 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 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 MST1 protein P26927 UNIPROT STK4 protein Q13043 UNIPROT up-regulates phosphorylation Thr183 DTMAKRNtVIGTPFW 9606 11805089 t llicata "We directly show that okadaic acid induces phosphorylation in the activation loop of mst, and, once phosphorylated, mst is rapidly translocated to the nucleus. when thr183 in mst1 was mutated to ala, no band could be detected by oa treatment,2 indicating that thr183 was the site of phosphorylation." SIGNOR-114289 PKA proteinfamily SIGNOR-PF17 SIGNOR "SMN complex" complex SIGNOR-C158 SIGNOR "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 19103745 t lperfetto "PKA increases SMN complex formation and SMN stability." SIGNOR-253122 CDK4 protein P11802 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser249 AVIPINGsPRTPRRG 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-135181 HIF1A protein Q16665 UNIPROT Aldolase proteinfamily SIGNOR-PF75 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 8955077 f "inferred from family member" 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-270229 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 BACH1 protein O14867 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity" "transcriptional regulation" 9606 31257027 t "inferred from family member" "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-270266 PRKCB protein P05771 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-248963 NT5E protein P21589 UNIPROT AMP smallmolecule CHEBI:456215 ChEBI "down-regulates quantity" "chemical modification" -1 31461341 t Luana "Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine." SIGNOR-269743 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 androst-5-ene-3beta,17beta-diol smallmolecule CHEBI:2710 ChEBI testosterone smallmolecule CHEBI:17347 ChEBI "up-regulates quantity" "precursor of" 10116 BTO:0000534;BTO:0000056 1537836 t lperfetto "We have recently characterized two types of rat 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) isoenzymes expressed in adrenals and gonads. | However, in the presence of NADH, type III isoenzyme, in common with the type I isoform, converts 5 alpha-androstane-3,17-dione (A-dione) and 5 alpha-dihydrotestosterone (DHT) to the corresponding 3 beta-hydroxysteroids." SIGNOR-268640 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NCOA1 protein Q15788 UNIPROT up-regulates phosphorylation 9606 BTO:0001130 12163482 t "inferred from 70% family members" lperfetto "Mapk also directly phosphorylates src-1 at thr1179 and ser1185. Phosphorylation of src-1 by mitogen-activated protein kinase (mapk) is required for optimal progesterone receptor-dependent transcription and for functional cooperation with camp response element-binding protein-binding protein" SIGNOR-270194 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 "AP-2 complex" complex SIGNOR-C245 SIGNOR Endocytosis phenotype SIGNOR-PH123 SIGNOR up-regulates 10116 BTO:0000142 15496985 f lperfetto "Intersectins 1 and 2, epsin2, NECAP and sorting nexin9 were identified as α‐appendage ligands in mass spectrometry of these samples" SIGNOR-260416 PTPN12 protein Q05209 UNIPROT GIT2 protein Q14161 UNIPROT down-regulates dephosphorylation Tyr592 NSTPESDyDNTPNDM 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-142719 SYCP2 protein Q9BX26 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "form complex" binding 9606 22394509 t miannu "The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region." SIGNOR-264199 (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol chemical CHEBI:94701 ChEBI RRM2 protein P31350 UNIPROT "down-regulates activity" "chemical inhibition" -1 7048062 t miannu "In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. 2-F-araATP was a potent inhibitor of ribonucleotide reductase" SIGNOR-258405 AURKA protein O14965 UNIPROT TP53 protein P04637 UNIPROT down-regulates phosphorylation Ser215 DRNTFRHsVVVPYEP 9606 15469940 t llicata "Here we show that p53 is phosphorylated by the mitotic kinase aurora-a at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (brooks, c. L., and gu, w. (2003) curr. Opin. Cell biol. 15, 164-171), the phosphorylation of p53 by aurora-a at ser-215 abrogates p53 dna binding and transactivation activity." SIGNOR-129809 RNF19B protein Q6ZMZ0 UNIPROT UCKL1 protein Q9NWZ5 UNIPROT "down-regulates quantity by destabilization" ubiquitination 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 has as one of its substrates, URKL-1, thus defining this cytolytic protein as an E3 ubiquitin ligase." SIGNOR-271590 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 PRKCD protein Q05655 UNIPROT LIMK2 protein P53671 UNIPROT down-regulates phosphorylation Ser283 EGTLRRRsLRRSNSI 9606 16820362 t "Translocation from Cytosol to Nucleus" gcesareni "Recently we have shown that limk2 shuttles between cytoplasm and nucleus in endothelial cells and that nuclear import is inhibited by protein kinase c-mediated phosphorylation of ser-283." SIGNOR-147716 CACNA1D protein Q01668 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-264326 DIABLO protein Q9NR28 UNIPROT BIRC3 protein Q13489 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000891 10929711 t amattioni "Smac promotes caspase-9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity." SIGNOR-80209 MASP1 protein P48740 UNIPROT C2 protein P06681 UNIPROT "up-regulates activity" cleavage Ser20 LYPGLADsAPSCPQN 9606 BTO:0000392 11907111 t lperfetto "The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase" SIGNOR-263420 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 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 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-89419 prednisone chemical CHEBI:8382 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 4188963 t dermatitis gcesareni SIGNOR-251705 AKT1 protein P31749 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation 9606 21620960 t gcesareni "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-252847 CDK2 protein P24941 UNIPROT ATRIP protein Q8WXE1 UNIPROT unknown phosphorylation Ser239 VIKPEACsPQFGKTS 9606 17638878 t lperfetto "Two novel phosphorylation sites on atrip were identified, s224 and s239" SIGNOR-156932 HDLBP protein Q00341 UNIPROT CTCF protein P49711 UNIPROT "up-regulates activity" binding 9606 BTO:0000599 24725430 t miannu "Vigilin interacts with CCCTC-binding factor (CTCF) and is involved in CTCF-dependent regulation of the imprinted genes Igf2 and H19. vigilin is present at several known CTCF target sites, such as the promoter regions of c-myc and BRCA1, the locus control region of β-globin, and several regions within the Igf2/H19 locus. These results reveal the functional relevance of vigilin and CTCF, and show that the CTCF-vigilin complex contributes to regulation of Igf2/H19." SIGNOR-266693 CDK9 protein P50750 UNIPROT TP53 protein P04637 UNIPROT unknown phosphorylation Ser33 LPENNVLsPLPSQAM 9606 16552184 t llicata "Here, we report for the first time that cyclin dependent kinase 9, whose well-known substrate is rna polymerase ii, can also phosphorylate p53. Specifically, ser33 on the n-terminus and, ser315 and ser392 on the c-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated." SIGNOR-145315 BIRC3 protein Q13489 UNIPROT CASP9 protein P55211 UNIPROT down-regulates binding 9606 9545235 t gcesareni "Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11" SIGNOR-56481 PINK1 protein Q9BXM7 UNIPROT LETM1 protein O95202 UNIPROT "up-regulates activity" phosphorylation Thr192 ILNGHSLtRRERRQF -1 29123128 t lperfetto "Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria." SIGNOR-262540 RPL36A protein P83881 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-262492 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 NR5A1 protein Q13285 UNIPROT CYP11B2 protein P19099 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002588 21169726 f miannu "Inhibitory SF-1 was found to decrease the sensitivity of CYP11B2 and aldosterone to Ang II stimulation, whereas a down-regulation of SF-1 enhanced basal CYP11B2 expression and aldosterone production in H295R cells." SIGNOR-254867 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 MAPK1 protein P28482 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 t 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-120566 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 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 "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 Ub:E2 complex SIGNOR-C497 SIGNOR UNK protein Q9C0B0 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-271219 MAPK1 protein P28482 UNIPROT DOCK1 protein Q14185 UNIPROT unknown phosphorylation Thr1772 QQTPPPVtPRAKLSF 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-262769 GSK3B protein P49841 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" phosphorylation Ser1490 AILNPPPsPATERSH 9606 SIGNOR-C110 16341017 t gcesareni "Glycogen synthase kinase 3 (gsk3), which is known for its inhibitory role in wnt through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of lrp6. We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin." SIGNOR-143041 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 IL6 protein P05231 UNIPROT IL6ST protein P40189 UNIPROT "up-regulates activity" -1 8511589 f 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-238617 PTPRF protein P10586 UNIPROT LRRC4B protein Q9NT99 UNIPROT "up-regulates activity" binding 9606 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-264049 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 SOCS5 protein O75159 UNIPROT EGFR protein P00533 UNIPROT "down-regulates quantity" binding 9606 BTO:0000007 15590694 t miannu "SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation." SIGNOR-271516 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 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 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. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B. FYVE-CENT binds directly to TTC19 and KIF13A." SIGNOR-265542 MYC protein P01106 UNIPROT CCND2 protein P30279 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 7526316 t gcesareni "C-myc directly activates transcription of cyclin d1, cyclin d2 and cdk4, and leads to cdk 4/6 activation." SIGNOR-27446 IKZF1 protein Q13422 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-255403 BTK protein Q06187 UNIPROT DDX41 protein Q9UJV9 UNIPROT "up-regulates activity" phosphorylation Tyr414 DVIQEVEyVKEEAKM 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-266404 PKI-402 chemical CID:44187953 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206259 LPAR proteinfamily SIGNOR-PF2 SIGNOR 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 ‚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-269963 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 RUNX1 protein Q01196 UNIPROT ELF4/RUNX1 complex SIGNOR-C47 SIGNOR "form complex" binding 9606 BTO:0001271 10207087 t miannu "We readily detected an in vivo physical interaction between mef and aml1 proteins in kasumi-1 cells/ coexpression of mef and aml1b synergistically activates promoter function" SIGNOR-66963 Quadazocine chemical CID:115077 PUBCHEM OPRK1 protein P41145 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-258418 taurine smallmolecule CHEBI:15891 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-258579 AURKB protein Q96GD4 UNIPROT DES protein P17661 UNIPROT down-regulates phosphorylation Ser60 VYQVSRTsGGAGGLG -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. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro." SIGNOR-100111 CDX2 protein Q99626 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-70954 TGFBR1 protein P36897 UNIPROT TP63 protein Q9H3D4 UNIPROT unknown phosphorylation Ser160 SSTFDALsPSPAIPS 9606 23166821 t llicata "We show that phosphorylation of _np63_ at s66/68 in response to ultraviolet (uv) irradiation is mediated by alk5" SIGNOR-199781 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AE/b7 integrin" complex SIGNOR-C186 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-259010 JAK2 protein O60674 UNIPROT STAT6 protein P42226 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-249532 PPP3CA protein Q08209 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser276 PQRSRSPsPQPSSHV 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-248690 MTOR protein P42345 UNIPROT ATG13 protein O75143 UNIPROT down-regulates phosphorylation 9606 19211837 t gcesareni "Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2." SIGNOR-183965 PCK1 protein P35558 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "down-regulates quantity" "chemical modification" 9606 30193097 t miannu "√Ǭ†PCK1 regulates an essential rate-limiting step by catalyzing the reversible conversion of oxaloacetate (OAA) into phosphoenolpyruvate (PEP).√Ǭ†" SIGNOR-266588 "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 GSK3B protein P49841 UNIPROT NOTCH2 protein Q04721 UNIPROT "down-regulates activity" phosphorylation Thr2068 LLDEYNVtPSPPGTV 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-101570 MOB1A protein Q9H8S9 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-169755 G6PC2 protein Q9NQR9 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI "up-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-266565 DRD5 protein P21918 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-256914 PHLPP1 protein O60346 UNIPROT AKT1 protein P31749 UNIPROT down-regulates dephosphorylation Ser473 RPHFPQFsYSASGTA 9606 BTO:0000527 15808505 t gcesareni "Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth." SIGNOR-252601 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT unknown phosphorylation Ser98 RLGRRKGsGPKKERR 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-249990 MAPK8 protein P45983 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 9606 BTO:0000567 8846788 t lperfetto "We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity." SIGNOR-236455 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 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 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 PRKACA protein P17612 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser396 FTWKRLRsHSRQYVS 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-128411 "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-270399 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 RFPL4A protein A6NLU0 UNIPROT CCNB1 protein P14635 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10029 BTO:0000246 12525704 t miannu "We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis." SIGNOR-271476 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 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser312 TESITATsPASMVGG 9606 18728222 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-180532 CNTF protein P26441 UNIPROT CNTFR protein P26992 UNIPROT up-regulates binding 9606 10966616 t gcesareni "Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr)" SIGNOR-81379 PRKACA protein P17612 UNIPROT HAND1 protein O96004 UNIPROT "down-regulates activity" phosphorylation Thr107 PKKERRRtESINSAF 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-249991 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001103 17194702 f 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-151688 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 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 CTDSP2 protein O14595 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-248299 KRT14 protein P02533 UNIPROT TRADD protein Q15628 UNIPROT "down-regulates activity" binding 9606 11684708 t "Regulation of binding" miannu "TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD." SIGNOR-251907 CUL1 protein Q13616 UNIPROT RNF7 protein Q9UBF6 UNIPROT "up-regulates activity" binding 9606 10851089 t miannu "SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34. " SIGNOR-271444 NKX2-5 protein P52952 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003265 19479054 f "Using antisense inhibition we disrupted the expression of NKX2-5 and studied changes in expression of cardiac-associated genes. Down-regulation of NKX2-5 resulted in increased beta-catenin while GATA4 was decreased. We demonstrated that this regulation was conferred by binding of NKX2-5 to specific elements (NKEs) in the promoter region of the beta-catenin and GATA4 genes. Using promoter-luciferase reporter assay combined with mutational analysis of the NKEs we demonstrated that the identified NKX2-5 binding sites were essential for the suppression of beta-catenin, and upregulation of GATA4 by NKX2-5." SIGNOR-253653 HBB protein P68871 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-251766 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 clofarabine chemical CHEBI:681569 ChEBI POLG protein P54098 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-258361 FLT3 protein P36888 UNIPROT FZD4 protein Q9ULV1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002882 15650056 f "AML-typical Flt3 mutations induce the expression of Frizzled-4 on the mRNA and protein level, mimicking the effects of IL-3." SIGNOR-261533 EFNB1 protein P98172 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion." SIGNOR-52517 TCL1A protein P56279 UNIPROT AKT1 protein P31749 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-81680 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 CXCL8 protein P10145 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-260257 BDKRB1 protein P46663 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-257362 PIKFYVE protein Q9Y2I7 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-253529 SNIP1 protein Q8TAD8 UNIPROT SMAD4 protein Q13485 UNIPROT down-regulates binding 9606 SIGNOR-C6 10887155 t gcesareni "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-78984 KATNAL2 protein Q8IYT4 UNIPROT TUBE1 protein Q9UJT0 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0001363 29136647 t miannu "KATNAL2 does not sever microtubules composed of α- and β-tubulin but does interact with δ- and ε-tubulin" SIGNOR-267176 "CHEVI complex" complex SIGNOR-C269 SIGNOR SEC22B protein O75396 UNIPROT "up-regulates activity" relocalization 9606 27319744 t lperfetto "VPS33B association with VIPAS39, α-tubulin, and SEC22B was identified by co-immunoprecipitation, mass spectra, and immunoblotting in human embryonic kidney 293T (HEK293T) cells. Also, pull-down experiments revealed that VIPAS39 bound to intact VPS33B; in contrast, α-tubulin and SEC22B separately interacted with the sec1-like domains of VPS33B. Vps33b deficiency in megakaryocytes disturbs the redistribution of Vipas39 and Sec22b to proplatelets, and interrupted the co-localization of Sec22b with Vwf-positive vesicles" SIGNOR-261832 "D-ribulose 5-phosphate" smallmolecule CHEBI:17363 ChEBI "D-xylulose 5-phosphate(2-)" smallmolecule CHEBI:57737 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-267062 SLC24A4 protein Q8NFF2 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-264402 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 IMP smallmolecule CHEBI:17202 ChEBI GDP smallmolecule CHEBI:17552 ChEBI "up-regulates quantity" "precursor of" 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-268130 NACC1 protein Q96RE7 UNIPROT ZBTB14 protein O43829 UNIPROT "up-regulates activity" binding -1 19121354 t miannu "NAC1 potentiated ZF5 mediated repression in Gal4-DBD fusion transient assays. GST pulldown assays further confirmed protein–protein interactions between these proteins and NAC1." SIGNOR-226443 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 MYCN protein P04198 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates quantity by repression" "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-254214 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser245 NQSMDTGsPAELSPT 9606 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-248297 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 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 STK38 protein Q15208 UNIPROT RAB3IP protein Q96QF0 UNIPROT "up-regulates activity" phosphorylation Ser288 KGHTRNKsTSSAMSG 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-263036 SMURF1 protein Q9HCE7 UNIPROT RAD23A protein P54725 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-272691 CDK4 protein P11802 UNIPROT MEF2C protein Q06413 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-176518 PI4K2B protein Q8TCG2 UNIPROT ADP(3-) smallmolecule CHEBI:456216 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-269102 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 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 Ub:E2 complex SIGNOR-C497 SIGNOR RNF112 protein Q9ULX5 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-271235 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1951 SPGYSPTsPTYSLTS 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-120080 "Cullin 7-RBX1-Skp1" complex SIGNOR-C528 SIGNOR AICDA protein Q9GZX7 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 31092637 t miannu " Further analysis indicated that CUL7 mediated AID ubiquitination by forming a complex with FBXW11. In a CUL7 fl/fl CD19 cre+ mouse model, we demonstrated that CUL7 knockout significantly enhanced AID protein levels in B cells in the germinal center and increased both the IgG1 and IgA class switching. Collectively, our results reveal a subtle regulation mechanism for tightly controlling AID protein levels. F-box proteins are components of SCF ubiquitin-ligase complexes that contain Skp1, CUL1, or CUL7, and an F-box protein" SIGNOR-272026 TSHB protein P01222 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-267047 Ub:E2 complex SIGNOR-C497 SIGNOR RNF149 protein Q8NC42 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-271201 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 SCRIB protein Q14160 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-270888 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr869 LGAEEKEyHAEGGKV 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-235956 AKT1 protein P31749 UNIPROT SKI protein P12755 UNIPROT down-regulates phosphorylation Thr458 QPRKRKLtVDTPGAP 9606 19875456 t llicata "The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7" SIGNOR-252527 DLG4 protein P78352 UNIPROT "Postsynaptic density assembly" phenotype SIGNOR-PH163 SIGNOR up-regulates 9606 17243894 f miannu "PSD-95 (the best-studied scaffold protein of the PSD, which binds to NR2 subunits of NMDA receptors) was found to be highly abundant in the adult forebrain PSD" SIGNOR-264230 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 PDHX protein O00330 UNIPROT GCG protein P01275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001731 12783165 f miannu "In glucagonoma cells transduced with a Pdx1-encoding lentiviral vector, insulin gene expression was induced while glucagon mRNA levels were reduced by 50 to 60%." SIGNOR-254901 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 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 FBXO22 protein Q8NEZ5 UNIPROT BACH1 protein O14867 UNIPROT "down-regulates quantity" ubiquitination 9606 31257023 t "Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22." SIGNOR-259331 D-serine smallmolecule CHEBI:16523 ChEBI "NMDA receptor_2A" complex SIGNOR-C347 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-268277 PAMPs stimulus SIGNOR-ST11 SIGNOR Pr3-ANCA complex SIGNOR-C475 SIGNOR "up-regulates quantity" 9606 BTO:0000133 15972951 f lperfetto "In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. |using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus." SIGNOR-270587 MAPK3 protein P27361 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-121402 KATNAL2 protein Q8IYT4 UNIPROT KATNB1 protein Q9BVA0 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 10751153 t miannu "Katanin, a heterodimeric microtubule-severing ATPase, is found localized at mitotic spindle poles. In this paper we demonstrate that human p60 katanin and the C-terminal domain of human p80 katanin both bind microtubules in vitro. Association of these two proteins results in an increased microtubule affinity and increased microtubule-severing activity in vitro. Association of these subunits in transfected HeLa cells increases microtubule disassembly activity and targeting to spindle poles. " SIGNOR-267180 TNKS2 protein Q9H2K2 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-263386 TIMM21 protein Q9BVV7 UNIPROT "MITRAC complex" complex SIGNOR-C538 SIGNOR "form complex" binding 9606 23260140 t "TIM21 is a constituent of MITRAC and presequence translocase complexes ► TIM21 ushers imported subunits of complexes I and IV to assembly intermediates" SIGNOR-272488 UBE2D2 protein P62837 UNIPROT KPC complex SIGNOR-C523 SIGNOR "up-regulates activity" binding 10090 BTO:0000944 15531880 t miannu " We now describe a previously unidentified E3 complex: KPC (Kip1 ubiquitination-promoting complex), consisting of KPC1 and KPC2. KPC1 contains a RING-finger domain, and KPC2 contains a ubiquitin-like domain and two ubiquitin-associated domains. KPC interacts with and ubiquitinates p27(Kip1) and is localized to the cytoplasm. Overexpression of KPC promoted the degradation of p27(Kip1), whereas a dominant-negative mutant of KPC1 delayed p27(Kip1) degradation.  Polyubiquitination activity of KPC was apparent with only Ubc4 or UbcH5A." SIGNOR-271515 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 PRKACA protein P17612 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR up-regulates phosphorylation 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-270232 RAI1 protein Q7Z5J4 UNIPROT CRY1 protein Q16526 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000614 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-266842 BCL11A protein Q9H165 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-251802 TGFBR2 protein P37173 UNIPROT TGFBR1 protein P36897 UNIPROT "up-regulates activity" phosphorylation Thr204 VQRTIARtIVLQESI 452646 7774578 t lperfetto "The TGF-beta type II receptor (T beta R-II) is a transmembrane serine/threonine kinase that, upon ligand binding, recruits and phosphorylates a second transmembrane kinase, T beta R-I, as a requirement for signal transduction. In contrast to the relatively innocuous nature of single site mutations in the ttsgsgsg sequence, mutation of thr200 or 204 to valine causes marked losses in ligand-induced phosphorylation and signaling." SIGNOR-32748 EXOC1 protein Q9NV70 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-270784 PHF6 protein Q8IWS0 UNIPROT UBTF protein P17480 UNIPROT down-regulates binding 9606 BTO:0001271 23229552 t miannu "We demonstrate that phf6 is a nucleolus, ribosomal rna promoter-associated protein. Phf6 directly interacts with upstream binding factor (ubf) through its phd1 domain and suppresses ribosomal rna (rrna) transcription by affecting the protein level of ubf" SIGNOR-200133 "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 PRKCG protein P05129 UNIPROT STXBP1 protein P61764 UNIPROT "down-regulates activity" phosphorylation Ser313 SLKDFSSsKRMNTGE 9913 BTO:0000259 12519779 t lperfetto "Munc18a is essential for neurotransmitter release by exocytosis and can be phosphorylated by PKC in vitro on Ser-306 and Ser-313. We demonstrate that it is phosphorylated on Ser-313 in response to phorbol ester treatment in adrenal chromaffin cells. Mutation of both phosphorylation sites to glutamate reduces its affinity for syntaxin and so acts as a phosphomimetic mutation." SIGNOR-249187 MAPK8 protein P45983 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "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-252355 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR IGF1R protein P08069 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20663909 t lperfetto "We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma." SIGNOR-249595 SKP1 protein P63208 UNIPROT CUL1 protein Q13616 UNIPROT up-regulates binding 9606 10023660 t gcesareni "The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin." SIGNOR-64511 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 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 ATM protein Q13315 UNIPROT WRN protein Q14191 UNIPROT unknown phosphorylation Ser1292 MTIGMHLsQAVKAGC -1 10608806 t llicata "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-250578 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 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 16543730 t lperfetto "Phosphorylation of GSK3 by PKB or SGK1 inhibits GSK3 activity|estern blotting using an antibody specific for the PKB/SGK1 consensus phosphorylation site in GSK3a/beta (serine 21 and 9 respectively) revealed an increase in GSK3a/beta phosphorylation in human embryonic kidney 293 (HEK293) cells overexpressing wild type SGK1, constitutively active SGK1, but not catalytically inactive SGK1.|The effect of SGK1 was mimicked by PKB and SGK3." SIGNOR-249167 CAMKK2 protein Q96RR4 UNIPROT PRKAA2 protein P54646 UNIPROT up-regulates phosphorylation Thr172 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-138364 DUOX1 protein Q9NRD9 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 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-264726 AKAP11 protein Q9UKA4 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 phosphorylation:Thr1136 AKEFAPAtPPSTPHN 26088133 t lperfetto "A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles." SIGNOR-264817 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 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 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 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 PRKCA protein P17252 UNIPROT NPHS1 protein O60500 UNIPROT "up-regulates activity" phosphorylation Thr1120 EYEESQWtGERDTQS 9606 BTO:0000007 21321125 t llicata "Binding of _-arrestin2 to the nephrin intracellular domain depended on phosphorylation of nephrin threonine residues 1120 and 1125 by pkc_." SIGNOR-178695 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 AMPK complex SIGNOR-C15 SIGNOR HNF4A protein P41235 UNIPROT down-regulates phosphorylation Ser303 DPDAKGLsDPGKIKR 9606 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-216511 etorphine chemical CHEBI:4912 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-258802 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 clonidine chemical CHEBI:46631 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-258903 Oxytocin protein P01178-PRO_0000020495 UNIPROT OXTR protein P30559 UNIPROT up-regulates binding 9606 1313946 t gcesareni "The oxytocin receptor, expressed in xenopus oocytes, specifically responds to oxytocin and induces an inward membrane current" SIGNOR-16758 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-245428 PAM16 protein Q9Y3D7 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-267699 DGC complex SIGNOR-C217 SIGNOR NRXN1 protein Q9ULB1 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-265446 AMHR2 protein Q16671 UNIPROT ACVR1 protein Q04771 UNIPROT up-regulates binding 9606 14746809 t gcesareni "See table2" SIGNOR-121593 PRKCE protein Q02156 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser710 GEKSFRRsVVGTPAY 9606 12058027 t miannu "In cells transfected with pkc? Or pkc? The phosphorylation of ser876 was markedly more pronounced than the phosphorylation of ser706/ser710 / the phosphorylation of ser706/ser710 in pkd2 reflects the activation of the kinase." SIGNOR-89415 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr319 TSVYESPySDPEELK 10090 BTO:0000782 10037717 t "the protein tyrosine kinase (PTK) ZAP-70 is rapidly phosphorylated on several tyrosine residues, presumably by two mechanisms: an autophosphorylation and a trans-phosphorylation by the Src-family PTK Lck. we demonstrate that phosphorylation of Tyr319 is required for the positive regulation of ZAP-70 function" SIGNOR-251393 "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 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 RARA protein P10276 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-268548 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM1 protein P11229 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-257468 F2RL1 protein P55085 UNIPROT CD44 protein P16070 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-254843 PIM1 protein P11309 UNIPROT SKP2 protein Q13309 UNIPROT "up-regulates activity" phosphorylation Ser64 SNLGHPEsPPRKRLK 9606 BTO:0000567 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-259818 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser221 PRTSPIMsPRTSLAE 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-248518 RAP1A protein P62834 UNIPROT CAMK1 protein Q14012 UNIPROT "up-regulates activity" 9606 21791615 f miannu "The present study indicates that Epac1 and Rap1 are involved in activation of CaMKI for Ser47 phosphorylation in GCM1. We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1." SIGNOR-262683 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 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-83217 TLN1 protein Q9Y490 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 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-257624 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 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 ABL1 protein P00519 UNIPROT CRK protein P46108 UNIPROT "down-regulates activity" phosphorylation Tyr221 GGPEPGPyAQPSVNT 9606 21779437 t lperfetto "Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl" SIGNOR-175135 "monoisononyl phthalate" chemical CHEBI:132593 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-268779 "TIM22 complex" complex SIGNOR-C424 SIGNOR "Insertion into mitochondrial membrane" phenotype SIGNOR-PH193 SIGNOR up-regulates 32901109 f lperfetto "The TIM22 complex is responsible for the translocation and insertion of hydrophobic membrane proteins, including mitochondrial carrier proteins and translocase subunits (Tim17, Tim22 and Tim23)" SIGNOR-267710 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 ZEB2 protein O60315 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11430829 t Luisa "SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation)." SIGNOR-268950 "precursor messenger RNA" smallmolecule CHEBI:139356 ChEBI "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity" "precursor of" 9606 19224921 t lperfetto "Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation." SIGNOR-268314 HARS1 protein P12081 UNIPROT histidine smallmolecule CHEBI:27570 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-270486 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM49D1 protein C9J1S8 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-271270 TPH2 protein Q8IWU9 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-264012 MAP2K7 protein O14733 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 11062067 t lperfetto "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-83725 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 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 olanzapine chemical CHEBI:7735 ChEBI HTR1E protein P28566 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-258508 STK4 protein Q13043 UNIPROT SAV1 protein Q9H4B6 UNIPROT up-regulates -1 16930133 t lperfetto "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-217833 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 P2RY10 protein O00398 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-257287 HDAC5 protein Q9UQL6 UNIPROT RUNX2 protein Q13950 UNIPROT down-regulates deacetylation 9606 16613856 t gcesareni "Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation" SIGNOR-145983 PRKACA protein P17612 UNIPROT PPP1R1B protein Q9UD71 UNIPROT "up-regulates activity" phosphorylation Thr34 MIRRRRPtPAMLFRL 10604473 t miannu "DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚ " SIGNOR-250031 PRKACA protein P17612 UNIPROT IMMT protein Q16891 UNIPROT "down-regulates activity" phosphorylation Ser528 ELQFRRLsQEQVDNF -1 27153535 t miannu "PKA directly phosphorylated the Ser528 residue of MIC60. Phosphorylation of MIC60 Interrupts Parkin Recruitment and Formation of the MICOS Complex" SIGNOR-266302 ASXL3 protein Q9C0F0 UNIPROT THRB protein P10828 UNIPROT "down-regulates activity" binding 9606 BTO:0000972 25450400 t miannu "We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXRα and TRβ, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXRα and TRβ were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXRα target genes through its recruitment to the LXR-response elements." SIGNOR-266766 SKP2 protein Q13309 UNIPROT CDKN1A protein P38936 UNIPROT down-regulates ubiquitination 9606 15998794 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." SIGNOR-138490 Thrombin-Thrombomodulin complex SIGNOR-C316 SIGNOR PROC protein P04070 UNIPROT "up-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Thrombin also activates the negative regulators of the cascade, after complexing with thrombomodulin (TM) and endothelial protein C receptor (EPCR), to activate protein C (PC) to activated PC (APC)." SIGNOR-263526 RPS6KB2 protein Q9UBS0 UNIPROT 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-178594 "HIF-1 complex" complex SIGNOR-C418 SIGNOR SLC2A1 protein P11166 UNIPROT "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-267450 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 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 zotepine chemical CHEBI:32316 ChEBI SLC6A2 protein P23975 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-257828 CDK4 protein P11802 UNIPROT FOXM1 protein Q08050 UNIPROT up-regulates phosphorylation Ser4 sPRRPLIL 9606 22094256 t lperfetto "We identified the forkhead box m1 (foxm1) transcription factor as a common critical phosphorylation target. Cdk4/6 stabilize and activate foxm1these data identify five overlapping in vivo and in vitro cdk4/6 target sites in foxm1 (s4, s35, t611, t620 and t627)" SIGNOR-177251 HSPA1A protein P0DMV8 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates 9606 16172114 f gcesareni "Hsp70 inhibited stress-induced jnk activation and jnk with sp600125 or by expression of a dominant negative mutant of jnk-blocked bax translocation as effectively as hsp70 overexpression" SIGNOR-140553 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 PRKCA protein P17252 UNIPROT INSR protein P06213 UNIPROT unknown phosphorylation Ser1062 AVKTVNEsASLRERI -1 7926007 t lperfetto "Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites." SIGNOR-248905 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 15618519 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-132672 PTPN11 protein Q06124 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "down-regulates activity" dephosphorylation 9606 16767162 t miannu "Tyr148 of beta-catenin is an shp2 target dephosphorylation site. Together, these results suggest that beta-catenin plays a suppressor role in cell transformation and that shp2, by dephosphorylating beta-catenin, promotes mitogenic, cell survival and transformation signals." SIGNOR-265824 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 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 TGFB1 protein P01137 UNIPROT ENG protein P17813 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002741 21146604 f miannu "In hepatic stellate cells, TGF-β1 upregulates endoglin expression most likely via the ALK5 pathway and requires the SP1 transcription factor." SIGNOR-255202 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 MYC protein P01106 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150;BTO:0000782 BTO:0000887;BTO:0001260 11313917 f amattioni "P27(kip1) gene is a target of transcriptional repression by c-myc." SIGNOR-107032 PPAT protein Q06203 UNIPROT L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "chemical modification" 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-267294 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 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 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT "down-regulates activity" phosphorylation Ser1710 HVTSKCGsLKNIRHR 9606 BTO:0000567 11029056 t miannu "CAMP-dependent protein kinase activity disrupts the MAP2-microtubule interaction in living HeLa cells. S319, S350, and S382 were thus identified as preferred targets of PKA" SIGNOR-250002 "AL/b2 integrin" complex SIGNOR-C169 SIGNOR ICAM1 protein P05362 UNIPROT "up-regulates activity" binding 10090 BTO:0003104 12808052 t lperfetto "The critical cytoplasmic regions of the alphaL/beta2 integrin in Rap1-induced adhesion and migration|Rap1 is a potent inside-out signal that increases LFA-1 adhesive activity." SIGNOR-253364 "Daunorubicin hydrochloride" chemical CHEBI:31456 ChEBI TOP2A protein P11388 UNIPROT "down-regulates activity" "chemical inhibition" 9606 1963303 t miannu "DNA topoisomerase II as the primary target of anti-tumor anthracyclines.Such studies have also given evidence of the peculiar features of the drug interference with DNA topoisomerase II activity. In contrast to other cytotoxic topoisomerase II inhibitors (acridines, epipodophyllotoxins), anthracyclines produce persistent DNA cleavable complexes. This property is more evident with doxorubicin derivatives than with daunorubicin derivatives." SIGNOR-259322 MET protein P08581 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr589 SHDSEENyVPMNPNL 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-250288 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT up-regulates phosphorylation Tyr242 FFQQQMIyDSPPSRA 9606 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-236314 (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 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 mTORC1 complex SIGNOR-C3 SIGNOR GRB10 protein Q13322 UNIPROT up-regulates phosphorylation 9606 21659604 t lperfetto "The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase." SIGNOR-217063 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 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 GFs stimulus SIGNOR-ST12 SIGNOR RTKs proteinfamily SIGNOR-PF38 SIGNOR up-regulates 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-256169 PIM proteinfamily SIGNOR-PF34 SIGNOR 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 cellshere 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-259424 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 CSNK2A1 protein P68400 UNIPROT EIF2B5 protein Q13144 UNIPROT "up-regulates activity" phosphorylation Ser717 LKEAEEEsSEDD 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-250859 DPP3 protein Q9NY33 UNIPROT KEAP1 protein Q14145 UNIPROT "down-regulates quantity by destabilization" cleavage 9606 35278345 t miannu "The influence of DPP3 on the Keap1-Nrf2/ARE signal pathway suggest a direct involvement of DPP3 in the oxidative stress response [8,14,31,53,99,100]. It was shown that DPP3 competes with Nrf2 through the ETGE motif to bind to Keap1 and consequently enhances the translocation of Nrf2 to the nucleus, thereby driving the expression of an array of genes encoding antioxidative enzymes [99]. More specifically, binding of DPP3 to Keap1 releases Nrf2, and thus, prevents its degradation through the 26S proteasome" SIGNOR-268464 GRK2 protein P25098 UNIPROT OPRM1 protein P35372 UNIPROT "down-regulates activity" phosphorylation Ser357 REFCIPTsSNIEQQN 9606 12123746 t "GRK2-mediated phosphorylation is involved in the development of agonist-induced μ-opioid receptor desensitization. two C-terminal amino acids, Ser355 and Thr357, are required for short-term homologous desensitization of μ-opioid receptors expressed in HEK 293 cells." SIGNOR-251458 BAX protein Q07812 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" binding 8358790 t lperfetto "Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered." SIGNOR-249612 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT "up-regulates quantity by stabilization" 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-172003 ATM protein Q13315 UNIPROT AURKB protein Q96GD4 UNIPROT down-regulates 9606 18250156 f gcesareni "Furthermore, atm-mediated i-2 phosphorylation results in the inhibition of the aurora-b kinase, the down-regulation of histone h3 serine 10 phosphorylation, and the activation of the g2/m checkpoint." SIGNOR-160644 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 PAK proteinfamily SIGNOR-PF13 SIGNOR MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation -1 10748018 t "inferred from 70% family members" miannu "PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991." SIGNOR-269973 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 NRF1 protein Q16656 UNIPROT SPAST protein Q9UBP0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22574173 f miannu "we demonstrate that SPAST transcription is positively regulated by NRF1 and SOX11." SIGNOR-254885 SOCS3 protein O14543 UNIPROT STAT3 protein P40763 UNIPROT down-regulates 9606 BTO:0000801 21628332 f lperfetto "SOCS3 attenuates IL-6-induced STAT3 anti-inflammatory effects, as well as IL-4-induced insulin receptor substrate-2/PI3K-mediated gene expression." SIGNOR-249567 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 ASXL1 protein Q8IXJ9 UNIPROT NCOA1 protein Q15788 UNIPROT "up-regulates activity" binding 9606 16606617 t 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-255931 CAMK2A protein Q9UQM7 UNIPROT PEA15 protein Q15121 UNIPROT up-regulates phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 15916534 t gcesareni "Pea-15 is a phosphoprotein containing a ser-104 phosphorylated by protein kinase c and a ser-116 phosphorylated by camkii (calcium/calmodulin-dependent protein kinase ii) or akt. Phosphorylation of ser-104 is implicated in the regulation of glucose metabolism, while phosphorylation at ser-116 is required for pea-15 recruitment to the disc (death-initiation signalling complex)" SIGNOR-137614 (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 PRKCA protein P17252 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 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-262752 ZAP70 protein P43403 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr319 TSVYESPySDPEELK 9606 BTO:0000661 10037717 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-247053 SOX4 protein Q06945 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR down-regulates 9606 BTO:0001271 24183681 f apalma "Collectively, our experiments identified the oncogene Sox4 as a factor mediating increased serial-replating ability and blocked differentiation of Cebpa-deficient progenitors." SIGNOR-255676 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 EPX protein P11678 UNIPROT EPX protein P11678 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-261706 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 PRKACA protein P17612 UNIPROT LASP1 protein Q14847 UNIPROT "down-regulates activity" phosphorylation Ser146 MEPERRDsQDGSSYR 9606 22665060 t llicata "Phosphorylation of lasp-1 by pka at serine 146 induces translocation of the lasp-1/zo-2 complex from the cytoplasm to the nucleus. Interaction occurs within the carboxyterminal proline-rich motif of zo-2 and the sh3 domain in lasp-1." SIGNOR-197720 ILK protein Q13418 UNIPROT PPP1R14C protein Q8TAE6 UNIPROT "up-regulates activity" phosphorylation Thr73 RHQQGKVtVKYDRKE 9606 12804574 t lperfetto "Pka predominantly phosphorylated a site distinct from the inhibitory t73 in kepi. Integrin-linked kinase phosphorylated KEPI (T73) and this dramatically increased inhibition of PP1c" SIGNOR-101835 CTDSP2 protein O14595 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser250 TGSPAELsPTTLSPV 9606 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-248298 USP8 protein P40818 UNIPROT MET protein P08581 UNIPROT "down-regulates quantity" destabilization 9606 BTO:0000567 16520378 t "Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation." SIGNOR-266903 CAMK2D protein Q13557 UNIPROT TPD52 protein P55327 UNIPROT unknown phosphorylation Ser176 KNSPTFKsFEEKVEN 9606 20946871 t gcesareni "Here we demonstrate, using site-specific mutations, that ca(2+)-sensitive phosphorylation at serine 136 modulates the accumulation of d52 at the plasma membrane within 2 min of cell stimulation" SIGNOR-168550 sulpiride chemical CHEBI:32168 ChEBI DRD3 protein P35462 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-258430 STOML2 protein Q9UJZ1 UNIPROT ZAP70 protein P43403 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-260377 VHL protein P40337 UNIPROT CDKN1C protein P49918 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000037 15824735 f miannu "three of the nine targets had been identified previously as candidate TSGs (DOC-2/DAB2, CDKN1C and SPARC) and all were upregulated by wild-type pVHL." SIGNOR-255601 TAF1 protein P21675 UNIPROT GTF2A1 protein P52655 UNIPROT "up-regulates activity" phosphorylation Ser281 DGTGDTSsEEDEDEE 9606 11278496 t lperfetto "TAFII 250 Phosphorylates Human Transcription Factor IIA on Serine Residues Important for TBP Binding and Transcription ActivityAdditional alanine substitutions at serines 280 and 281 reduced phosphorylation to undetectable levels" SIGNOR-246634 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 WNT3A protein P56704 UNIPROT FZD8 protein Q9H461 UNIPROT up-regulates binding 9606 22653731 t gcesareni "Structural basis of wnt recognition by frizzled." SIGNOR-197638 CAMK2G protein Q13555 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 22888005 t gcesareni "The kinase activity of camkii was essential for the activation of notch signaling. We also determined that camkii could enhance the association between notch1-ic and rbp-jk. Furthermore, the physical association between rbp-jk and smrt was substantially suppressed by camkii. 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-191777 AKT2 protein P31751 UNIPROT ANKRD2 protein Q9GZV1 UNIPROT up-regulates phosphorylation Ser99 QERVRKTsLDLRREI 10090 BTO:0000165;BTO:0000222 21737686 t llicata "In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions." SIGNOR-236978 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 AURKA protein O14965 UNIPROT H3C1 protein P68431 UNIPROT unknown phosphorylation Ser11 TKQTARKsTGGKAPR 10090 12234980 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "In the present study, chromosome number instability and increased tumor invasiveness were noted in constitutively AIM-1-overexpressing cells in vivo. Increased mitotic Ser-10 phosphorylation was also observed in various colorectal tumor cells with high AIM-1 expression levels. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus, may play a role in carcinogenesis." SIGNOR-118886 PRKG1 protein Q13976 UNIPROT VASP protein P50552 UNIPROT "down-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-268289 CTDSPL protein O15194 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser245 NQSMDTGsPAELSPT 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-248310 SDH complex SIGNOR-C400 SIGNOR fumarate(2-) smallmolecule CHEBI:29806 ChEBI "up-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-266277 MYT1L protein Q9UL68 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0002572 28379941 t miannu "ChIP–seq experiments showed that 80% of Myt1l targets, including the transcription factor Hes1, were co-bound by the repressive Sin3b–HDAC1 complex early during reprogramming" SIGNOR-266775 FOXO proteinfamily SIGNOR-PF27 SIGNOR PCK1 protein P35558 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 22521266 t gcesareni "Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase)." SIGNOR-252924 TACR3 protein P29371 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-257179 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 8702662 t lperfetto "A fourth peptide derived from slp-76 encompassing tyr residues 423 and 426 was also phosphorylated by zap-70 but with a 10-15-fold lesser efficiency compared to tyr-113, _128, and _145. Phosphorylation of slp-76 by the zap-70 protein-tyrosine kinase is required for t-cell receptor function" SIGNOR-42968 TARBP2 protein Q15633 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-140229 MYC protein P01106 UNIPROT TYMS protein P04818 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-267374 PCDHA10 protein Q9Y5I2 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-265696 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 motesanib chemical CHEBI:51098 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-258253 CSNK2A1 protein P68400 UNIPROT CDC37 protein Q16543 UNIPROT "up-regulates activity" phosphorylation Ser13 VWDHIEVsDDEDETH -1 12930845 t llicata "Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site." SIGNOR-250838 PRKCA protein P17252 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 15730925 f irozzo "PKC-alpha asODN (antisense oligonucleotides) could inhibit the growth and proliferation of HepG2 and induce its apoptosis by blocking the cell signal transduction related to PKC-alpha in vitro, and may be potentially used in the prevention and management of recurrent and metastatic HCC." SIGNOR-256266 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 GSK3A protein P49840 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-198126 FOXO1 protein Q12778 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 18423396 f fspada "Akt1/Pkb-alpha was found to be the major regulator of phosphorylation and nuclear export of Foxo1, whose presence in the nucleus strongly attenuates adipocyte differentiation." SIGNOR-178281 EIF2AK1 protein Q9BQI3 UNIPROT EIF2S1 protein P05198 UNIPROT down-regulates phosphorylation Ser52 MILLSELsRRRIRSI 9606 3352609 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-24543 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 RUNX1 protein Q01196 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 9606 19334039 f lperfetto "AML1/RUNX1 mutants play a central role in the pathogenesis of MDS/AML. Both AML1 mutants are initiating factors for MDS-genesis by inhibiting differentiation of hematopoietic stem cells, and Ni-type mutant requires acquisition of proliferation ability." SIGNOR-249631 2-(2H-Benzo[b][1,4]oxazin-4(3H)-yl)-N-benzyl-5,6,7,8-tetrahydroquinazolin-4-amine chemical CID:49830260 PUBCHEM VCP protein P55072 UNIPROT "down-regulates activity" "chemical inhibition" -1 23316025 t Luana "Inhibition of p97 by ML240 and ML241 is ATP competitive. To determine the mechanism by which ML240 and ML241 inhibited p97 ATPase, we evaluated rates of ATP hydrolysis at different concentrations of ATP. ML240 and ML241 inhibited p97competitively with respect to ATP with a Kivalues of 0.22 mm and 0.35 mm respectively." SIGNOR-261093 INS protein P01308 UNIPROT DUSP6 protein Q16828 UNIPROT down-regulates 9606 22521266 f gcesareni "In conclusion,insulinlikely promotes mkp-3 protein degradation" SIGNOR-197203 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 PRKAA1 protein Q13131 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17609368 f gcesareni "Several in vivo studies using aicar to activate ampk chronically determined that mitochondrial enzymes [e.g., cytochrome c, uncoupling protein 3 (ucp-3)] and proteins involved in glucose uptake (glut4)are increased at the transcriptional level in skeletal muscle." SIGNOR-156786 NFE2L2 protein Q16236 UNIPROT NQO1 protein P15559 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 8962164 f irozzo "These results indicated that hARE-mediated expression of the NQO1 gene and its induction by xenobiotics and antioxidants are mediated by Nrf1 and Nrf2." SIGNOR-256279 "Translation release factor ERF1-ERF3" complex SIGNOR-C494 SIGNOR 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR "down-regulates activity" binding 9606 28368393 t miannu "The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism." SIGNOR-270817 CHEK1 protein O14757 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 BTO:0001321 15659650 t lperfetto "CHK1 and CHK2 phosphorylate the p53 N terminus at Ser15, Thr18, Ser20, and Ser37" SIGNOR-217799 Ub:E2 complex SIGNOR-C497 SIGNOR RMND5B protein Q96G75 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-271256 MAPK1 protein P28482 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser454 YVPMNPNsPPRQHSS 10029 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-249396 TFDP1 protein Q14186 UNIPROT TYMS protein P04818 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-253861 PPP2R5B protein Q15173 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR 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-144808 RDH10 protein Q8IZV5 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-265120 CyclinB/CDK1 complex SIGNOR-C17 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-216745 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 SB-202190 chemical CHEBI:79090 ChEBI PCSK7 protein Q16549 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000876 9738669 t gcesareni "Sb202190, a selective inhibitor of p38 mitogen activated protein kinase, is a powerful regulator of lps-induced mrnas in monocytes." SIGNOR-60130 MAPK1 protein P28482 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1787 SPNYSPTsPSYSPTS 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-120124 palbociclib chemical CHEBI:85993 ChEBI CDK6 protein Q00534 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205707 RIPK3 protein Q9Y572 UNIPROT PYGL protein P06737 UNIPROT up-regulates binding 9606 19632174 t gcesareni "Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro." SIGNOR-186939 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 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 TNFRSF17 protein Q02223 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates 9606 10903733 f miannu "Bcma overexpression induces nf-kb activation" SIGNOR-79510 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 PCDH9 protein Q9HC56 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-269035 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 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 "UV stress" stimulus SIGNOR-ST7 SIGNOR CDKN2A protein P42771 UNIPROT up-regulates 9606 11830546 f miannu "The expression of the melanoma susceptibility gene product p16 is increased after UVR both in epidermally derived cell lines and in human skin. The increased expression of p16 after exposure to suberythemal doses of UVR is potentiated by α-MSH, a ligand for MC1R, and this effect is mimicked by cAMP, the intracellular mediator of α-MSH signaling via the MC1 receptor." SIGNOR-252376 CDK5 protein Q00535 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 9606 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-145967 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Ser518 KGGTPAGsARGSPTR 9606 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-145975 KLF14 protein Q8TD94 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 19088080 f lperfetto "Mechanistically, KLF14 represses the TGFbetaRII promoter via a co-repressor complex containing mSin3A and HDAC2." SIGNOR-271696 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 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1948 SPTSPGYsPTSPTYS 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-203608 Ethylketocyclazocine chemical CHEBI:4901 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-258782 AMPK complex SIGNOR-C15 SIGNOR NOS3 protein P29474 UNIPROT up-regulates phosphorylation Ser1177 TSRIRTQsFSLQERQ 9606 BTO:0000567 18303014 t lperfetto "The central finding of this report is that rosiglitazone rapidly stimulates no production and enos ser-1177 phosphorylation in an ampk-dependent manner" SIGNOR-216627 NRXN3 protein Q9HDB5 UNIPROT NLGN2 protein Q8NFZ4 UNIPROT "up-regulates activity" binding 9606 BTO:0000142 22626546 t miannu "The neurexin–NL2 interaction is sufficient to induce GABAergic differentiation and clustering of GABAARs at postsynaptic sites" SIGNOR-265456 wortmannin chemical CHEBI:52289 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 7503989 t gcesareni "Wortmannin inhibited the activity of partially purified pi3-kinase from calf thymus, as well as the pi3-kinase activity in anti-pi3-kinase p85 immunoprecipitates from rbl-2h3 cells, at a concentration as low as 1.0 nm and with ic50 values of 3.0 nm." SIGNOR-26677 MITF protein O75030 UNIPROT PMEL protein P40967 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12819038 f miannu "The results of the present work demonstrate that the essential melanocyte-specific transcription factor MITF regulates expression of the genes encoding the melanoma tumor markers MLANA and SILV. MITF up- or down-regulation is seen to correspondingly modulate expression of MLANA and SILV in parallel directions, at both mRNA and protein levels." SIGNOR-254589 NTS protein P30990 UNIPROT NTSR1 protein P30989 UNIPROT up-regulates binding 9606 BTO:0000975 1331689 t gcesareni "The rat neurotensin receptor cdna sequence was transfected in chinese hamster ovary cells and cellular clones which stably express the corresponding protein were isolated and characterized. The scatchard analysis of the specific binding of [3h]neurotensin indicated a kd value of 0.45 +/- 0.08 nm and a bmax value of 3.27 +/- 0.29 pmol/mg of protein. ...Neurotensin Stimulated the phosphoinositides hydrolysis" SIGNOR-17369 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 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 DSCAML1 protein Q8TD84 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-264278 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser951 GFHPRRSsQGATQMP 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-249204 MRGPRX1 protein Q96LB2 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-257384 STK3/4 proteinfamily SIGNOR-PF41 SIGNOR LATS1 protein O95835 UNIPROT up-regulates phosphorylation 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¬ñ588) 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-270217 EGFR protein P00533 UNIPROT STAM2 protein O75886 UNIPROT unknown phosphorylation Tyr192 HTETKSLyPSSEIQL -1 11687594 t llicata "Another major tyrosine phosphorylation site of STAM2 was identified as Tyr-192" SIGNOR-251097 TSHR protein P16473 UNIPROT GNAS protein P63092 UNIPROT "up-regulates activity" binding 9606 25878058 t scontino "The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor." SIGNOR-267136 "1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester" chemical CHEBI:92418 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-258634 PRKAA2 protein P54646 UNIPROT SREBF1 protein P36956 UNIPROT down-regulates phosphorylation Ser396 TAVHKSKsLKDLVSA 9606 SIGNOR-C15 21459323 t gcesareni "Here we demonstrate that ampk interacts with and directly phosphorylates sterol regulatory element binding proteins (srebp-1c and -2). Ser372" SIGNOR-173031 IL3 protein P08700 UNIPROT NFIL3 protein Q16649 UNIPROT up-regulates 10090 10082541 f lperfetto "We previously reported that NFIL3 is an IL-3-responsive gene in Baf-3 cells" SIGNOR-242763 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 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 MAPK12/CARM1 complex SIGNOR-C218 SIGNOR SNTB1 protein Q13884 UNIPROT "up-regulates activity" binding 29681515 t apalma "Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated" SIGNOR-255978 SLC2A2 protein P11168 UNIPROT glucose chemical CHEBI:17234 ChEBI "up-regulates quantity" relocalization 9606 25421524 t "The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion." SIGNOR-267386 HES1 protein Q14469 UNIPROT NOC3L protein Q8WTT2 UNIPROT "down-regulates quantity" "transcriptional regulation" 9823 BTO:0003298 23611667 t "The expression level of FAD24 is inversely associated with that of HES1 in porcine MSCs after adipogenic induction. Enforced overexpression of HES1 in MSCs during the early stage of adipogenesis significantly repressed the transcription of FAD24 (P < 0.01) and the other pro-adipogenic genes" SIGNOR-253059 Ub:E2 complex SIGNOR-C497 SIGNOR IRF2BP2 protein Q7Z5L9 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-271128 DYRK2 protein Q92630 UNIPROT DPYSL3 protein Q14195 UNIPROT "up-regulates activity" phosphorylation Thr509 PVFDLTTtPKGGTPA 9606 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-145979 RELA protein Q04206 UNIPROT COMT protein P21964 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000100 19291302 f "Regulation of expression" miannu "TNFα-dependent COMT downregulation was indeed mediated by the NF-κB pathway. Transient expression of p65, the essential component of NF-κB complexes, or IKKβ, the major positive regulator of NF-κB activition, significantly decreased P2-COMT reporter expression." SIGNOR-251964 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 OLIG1 protein Q8TAK6 UNIPROT OLIG2 protein Q13516 UNIPROT up-regulates 9606 BTO:0000938 25206819 f miannu "During central nervous system development, olig1 assists olig2 in formation of the motor neuron progenitor domain (pmn), the area responsible for generation of motor neurons and oligodendrocytes" SIGNOR-205304 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI TBK1 protein Q9UHD2 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190795 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 LTB4R2 protein Q9NPC1 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-256674 ITGB1BP1 protein O14713 UNIPROT "AL/b2 integrin" complex SIGNOR-C169 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-257650 RAB38 protein P57729 UNIPROT BLOC-2 complex SIGNOR-C252 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-260697 linifanib chemical CHEBI:91435 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-258242 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 FXN protein Q16595 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-262125 NLRP1 protein Q9C000 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-256407 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 Ub:E2 complex SIGNOR-C497 SIGNOR DTX4 protein Q9Y2E6 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-271108 PPP2CA protein P67775 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-248621 PPP2CA protein P67775 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Thr641 TRHPPVLtPPDQEVI 10116 8749392 t "Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme." SIGNOR-248622 adenosine smallmolecule CHEBI:16335 ChEBI ADORA3 protein P0DMS8 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-268422 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser217 AHYSPRTsPIMSPRT 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-248372 BTC protein P35070 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-147823 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 KDR protein P35968 UNIPROT GRB2 protein P62993 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-261948 EIF1 protein P41567 UNIPROT "60S cytosolic large ribosomal subunit" complex SIGNOR-C287 SIGNOR "down-regulates activity" 9606 14600024 f lperfetto "Binding of eIF1 to the 40S subunit would block access of the 60S" SIGNOR-269144 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 NDUFS6 protein O75380 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-262180 PTPRF protein P10586 UNIPROT PLCG1 protein P19174 UNIPROT down-regulates dephosphorylation 9606 11121408 t gcesareni "Here we show that lar reduces the constitutive tyrosine autophosphorylation and kinase activity of ret-men2a but not ret-men2b, accompanying a significant decrease of phosphorylation of phospholipase cgamma, akt, and erk1/2." SIGNOR-85166 2-cyclohexyl-6-methoxy-N-(1-propan-2-yl-4-piperidinyl)-7-[3-(1-pyrrolidinyl)propoxy]-4-quinazolinamine chemical CHEBI:95074 ChEBI EHMT1 protein Q9H9B1 UNIPROT "down-regulates activity" "chemical inhibition" -1 26320100 t miannu "Using a small-molecule screen, we found that UNC0638, a selective inhibitor of EHMT1 and EHMT2 histone methyltransferases, induces γ-globin expression." SIGNOR-262239 Ub:E2 complex SIGNOR-C497 SIGNOR HERC3 protein Q15034 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-271291 GARS1 protein P41250 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 ChEBI "up-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-270480 KRT1 protein P04264 UNIPROT MPO protein P05164 UNIPROT "up-regulates quantity" binding 9606 17591979 t "Regulation of binding" miannu "CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1" SIGNOR-251886 PPP2CB protein P62714 UNIPROT PRKCB protein P05771-2 UNIPROT "down-regulates activity" dephosphorylation Thr641 TRHPPVLtPPDQEVI 10116 8749392 t "Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme." SIGNOR-248587 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 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-271324 RELN protein P78509 UNIPROT VLDLR protein P98155 UNIPROT up-regulates binding 9606 11278667 t gcesareni "The hypothesis that the vldl receptor signals in response to reelin binding was recently supported by studies (37) showing direct binding of reelin to the vldl receptor and changes in tyrosine phosphorylation in response to reelin-vldl receptor association." SIGNOR-106295 Naphtho[1,2-d]thiazol-2-amine chemical CID:94880 PUBCHEM KCNN2 protein Q9H2S1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258027 SMARCB1 protein Q12824 UNIPROT CCNA1 protein P78396 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-92779 RPS6KA5 protein O75582 UNIPROT H3C1 protein P68431 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-138483 CDK5 protein Q00535 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Ser75 NSSDTVTsPQRAGPL 9606 BTO:0000938 10544291 t llicata "These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development." SIGNOR-71950 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 UPF2 protein Q9HAU5 UNIPROT UPF1 protein Q92900 UNIPROT "up-regulates activity" binding -1 18066079 t miannu "UPF2 and UPF3b increase UPF1 ATPase activity" SIGNOR-265246 DCAF1 protein Q9Y4B6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 9606 BTO:0005907 25026211 t miannu "CRL4 DCAF1 ubiquitylates and inhibits Lats." SIGNOR-272228 CSNK2A1 protein P68400 UNIPROT ESR1 protein P03372 UNIPROT down-regulates phosphorylation Ser559 PTSRGGAsVEETDQS 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-162657 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR BGN protein P21810 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15536164 f miannu "Biglycan, NGAL, and MMP-9 are transcriptionally up-regulated by NF-kappaB, a transcription factor that is activated in FAP nerves and SG." SIGNOR-254797 TEAD1 protein P28347 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 21211055 f gcesareni "Tead1 can regulate transcription of the foxo3a gene through the binding to the m-cat element, demonstrated with independent chip-pcr analysis, emsa and luciferase reporter system assay. The over-expression and inhibition analysis suggest that foxo3a was positively regulated by tead1." SIGNOR-253003 PLAG1 protein Q6DJT9 UNIPROT IGF2 protein P01344 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14695992 f miannu "Plag1 has been shown be a transcriptional activator of igf2" SIGNOR-120363 MEF2D protein Q14814 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-238751 AKT1 protein P31749 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-249627 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 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM2 protein Q14416 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-264071 SRC protein P12931 UNIPROT RAC1 protein P63000 UNIPROT up-regulates phosphorylation 9606 17991704 t gcesareni "N attractive hypothesis consistent with our present data is that the gef responsible for rac activation in mce cells may be activated by src family kinase tyrosine phosphorylationour results present a novel mechanism by which the pi3k and src signaling cascades cooperate to activate rac and promote intestinal epithelial cell migration downstream of egfr." SIGNOR-158954 KEAP1 protein Q14145 UNIPROT NFE2L2 protein Q16236 UNIPROT down-regulates binding 9606 24997453 t miannu "Keap1 is an oxidative stress-sensing protein and is a negative regulator of nuclear factor-erythroid-2-related factor 2 (nrf2)." SIGNOR-205229 PI3K complex SIGNOR-C156 SIGNOR 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-252703 CHD1 protein O14646 UNIPROT SF3a complex SIGNOR-C345 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 18042460 t miannu "CHD1 was found to bridge core spliceosomal components to H3K4me3 via specific interactions with the SF3a sub-complex of U2 snRNP. The recruitment of SF3a and the efficiency of pre-mRNA splicing were perturbed upon reduction of CHD1 and H3K4me3." SIGNOR-263951 MAP3K14 protein Q99558 UNIPROT CHUK protein O15111 UNIPROT "up-regulates activity" phosphorylation Ser180 DQGSLCTsFVGTLQY 9606 SIGNOR-C14 9520446 t lperfetto "NIK preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa." SIGNOR-55946 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 glucose chemical CHEBI:17234 ChEBI PRKAA1 protein Q13131 UNIPROT "down-regulates activity" 10090 BTO:0000222 18477450 f "Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK)." SIGNOR-256136 VPS39 protein Q96JC1 UNIPROT SMAD4 protein Q13485 UNIPROT "down-regulates activity" relocalization 9534 12941698 t miannu "The data demonstrating binding of TLP to TGF-β and activin type II receptors and selective inhibition of Smad3/Smad4 complex formation by deregulated TLP suggest that TLP is involved in localizing these receptors and Smad4 to specific intracellular compartments, where it regulates formation of Smad3/Smad4 but not Smad2/Smad4 complexes." SIGNOR-261377 RAB22A protein Q9UL26 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-260621 4-hydroxy-17beta-estradiol smallmolecule CHEBI:62845 ChEBI 17beta-estradiol smallmolecule CHEBI:16469 ChEBI "up-regulates quantity" "precursor of" 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-269755 MAPK3 protein P27361 UNIPROT MYL1 protein P05976 UNIPROT up-regulates phosphorylation 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni "Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein." SIGNOR-148002 IKBKB protein O14920 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" phosphorylation Ser672 VRGPVSGsPDSMNAS 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-251275 KDR protein P35968 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 phosphorylation:Tyr1175 AQQDGKDyIVLPISE 16835467 t gcesareni "(vegfr) phosphorylated y1175 creates a binding site for phospholipase cgamma1 (plc-gamma1)" SIGNOR-147870 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 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 dexamethasone chemical CHEBI:41879 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-106472 EIF2B4 protein Q9UI10 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-269142 CSNK2A1 protein P68400 UNIPROT RGS19 protein P49795 UNIPROT unknown phosphorylation Ser24 ADRPPSMsSHDTASP -1 10760275 t llicata "Phosphorylation was Mn(2+)-dependent, using both purified CK2 and CCVs. Ser-24 was identified as one of the phosphorylation sites. Our results establish that GAIP is phosphorylated and that only the membrane pool is phosphorylated, suggesting that GAIP can be regulated by phosphorylation events taking place at the level of clathrin-coated pits and vesicles." SIGNOR-250943 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 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 FBH1 protein Q8NFZ0 UNIPROT RAD51 protein Q06609 UNIPROT "up-regulates activity" binding -1 25585578 t miannu "The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64." SIGNOR-272451 FBH1 protein Q8NFZ0 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding -1 25585578 t miannu "The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64." SIGNOR-272452 RPS6KA5 protein O75582 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 12763138 t gcesareni "The stat3-mediated transactivation was reduced by blocking the stat3 serine phosphorylation with the mek inhibitor u0126 or by expression of kinase-inactive msk1." SIGNOR-101251 NF1 protein P21359 UNIPROT ADCY3 protein O60266 UNIPROT up-regulates 9606 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-204034 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR AKT proteinfamily SIGNOR-PF24 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-255493 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 MAPK1 protein P28482 UNIPROT SMAD3 protein P84022 UNIPROT unknown phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 19914168 t lpetrilli "In contrast, ERK2 phosphorylated all four Smad1 residues almost evenly, while showing a preference for S204 over S208 and S213 in Smad3" SIGNOR-161698 F2RL1 protein P55085 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-257359 "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 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 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 CSMD1 protein Q96PZ7 UNIPROT C4B protein P0C0L5 UNIPROT "down-regulates quantity" binding 9606 28345259 t miannu "CUB and sushi multiple domains 1 (CSMD1) is a relatively poorly studied large transmembrane protein of 390 kDa composed of 14 N-terminal CUB domains interspersed with complement control protein (CCP) domains followed by 15 consecutive CCP domains. The active domains of CSMD1 were then identified in CCP17-21, which were shown to interact with C4b and C3b and present these complement proteins for degradation by factor" SIGNOR-265149 AMOT/MPP5/INADL/LIN7C complex SIGNOR-C27 SIGNOR WWTR1 protein Q9GZV5 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-170361 LRRK2 protein Q5S007 UNIPROT LRRK2 protein Q5S007 UNIPROT unknown phosphorylation Thr1404 GREEFYStHPHFMTQ 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." SIGNOR-188433 EIF2S1 protein P05198 UNIPROT HBG2 protein P69892 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 24714526 f miannu "Reduction of globin inclusions and induction of ATF4 and HbF by the HRI-eIF2αP signaling provide strong bases for targeting this pathway for novel pharmaceutical therapy of hemoglobinopathy." SIGNOR-251818 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 GNB1 protein P62873 UNIPROT SRC protein P12931 UNIPROT "up-regulates activity" 15345719 f "In this study, we investigated the possible role of the Gβγ heterodimer in signaling Gi-induced Src activation" SIGNOR-251107 NUDCD2 protein Q8WVJ2 UNIPROT PAFAH1B1 protein P43034 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000567 20133715 t miannu "The type I lissencephaly gene product LIS1, a key regulator of cytoplasmic dynein, is critical for cell proliferation, survival, and neuronal migration. However, little is known about the regulation of LIS1. Here, we identify a previously uncharacterized mammalian homolog of Aspergillus NudC, NudCL2 (NudC-like protein 2), as a regulator of LIS1. NudCL2 is localized to the centrosome in interphase, and spindle poles and kinetochores during mitosis, a pattern similar to the localization of LIS1 and cytoplasmic dynein. Depletion of NudCL2 destabilized LIS1 and led to phenotypes resembling those of either dynein or LIS1 deficiency. NudCL2 complexed with and enhanced the interaction between LIS1 and Hsp90. Either disruption of the LIS1-Hsp90 interaction with the C terminus of NudCL2 or inhibition of Hsp90 chaperone function by geldanamycin decreased LIS1 stability." SIGNOR-252167 AKT3 protein Q9Y243 UNIPROT FOXO3 protein O43524 UNIPROT down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 19188143 t gcesareni "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-183648 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 ALDH1A1 protein P00352 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-265122 NOXA1 protein Q86UR1 UNIPROT BCL2 protein P10415 UNIPROT "down-regulates activity" 9606 19879762 t lperfetto "BH3-only proteins containing only a single BH domain and including Puma, Noxa, Bid and Bad as well as other factors are particularly important for such neutralisation, binding and regulating the anti-apoptotic Bcl-2 proteins to promote apoptosis" SIGNOR-209684 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 NDN protein Q99608 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates activity" binding 10090 BTO:0000920 24392139 t lperfetto "Necdin interacts with E2F transcription factors and suppresses E2F1-dependent transcriptional activation of the cyclin-dependent kinase Cdk1 gene. Here we show that necdin serves as a suppressor of NPC proliferation in the embryonic neocortex." SIGNOR-253382 ZDHHC2 protein Q9UIJ5 UNIPROT DLG4 protein P78352 UNIPROT "up-regulates activity" palmitoylation Cys3 cLCIVTTK 9606 23836932 t "Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation." SIGNOR-262296 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser628 LSLGSGIsQCGYSST 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250817 VWF protein P04275 UNIPROT "AIIB/b3 integrin" complex SIGNOR-C173 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-261854 trimethyl-[(5-methyl-2-furanyl)methyl]ammonium chemical CHEBI:94038 ChEBI CHRM4 protein P08173 UNIPROT "up-regulates activity" "chemical activation" 10029 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-258646 "D-glyceraldehyde 3-phosphate(2-)" smallmolecule CHEBI:59776 ChEBI "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI "up-regulates quantity" "precursor of" 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-266493 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 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR RAD51 protein Q06609 UNIPROT "up-regulates activity" ubiquitination Lys64 KKELINIkGISEAKA -1 25585578 t miannu "The F-box DNA helicase 1 (FBH1) is a 3'-5' DNA helicase with a putative function as a negative regulator of HR. It is the only known DNA helicase to contain an F-box, suggesting that one of its functions is to act as a ubiquitin ligase as part of an SCF (SKP1, CUL1 and F-box) complex. Here we report that the central player in HR, RAD51, is ubiquitylated by the SCF(FBH1) complex. Expression of an ubiquitylation-resistant form of RAD51 in human cells leads to hyperrecombination, as well as several phenotypes indicative of an altered response to DNA replication stress. However, K58/64R RAD51 was ubiquitylated much less efficiently by FBH1 in vitro than was wild-type (WT) RAD51 (Fig. 1d), confirming that the primary sites of modification by FBH1 on RAD51 are K58 and K64." SIGNOR-272454 PRKAA1 protein Q13131 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser366 SPQVRTLsGSRPPLL -1 14709557 t miannu "AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase" SIGNOR-250402 CYP17A1 protein P05093 UNIPROT 17alpha-hydroxypregnenolone smallmolecule CHEBI:28750 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-268655 AURKA protein O14965 UNIPROT NEDD9 protein Q14511 UNIPROT "up-regulates activity" phosphorylation Ser296 PVARRHQsLSPNHPP 9606 BTO:0000093 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-262654 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 HNF1A protein P20823 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-254437 PKA proteinfamily SIGNOR-PF17 SIGNOR PHKA1 protein P46020 UNIPROT "down-regulates activity" phosphorylation 9606 10487978 t "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-267409 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 PHB2 protein Q99623 UNIPROT MEF2A protein Q02078 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto "Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation." SIGNOR-235840 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Ser45 FHGVAILsPLLNIEK -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-265957 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 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 13760840 t gcesareni SIGNOR-251700 alvocidib chemical CHEBI:47344 ChEBI CDK5 protein Q00535 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192104 EXOSC6 protein Q5RKV6 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-261389 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 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 FBXO7 protein Q9Y3I1 UNIPROT CRBN protein Q96SW2 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0005490 30026574 t miannu "We have shown that CRBN is also targeted for degradation by SCFFbxo7 ubiquitin ligase. " SIGNOR-272311 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER2 protein P43116 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-257570 serotonin smallmolecule CHEBI:28790 ChEBI HTR5A protein P47898 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-264298 thapsigargin chemical CHEBI:9516 ChEBI ATP2A2 protein P16615 UNIPROT "down-regulates activity" "chemical inhibition" 9534 30814986 t lperfetto "Treatment of Vero cells with SERCA-specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV) replication. |Thapsigargin inhibits NDV-induced SERCA2 expression in Vero cells" SIGNOR-262021 NADP(3-) smallmolecule CHEBI:58349 ChEBI NADPH(4-) smallmolecule CHEBI:57783 ChEBI "up-regulates quantity" "precursor of" 9606 33064660 t miannu "Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP." SIGNOR-268078 creatine smallmolecule CHEBI:16919 ChEBI CKMT2 protein P17540 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-265785 NF2 protein P35240 UNIPROT STK3 protein Q13188 UNIPROT "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-261955 ZFHX3 protein Q15911 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11314020 f miannu "We investigated AFP gene regulation in AFP-GC by an active transcription factor, HNF1 (hepatocyte nuclear factor 1) and a repressive transcription factor, ATBF1 (AT motif binding factor 1). CAT assays showed the direct inhibition of AFP gene expression by ATBF1." SIGNOR-254436 SEC62 protein Q99442 UNIPROT Protein_translocation phenotype SIGNOR-PH176 SIGNOR up-regulates 22375059 f lperfetto "Silencing the SEC62 gene inhibits post-translational transport of small presecretory proteins into the human ER" SIGNOR-265280 FGFR1 protein P11362 UNIPROT "Non-structural protein 2" protein P0C6X7-PRO_0000037310 UNIPROT "down-regulates activity" "chemical inhibition" 9606 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-260150 CDK1 protein P06493 UNIPROT AR protein P10275 UNIPROT up-regulates phosphorylation Ser83 QQQQQETsPRQQQQQ 9606 BTO:0001130 21799006 t gcesareni "At first, the data show that cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins although ar was reported as substrates for cdk9 (5) as well as cdk1" SIGNOR-175692 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 11350724 t lperfetto "Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein– protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptor’s repertoire of activated intracellular pathways." SIGNOR-107712 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 CFAP53 protein Q96M91 UNIPROT ODAD4 protein Q96NG3 UNIPROT "up-regulates activity" binding 10090 BTO:0000379 33347437 t miannu "CFAP53 likely facilitates the transport of TTC25 and the dyneins into cilia. CFAP53 at the centriolar satellites may form a complex with TTC25 and ODAs, including DNAH5 and DNAH11, and regulate their trafficking into the cilium (Fig 10B)." SIGNOR-265543 CDK1 protein P06493 UNIPROT CASP9 protein P55211 UNIPROT down-regulates phosphorylation Thr125 PEVLRPEtPRPVDIG 9606 SIGNOR-C17 16287866 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-141621 CDK1 protein P06493 UNIPROT WAC protein Q9BTA9 UNIPROT "up-regulates activity" phosphorylation Thr244 AETHSSStPVQHPIK 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-265032 NANOG protein Q9H9S0 UNIPROT SOX17 protein Q9H6I2 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-253168 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 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR CEBPB protein P17676 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000527 25303533 t miannu "KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ." SIGNOR-272456 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR CEBPD protein P49716 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000527 25303533 t miannu "KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ." SIGNOR-272457 KLHL9 protein Q9P2J3 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000527 25303533 t miannu "KLHL9 mediates poly-ubiquitylation of C/EBPβ and C/EBPδ isoforms. We confirmed KLHL9 deletions in an independent cohort and showed that this protein is necessary for Cul3-ligase mediated ubiquitylation and proteasomal degradation of established MES-GBM MRs, C/EBPβ and C/EBPδ." SIGNOR-272458 EGFR protein P00533 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr194 ALEKKSNyEVLEKDV 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-167646 PTPN1 protein P18031 UNIPROT IGF1R protein P08069 UNIPROT "down-regulates activity" dephosphorylation 9606 11884589 t lperfetto "Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells." SIGNOR-115709 STAT3 protein P40763 UNIPROT IL10 protein P22301 UNIPROT up-regulates "transcriptional regulation" 9606 22378047 f "IL-10 activates STAT3-mediated expression of genes (Il10, Tgfb1, Mrc1) associated with an M2-like phenotype" SIGNOR-254515 ADRA1D protein P25100 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-256951 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR NABP2 protein Q9BQ15 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25249620 t miannu "Here, we report that hSSB1 is the bona fide substrate for an Fbxl5-containing SCF (Skp1-Cul1-F box) E3 ligase. Fbxl5 interacts with and targets hSSB1 for ubiquitination and degradation, which could be prevented by ATM-mediated hSSB1 T117 phosphorylation. " SIGNOR-272462 THRA protein P10827 UNIPROT RARB protein P10826 UNIPROT up-regulates binding 9606 15650024 t gcesareni "Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs" SIGNOR-133243 CAMK2B protein Q13554 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-154771 BTK protein Q06187 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation Tyr694 LAKAVDGyVKPQIKQ -1 11413148 t llicata "Ectopically expressed BTK kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr(694) mutant) STAT5A enhanced its DNA binding activity." SIGNOR-250603 GRM8 protein O00222 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-264351 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 N-tert-butyl-3-[[5-methyl-2-[4-[2-(1-pyrrolidinyl)ethoxy]anilino]-4-pyrimidinyl]amino]benzenesulfonamide chemical CHEBI:91408 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-258301 NF1 protein P21359 UNIPROT ADCY5 protein O95622 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-204140 NOTCH4 protein Q99466 UNIPROT MAML3 protein Q96JK9 UNIPROT up-regulates binding 9606 12370315 t 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-94109 FOXO1 protein Q12778 UNIPROT NPY protein P01303 UNIPROT "up-regulates quantity by expression" "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-263502 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193549 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 "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 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 SGK1 protein O00141 UNIPROT SLC2A4 protein P14672 UNIPROT "up-regulates activity" phosphorylation Ser274 LERERPLsLLQLLGS 8355 BTO:0000887 17382906 t lperfetto "We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274." SIGNOR-236653 CSNK1E protein P49674 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates phosphorylation Thr41 YSTTPGGtLFSTTPG 9606 BTO:0000150 24247720 t lperfetto "Mechanistic investigations showed that ck1_ interacted with and phosphorylated 4e-bp1 at two novel sites t41 and t50, which were essential for 4e-bp1 inactivation along with increased mrna translation and cell proliferation." SIGNOR-203240 lapatinib chemical CHEBI:49603 ChEBI KDR protein P35968 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-257898 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 SHANK1 protein Q9Y566 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-264583 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 STK11 protein Q15831 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 9606 17108107 t gcesareni "We show that lkb1 physically associates with p53 in the nucleus and directly or indirectly phosphorylates p53 ser15 (previously shown to be phosphorylated by amp-dependent kinase) and p53 ser392" SIGNOR-150834 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 PRTN3 protein P24158 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Pro48 RSFLLRNpNDKYEPF -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-263577 LTF protein P02788 UNIPROT iron(3+) smallmolecule CHEBI:29034 ChEBI "up-regulates quantity" relocalization 9606 11747454 t "Lactoferrin (Lf), a major iron-binding protein in human milk, has been suggested to have multiple biological roles such as facilitating iron absorption, modulating the immune system, embryonic development, and cell proliferation." SIGNOR-272473 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 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 "Naloxone benzoylhydrazone" chemical CID:9601084 PUBCHEM 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-258422 CRCP protein O75575 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-266134 RAVER1 protein Q8IY67 UNIPROT PTBP1 protein P26599 UNIPROT "up-regulates activity" binding 9606 14633994 t "Raver1 was identified in two-hybrid screens by its interactions with the cytoskeletal proteins actinin and vinculin, and was also found to interact with PTB || Here we show that raver1 is able to promote the smooth muscle-specific alternative splicing of TM by enhancing PTB-mediated repression of exon 3. This suggests a novel mechanism for PTB-mediated splicing repression involving recruitment of raver1 as a potent splicing co-repressor." SIGNOR-272475 TP53 protein P04637 UNIPROT ZNF365 protein Q70YC5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23776040 t "Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability| Our study identified ZNF365 as a necessary target whose activation by p53 in the presence of critically short telomeres contributes to genomic stability. We provide evidence that loss of ZNF365 leads to increased expression of CFS and dysfunctional telomeres, aberrant sister telomere recombination, and increased aneuploidy" SIGNOR-272476 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 SIRT5 protein Q9NXA8 UNIPROT ACOX1 protein Q15067 UNIPROT "down-regulates activity" "catalytic activity" 9606 BTO:0000007 29491006 t Monia "SIRT5‐mediated desuccinylation inhibits ACOX1 activity by suppressing its active dimer formation." SIGNOR-261210 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 CDK1 protein P06493 UNIPROT STIM1 protein Q13586 UNIPROT down-regulates phosphorylation Ser668 IGEETDSsPGRKKFP 9606 19881501 t gcesareni "Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce." SIGNOR-189017 IL1R1 protein P14778 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "up-regulates activity" phosphorylation 9606 BTO:0000801 9625767 t "inferred from 70% of family members" 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-269883 TLR4 protein O00206 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 28137827 t miannu "Binding of S100A9 to TLR4 stimulates the phosphorylation of JNK, ERK1/2, and p38 MAPK, which leads to the activation of c-Jun, CREB, and NF-κB. Activation of neutrophils by S100A9 also proceeds via p38 MAPK, JNK, and ERK1/2 phosphorylation." SIGNOR-263652 MYC protein P01106 UNIPROT UBTF protein P17480 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000539 15282543 t lperfetto "MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter." SIGNOR-269644 MAPK7 protein Q13164 UNIPROT MAP2K5 protein Q13163 UNIPROT up-regulates phosphorylation Ser137 QHSSPAVsDSLPSNS 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-99131 48S_initiation_complex complex SIGNOR-C454 SIGNOR MRNA_scanning phenotype SIGNOR-PH208 SIGNOR up-regulates 9606 29401259 f lperfetto "The 48S complex scans mRNA from 5′ to 3′ until it identifies an AUG start codon in an appropriate sequence context (Kozak consensus)" SIGNOR-269168 "3-phosphonato-D-glyceroyl phosphate(4-)" smallmolecule CHEBI:57604 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 ChEBI "up-regulates quantity" "precursor of" 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-266501 KCTD10 protein Q9H3F6 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-264237 CENPE protein Q02224 UNIPROT BUB1B protein O60566 UNIPROT "up-regulates activity" binding -1 12925705 t miannu "CENP-E binds to and directly stimulates the kinase activity of purified BubR1 in vitro." SIGNOR-266118 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 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 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 BGJ-398 chemical CHEBI:63451 ChEBI FGFR2 protein P21802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190266 ETS1 protein P14921 UNIPROT GFI1 protein Q99684 UNIPROT "down-regulates activity" binding 9606 BTO:0002181 17213822 t miannu "Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. Luciferase (Luc) assays using artificial reporters showed that GFI1 repressed ETS1-mediated transcriptional activation and ETS1 repressed GFI1-mediated transcriptional activation, in a dose-dependent manner." SIGNOR-254202 8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one chemical CHEBI:91361 ChEBI PRKDC protein P78527 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194865 SOX17/POU5F1 complex SIGNOR-C451 SIGNOR PRDM14 protein Q9GZV8 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-269242 AGTR1 protein P30556 UNIPROT GNA13 protein Q14344 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-171760 TSC22D3 protein Q99576 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000011 12671681 f "In this study, we showed that GILZ, which is transcriptionally induced by GCs, inhibits the transcription of the PPAR-γ2 gene and blocks adipocyte differentiation" SIGNOR-253296 NAE complex SIGNOR-C131 SIGNOR CUL3 protein Q13618 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-243157 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 INS protein P01308 UNIPROT APOB protein P04114 UNIPROT "down-regulates quantity by destabilization" 9606 23721961 f miannu "Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. Though insulin does not alter ApoB mRNA levels, it inhibits ApoB translation by promoting the trafficking of ApoB mRNA into P-bodies, aggregates of translationally repressed mRNAs" SIGNOR-252114 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 UNC5C protein O95185 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-268165 RNF26 protein Q9BY78 UNIPROT SQSTM1 protein Q13501 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000567 27368102 t miannu "SQSTM1 Is a Substrate for RNF26 and the DUB USP15. Catalytically competent RNF26 (light red) recruits SQSTM1 (blue) and mediates ubiquitin ligation (red), which serves to attract UBDs of specific vesicle-associated adaptors." SIGNOR-269830 LAMTOR2 protein Q9Y2Q5 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-164772 AKT proteinfamily SIGNOR-PF24 SIGNOR AR protein P10275 UNIPROT "down-regulates activity" phosphorylation Ser792 CVRMRHLsQEFGWLQ 9534 BTO:0001538 11404460 t lperfetto "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Here, we demonstrate that akt phosphorylates the androgen receptor (ar) at ser-210 and ser-790" SIGNOR-244136 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 "mono(2-ethylhexyl) phthalate" chemical CHEBI:17243 ChEBI PPARG protein P37231 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-268751 LRRK2 protein Q5S007 UNIPROT SH3GL1 protein Q99961 UNIPROT down-regulates phosphorylation 9606 22998870 t miannu "We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association." SIGNOR-192068 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 SP1 protein P08047 UNIPROT MET protein P08581 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-241490 Ub:E2 complex SIGNOR-C497 SIGNOR RNF181 protein Q9P0P0 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-271230 NFATC1 protein O95644 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-264026 TEX12 protein Q9BXU0 UNIPROT Synaptonemal_complex complex SIGNOR-C351 SIGNOR "form complex" binding 9606 22394509 t miannu "The synaptonemal complex (SC) is a proteinaceous structure of chromosome bivalents whose assembly is indispensable for the successful progression of the first meiotic division of sexually reproducing organisms. four proteins were identified that locate specifically to the CE: SYCE1, SYCE2, SYCE3 and TEX12. These three proteins (SYCP1, SYCE1 and SYCE3) are essential for synapsis initiation, as no CE-structures are formed in the absence of any of these proteins. The final step, i.e. synapsis extension over the entire length of the homologs, requires loading of both SYCE2 and TEX12. In their absence, short pieces of CE-like structures composed of SYCP1, SYCE1 and SYCE3 are formed that, however, cannot mature to a SC central region." SIGNOR-264203 ERBB3 protein P21860 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-146861 MTOR protein P42345 UNIPROT AKT1 protein P31749 UNIPROT "up-regulates activity" phosphorylation Ser473 RPHFPQFsYSASGTA 9606 SIGNOR-C2 21157483 t lperfetto "Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt.Recent findings have revealed novel important roles for mTORC2 in the phosphorylation of AGC kinase family members. mTORC2 phosphorylates and activates Akt, SGK, and PKC, which regulate cell survival, cell cycle progression and anabolism" SIGNOR-170604 GATA1 protein P15976 UNIPROT SPI1 protein P17947 UNIPROT "down-regulates activity" binding 9606 BTO:0004826 10753833 t irozzo "GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region." SIGNOR-256050 "JNJ-28312141 free base" chemical CID:11676971 PUBCHEM FLT3 protein P36888 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-258125 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 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-66767 ATP13A1 protein Q9HD20 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0004093 29650961 f doi.org/10.1101/185272 francesca "Loss of ATP13A3 led to marked inhibition of serum-stimulated proliferation of BOECs, and increased apoptosis in serum-deprived conditions" SIGNOR-261217 AKT proteinfamily SIGNOR-PF24 SIGNOR CCNF protein P41002 UNIPROT "up-regulates activity" phosphorylation Thr31 RRRPRNLtILSLPED 9606 BTO:0001938 28954236 t miannu "AKT phosphorylation of cyclin F enhances its stability and promotes assembly into productive E3 ligase complexes." SIGNOR-266360 AHR protein P35869 UNIPROT UGT1A1 protein P22309 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 18172616 f miannu "Human UDP-glucuronosyltransferase (UGT)1A1 is a critical enzyme responsible for detoxification and metabolism of endogenous and exogenous lipophilic compounds, such as potentially neurotoxic bilirubin and the anticancer drug irinotecan SN-38, via conjugation with glucuronic acid. A 290-bp distal enhancer module, phenobarbital-responsive enhancer module of UGT1A1 (gtPBREM), fully accounts for constitutive androstane receptor (CAR)-, pregnane X receptor (PXR)-, glucocorticoid receptor (GR)-, and aryl hydrocarbon receptor (AhR)-mediated activation of the UGT1A1 gene." SIGNOR-253734 "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 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 AKT1 protein P31749 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000150;BTO:0001130 16854453 t gcesareni "Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity." SIGNOR-147963 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 GNG2 protein P59768 UNIPROT PI3K complex SIGNOR-C156 SIGNOR 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-252682 tRNA(Arg) smallmolecule CHEBI:29171 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-270369 FLT3 protein P36888 UNIPROT ID1 protein P41134 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18559972 f apalma "In this study, we used specific tyrosine kinase inhibitors to identify critical target genes that are regulated by oncogenic tyrosine kinases. Using oligonucleotide microarrays, we identified genes that are either up- or down-regulated by selective small molecule inhibitors that target the ABL, PDGFβR, or FLT3 kinases. Genes induced by these inhibitors are presumably repressed by activated tyrosine kinases.Among these genes, we detected a 5- to 50-fold reduction in Id1 expression when the cancer cells were treated with inhibitors." SIGNOR-255698 ELF3 protein P78545 UNIPROT KRT4 protein P19013 UNIPROT "down-regulates quantity by repression" "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-254291 MYF5 protein P13349 UNIPROT DES protein P17661 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 8382796 t lperfetto "Desmin, the muscle specific intermediate filament (IF) protein, is expressed at low levels in myoblasts and at the onset of differentiation its expression increases several fold. In an effort to explore the mechanism involved in the tissue-specific and developmentally regulated expression of desmin, we have isolated the mouse desmin gene.Co-transfection of myoD, myogenin, MRF4 and Myf5, with the desmin-CAT construct into 10T-1/2 cells demonstrated that all these factors could transactivate desmin gene expression" SIGNOR-241494 TGFA protein P01135 UNIPROT NKD2 protein Q969F2 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 18757723 t miannu "Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2." SIGNOR-271739 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 AMPK complex SIGNOR-C15 SIGNOR MFF protein Q9GZY8 UNIPROT "up-regulates activity" phosphorylation Ser172 GQLVRNDsLWHRSDS 9606 BTO:0001938 26816379 t gcesareni "A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission." SIGNOR-249655 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 CENPC protein Q03188 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-265200 SMURF2 protein Q9HAU4 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR down-regulates ubiquitination 9606 22298955 t "inferred from 70% of 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-269845 TGFB1 protein P01137 UNIPROT PIK3CG protein P48736 UNIPROT "up-regulates activity" 9606 19114990 f lperfetto "First, TGF-beta can rapidly activate PI3K, as indicated by the phosphorylation of its downstream effector Akt" SIGNOR-217812 SLITRK5 protein O94991 UNIPROT PTCH1 protein Q13635 UNIPROT "down-regulates activity" binding 10090 BTO:0001593 34326333 t miannu "SLITRK5 interacts with SHH and PTCH1. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation." SIGNOR-268438 TLR4 protein O00206 UNIPROT MAP3K8 protein P41279 UNIPROT "up-regulates activity" 10090 16484370 f "Our findings indicate that the Tpl2/MEK/ERK signaling module is a master regulator of ERK-dependent gene expression downstream of TLRs in different hemopoietic cells" SIGNOR-256083 "cyclosporin A" chemical CHEBI:4031 ChEBI Calcineurin complex SIGNOR-C155 SIGNOR down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-252307 CDH4 protein P55283 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" 10090 18701479 t lperfetto "Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS." SIGNOR-253103 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 SIRT2 protein Q8IXJ6 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates deacetylation 9606 BTO:0000887;BTO:0001103 12887892 t gcesareni "Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities." SIGNOR-104251 CDC42 protein P60953 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 21902831 f lperfetto "Precisely how this complex results in p38 activation is not known, but complex recruitment of the gtpase cdc42 is required for p38 phosphorylation." SIGNOR-176501 arecoline chemical CHEBI:2814 ChEBI CHRM1 protein P11229 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-258641 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 19723038 t lperfetto "The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases. These include epidermal growth factor receptor (egfr) kinase, src, janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)." SIGNOR-187775 PPARD protein Q03181 UNIPROT CAT protein P04040 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-255051 "Secukinumab (Cosentyx)" antibody DB09029 DRUGBANK IL17A protein Q16552 UNIPROT "down-regulates activity" binding 9606 30793255 t "Secukinumab (Cosentyx®), a first-in-class fully human monoclonal antibody against interleukin-17A" SIGNOR-272494 NR1H3 protein Q13133 UNIPROT BHLHE40 protein O14503 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19032342 f lperfetto "LXRα and LXRβ are potent positive regulators for hepatic Dec1" SIGNOR-253691 RPS6KB1 protein P23443 UNIPROT SREBF1 protein P36956 UNIPROT up-regulates 10090 BTO:0002572 20670887 f lperfetto "We find that srebp1 and 2 promote proliferation downstream of mtorc1, and the activation of these transcription factors is mediated by s6k1." SIGNOR-167190 ERAP2 protein Q6P179 UNIPROT oligopeptide smallmolecule CHEBI:25676 ChEBI "down-regulates quantity" "chemical modification" 9606 15908954 t "The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2." SIGNOR-272495 ERAP2 protein Q6P179 UNIPROT "peptide antigen" smallmolecule CHEBI:166824 ChEBI "up-regulates quantity" "chemical modification" 9606 15908954 t "The generation of many HLA class I peptides entails a final trimming step in the endoplasmic reticulum that, in humans, is accomplished by two 'candidate' aminopeptidases | We show here that one of these, ERAP1, was unable to remove several N-terminal amino acids that were trimmed efficiently by the second enzyme, ERAP2." SIGNOR-272496 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 LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR WWTR1 protein Q9GZV5 UNIPROT "down-regulates activity" phosphorylation Ser89 AQHVRSHsSPASLQL 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-256187 ICOSLG protein O75144 UNIPROT ICOS protein Q9Y6W8 UNIPROT "up-regulates activity" binding 9606 27559335 t "ICOSL expression is largely restricted to professional antigen-presenting cells (APCs), including B cells [in which ICOSL is regulated by BAFFR and non-canonical NFκB signaling (20)], macrophages, and dendritic cells (DCs) (12, 17, 21, 22), but is also expressed by certain endothelial cells (23) and lung epithelium" SIGNOR-272497 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 captopril chemical CHEBI:3380 ChEBI ACE protein P12821 UNIPROT "down-regulates activity" "chemical inhibition" -1 9187274 t miannu "We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range." SIGNOR-258612 KLF14 protein Q8TD94 UNIPROT SPHK1 protein Q9NYA1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 24759103 t Luana "KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells" SIGNOR-266047 PPP3CB protein P16298 UNIPROT 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-248379 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 PIAS1 protein O75925 UNIPROT SATB2 protein Q9UPW6 UNIPROT "down-regulates activity" sumoylation Lys350 PPIPRAVkPEPTNSS 9606 BTO:0000007 14701874 t gianni "We found that SATB2 differs from the closely related thymocyte-specific protein SATB1 by modifications of two lysines with the small ubiquitive related modifier (SUMO), which are augmented specifically by the SUMO E3 ligase PIAS1." SIGNOR-269112 PAMPs stimulus SIGNOR-ST11 SIGNOR ITLN1 protein Q8WWA0 UNIPROT "up-regulates activity" binding 26148048 t "Human intelectin-1 (hIntL-1) does not bind known human glycan epitopes but does interact with multiple glycan epitopes found exclusively on microbes: β-linked D-galactofuranose (β-Galf), D-phosphoglycerol-modified glycans, heptoses, D-glycero-D-talo-oct-2-ulosonic acid (KO) and 3-deoxy-D-manno-oct-2-ulosonic acid (KDO). | This ligand selectivity suggests that hIntL-1 functions in microbial surveillance." SIGNOR-272498 GPR25 protein O00155 UNIPROT GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 29727602 t "GPR25 is expressed in human memory T-cells and NK-cells and identified as a primary causal gene associated with autoimmune |Within the class A GPCR family, GPR25 shares a relatively high degree of amino acid sequence identity (29e34%) with vertebrate Apelin receptor (APLNR) diseases revealed by cis-eQTL mapping based on a genome-wide association study (GWAS)." SIGNOR-272501 PPP5C protein P53041 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates activity" dephosphorylation Ser667 SSLIRKRsTRRSVRG 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-272506 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 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT "up-regulates activity" dephosphorylation Ser667 SSLIRKRsTRRSVRG 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-272508 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 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 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 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 CENPE protein Q02224 UNIPROT MAD2L1 protein Q13257 UNIPROT "up-regulates activity" 10090 12925705 f lperfetto "CENP-E is required for efficient recruitment of BubR1, Mad1, and Mad2 to attached and newly unattached kinetochores" SIGNOR-252045 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 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT "up-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-272509 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 WNT5A protein P41221 UNIPROT FZD5 protein Q13467 UNIPROT up-regulates binding 9606 9054360 t gcesareni "These results identify hfz5 as a receptor for wnt-5a." SIGNOR-46897 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 PKA proteinfamily SIGNOR-PF17 SIGNOR ABCB1 protein P08183 UNIPROT "up-regulates activity" dephosphorylation Ser683 QAQDRKLsTKEALDE 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-272510 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 CSNK1E protein P49674 UNIPROT DVL2 protein O14641 UNIPROT "up-regulates activity" phosphorylation 6239 10517632 t gcesareni "In addition, CKI bound to and increased the phosphorylation of dishevelled, a known component of the Wnt pathway" SIGNOR-244097 HOXD13 protein P35453 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-241235 PIM1 protein P11309 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates activity" dephosphorylation Ser683 QAQDRKLsTKEALDE 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-272511 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 PRKCA protein P17252 UNIPROT FLNC protein Q14315 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser2236 ERLGSFGsITRQQEG 10090 BTO:0000165 32444788 t miannu "We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236." SIGNOR-262617 FUS protein P35637 UNIPROT GRIA4 protein P48058 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-262806 PP1 proteinfamily SIGNOR-PF54 SIGNOR SP1 protein P08047 UNIPROT "down-regulates activity" dephosphorylation 9606 12684058 t lperfetto "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-264669 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 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 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 HNRNPU protein Q00839 UNIPROT ZFY protein P08048 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-262287 PIM1 protein P11309 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR down-regulates 16146838 f 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-256657 HAP1 protein P54257 UNIPROT KIF5C protein O60282 UNIPROT "up-regulates activity" binding 9606 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-264062 PAX3-FOXO1 "fusion protein" SIGNOR-FP12 SIGNOR FGFR4 protein P22455 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-251569 PKC proteinfamily SIGNOR-PF53 SIGNOR ABCB1 protein P08183 UNIPROT "up-regulates activity" dephosphorylation Ser667 SSLIRKRsTRRSVRG 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-272513 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 MRE11 protein P49959 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 17713585 t esanto "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-157475 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR PDCD4 protein Q53EL6 UNIPROT down-regulates phosphorylation Ser67 KRRLRKNsSRDSGRG 9606 BTO:0000007 BTO:0001253 18296647 t gcesareni "Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation." SIGNOR-160982 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser337 DPRGRLRsADSENAL 9606 12761205 t lperfetto "Inhibition of mitogen-activated kinase kinase kinase 3 activity through phosphorylation by the serum- and glucocorticoid-induced kinase 2" SIGNOR-101216 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 SMC3 protein Q9UQE7 UNIPROT "RAD21L Cohesin complex" complex SIGNOR-C355 SIGNOR "form complex" binding 10090 BTO:0000534 21242291 t miannu "RAD21L associates with SMC3, STAG3, and either SMC1α or SMC1β. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21." SIGNOR-264537 DOCK1 protein Q14185 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0001909 25533347 t miannu "We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth." SIGNOR-266822 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 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 CP-91149 chemical CID:9843900 PUBCHEM PYGL protein P06737 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191112 KIF5A protein Q12840 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-272523 MAPK1 protein P28482 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates activity" phosphorylation Ser167 FLISPPAsPPVGWKQ 10090 BTO:0000165 12063245 t 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-249198 KIF18A protein Q8NI77 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-272526 GRIP1 protein Q9Y3R0 UNIPROT GRIPAP1 protein Q4V328 UNIPROT "up-regulates activity" binding 10116 BTO:0000142 10896157 t Giorgia "We have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. GRIP1 has seven PDZ domains, which mediate protein–protein interactions, allowing the recruitment of GRASP-1 to a large signal-transducing complex" SIGNOR-260638 CXCL10 protein P02778 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-261031 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation 9606 9922370 t lperfetto "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-244688 PDK4 protein Q16654 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-33201 EDNRA protein P25101 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-257253 CAMK4 protein Q16566 UNIPROT HDAC5 protein Q9UQL6 UNIPROT down-regulates phosphorylation Ser259 FPLRKTAsEPNLKVR 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-236571 DCAF1 protein Q9Y4B6 UNIPROT Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR "up-regulates activity" binding 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-271675 KIF2C protein Q99661 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-272529 KIF17 protein Q9P2E2 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-272530 KIF3A protein Q9Y496 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-272531 LRP2 protein P98164 UNIPROT PTCH1 protein Q13635 UNIPROT "up-regulates quantity" binding 9606 BTO:0000142 26872844 t miannu "LRP2 Promotes SHH Activity in Neurogenic Niches of the Developing and Adult Brain. In the RDVM, LRP2 forms a co-receptor complex with PTCH1 facilitating SHH binding and internalization of SHH/PTCH1 complexes, a prerequisite for pathway activation (Fig. 3B)." SIGNOR-265257 ZSTK-474 chemical CHEBI:90545 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252646 3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide chemical CHEBI:91354 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190146 UBE2G2 protein P60604 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-267483 CHCHD1 protein Q96BP2 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-261460 S100A9 protein P06702 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates quantity by stabilization" binding 9606 BTO:0000876 16690079 t miannu "Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner" SIGNOR-261936 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 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-53739 GRB2 protein P62993 UNIPROT INPP5D protein Q92835 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-268449 KIF3C protein O14782 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-272536 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 MET protein P08581 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr407 IIDEEDTyTMPSTRD 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-147187 KIF3A protein Q9Y496 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-272538 ROCK1 protein Q13464 UNIPROT MYL9 protein P24844 UNIPROT "up-regulates activity" phosphorylation Thr19 KKRPQRAtSNVFAMF -1 21457715 t Giulio "Activation of the catalytic ATPase domain residing in the N‐terminus of the heavy chain relies on the reversible phosphorylation of the associated MLC on Ser19 (monophosphorylation), or in some cases on both Thr18 and Ser19 (diphosphorylation)|We detected Ser19 of MLC as the common phosphorylation site for the catalytic domains of MRCK_/_, ROK_, MLCK and PAK_, but only ROK_ and CRIK are able to phosphorylate both Thr18 and Ser19 residues causing diphosphorylation." SIGNOR-260308 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR "aspartic acid" smallmolecule CHEBI:22660 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-270373 CSNK2A1 protein P68400 UNIPROT CBX5 protein P45973 UNIPROT up-regulates phosphorylation Ser13 KRTADSSsSEDEEEY 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-171703 GRK1 protein Q15835 UNIPROT GRK1 protein Q15835 UNIPROT "down-regulates activity" phosphorylation Thr492 QDVGAFStVKGVAFD -1 1527025 t "The major autophosphorylation site yielded the following sequence: DVGAFS488T489VKGVAFEK, where Ser488 and Thr489 are phosphorylated. Additionally, a minor autophosphorylation site was identified at Ser21. we speculate that autophosphorylation of RK may lower the affinity of the enzyme for Rho* via repulsion between phosphorylated sites on Rho* and the kinase." SIGNOR-251188 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 felodipine chemical CHEBI:585948 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-257766 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 protein A0A3G5BIY8 UNIPROT DDX5 protein P17844 UNIPROT "up-regulates activity" binding 9606 19224332 t lperfetto "To our knowledge, this is the first report to show that SARS-CoV helicase can interact directly with multifunctional protein Ddx5 in cell culture and that inhibition of Ddx5 results in the suppression of viral replication. We speculate that Ddx5 may act as a coactivator by direct binding to the SARS-CoV helicase, resulting in enhanced viral genome transcription and virus proliferation." SIGNOR-260250 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 CALM3 protein P0DP25 UNIPROT PP2B proteinfamily SIGNOR-PF18 SIGNOR up-regulates binding 9606 11796223 t "inferred from 70% of family members" miannu "Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain." SIGNOR-269891 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 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-55310 SNCA protein P37840 UNIPROT CADPS2 protein Q86UW7 UNIPROT "down-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-268929 TLR4 protein O00206 UNIPROT TIRAP protein P58753 UNIPROT up-regulates binding 9606 11544529 t fstefani "Mal (myd88-adapter-like) is required for toll-like receptor-4 signal transduction." SIGNOR-110337 DNMT3A protein Q9Y6K1 UNIPROT MEIS1 protein O00470 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 28288143 f miannu "Our results indicate that, in the absence of mixed lineage leukemia fusions, an alternative pathway for engaging an oncogenic MEIS1-dependent transcriptional program can be mediated by DNMT3A mutations.Under these circumstances, those AML patients carrying the alteration in the DNA methyltransferase would undergo a hypomethylation event at the MEIS1 promoter that would lead to the overexpression of this key oncogene in leukemia." SIGNOR-256125 EPGN protein Q6UW88 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0001253 20513444 t "EPGN may stimulate the phosphorylation of EGFR and mitogen-activated protein kinases" 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-165779 PTPN2 protein P17706 UNIPROT KDR protein P35968 UNIPROT unknown dephosphorylation Tyr996 EEAPEDLyKDFLTLE 9606 BTO:0000007 18840653 t "We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well." SIGNOR-248398 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 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 haloperidol chemical CHEBI:5613 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-258523 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 "(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 PLK1 protein P53350 UNIPROT KIF2B protein Q8N4N8 UNIPROT "up-regulates activity" phosphorylation Ser204 HLDSSKIsVLEPPQE 9606 22535524 t lperfetto "We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors." SIGNOR-252050 Riluzole chemical CHEBI:8863 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-258053 PLK3 protein Q9H4B4 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Ser198 SDELMEFsLKDQEAK 9606 14968113 t lperfetto "Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation" SIGNOR-122094 PRKCA protein P17252 UNIPROT CYTH2 protein Q99418 UNIPROT "down-regulates activity" phosphorylation Ser392 AARKKRIsVKKKQEQ 9606 10531036 t lperfetto "ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'." SIGNOR-249023 KEAP1 protein Q14145 UNIPROT CUL3 protein Q13618 UNIPROT "up-regulates activity" binding 9534 BTO:0001538 15983046 t miannu "Keap1 is a BTB-Kelch protein that functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 targets its substrate, the Nrf2 transcription factor, for ubiquitination and subsequent degradation by the 26 S proteasome.  The N-terminal BTB domain and central linker region of Keap1 bind Cul3, whereas the C-terminal Kelch domain of Keap1 binds Nrf2 via residues located within loops that extend out from the bottom of the Kelch domain" SIGNOR-268925 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 GABRB3 protein P28472 UNIPROT "GABA-A (a4-b3-d) receptor" complex SIGNOR-C327 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-263747 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 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 TFIID complex SIGNOR-C343 SIGNOR TFIIA complex SIGNOR-C395 SIGNOR "up-regulates activity" relocalization 9606 8990153 t lperfetto "PIC assembly begins with TFIID recognizing the TATA element, followed by coordinated accretion of TFIIB, the nonphosphorylated form of pol II (pol IIA) plus TFIIF, TFIIE, and TFIIH." SIGNOR-269307 Cell_cycle_exit phenotype SIGNOR-PH41 SIGNOR Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 10090 9388774 f gcesareni "Myogenic precursor cells withdraw irreversibly from the cell cycle as they differentiate into mature myotubes. Cell cycle exit occurs early during the differentiation program and is required for normal expression of the contractile phenotype." SIGNOR-243206 ARPC4 protein P59998 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-251517 ERG protein P11308 UNIPROT CXCR4 protein P61073 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19396168 f miannu "ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression." SIGNOR-253911 SUGT1 protein Q9Y2Z0 UNIPROT "MIS12 complex" complex SIGNOR-C362 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 22869522 t lperfetto "Here we identify Sgt1, a cochaperone for Hsp90, as a novel Plk1 substrate during mitosis|This phosphorylation event enhances the association of the Hsp90-Sgt1 chaperone with the MIS12 complex to stabilize this complex at the kinetochores and thus coordinates the recruitment of the NDC80 complex to form efficient microtubule-binding sites." SIGNOR-265223 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 ITCH protein Q96J02 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates ubiquitination 9606 15350225 t gcesareni "Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription." SIGNOR-128647 EPAS1 protein Q99814 UNIPROT PTPRZ1 protein P23471 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 15833863 f miannu "A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Ten genes were preferentially activated by HIF-2alpha, including two (CACNA1A and PTPRZ1) implicated in neurologic diseases." SIGNOR-264333 TEK protein Q02763 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr1102 MLEERKTyVNTTLYE 14665640 t gcesareni "Our results identified a novel interaction between Tie2 with the adapter molecule ShcA and suggested that this interaction may play a role in the regulation of migration and three-dimensional organization of endothelial cells induced by angiopoietin-1. Furthermore, Tyr-1101 of Tie2 was identified as the primary binding site for the SH2 domain of ShcA." SIGNOR-242573 FBP1 protein P09467 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-267611 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM65 protein Q6PJ69 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-271171 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 NDUFC2 protein O95298 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-262174 TNF protein P01375 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 10485710 t gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)" SIGNOR-70625 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 ITGB6 protein P18564 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-257724 HSPA8 protein P11142 UNIPROT "Chaperone-mediated autophagy" phenotype SIGNOR-PH118 SIGNOR "up-regulates activity" -1 2799391 f "A 73-kilodalton (kD) intracellular protein was found to bind to peptide regions that target intracellular proteins for lysosomal degradation in response to serum withdrawal. This protein cross-reacted with a monoclonal antibody raised to a member of the 70-kD heat shock protein (hsp70) family, and sequences of two internal peptides of the 73-kD protein confirm that it is a member of this family." SIGNOR-259991 TGFBR2 protein P37173 UNIPROT PARD6A protein Q9NPB6 UNIPROT up-regulates phosphorylation Ser345 RGDGSGFsL 9606 BTO:0004183 15761148 t lperfetto "We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345." SIGNOR-227484 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 DUSP5 protein Q16690 UNIPROT MAPK3 protein P27361 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-67358 HDLBP protein Q00341 UNIPROT CSF1R protein P07333 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000150 33941620 t 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-266696 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 nifedipine chemical CHEBI:7565 ChEBI NR1I2 protein O75469 UNIPROT "up-regulates activity" "chemical activation" 9606 9770465 t miannu "In addition to rifampicin, other known inducers of human CYP3A4 expression, including nifedipine and clotrimazole, also activated hPAR." SIGNOR-259066 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 CAMK2A protein Q9UQM7 UNIPROT CAMK2A protein Q9UQM7 UNIPROT down-regulates phosphorylation Ser314 MLATRNFsGGKSGGN 9606 1324926 t lperfetto "After removal of ca2+/calmodulin, the autonomous kinase undergoes a burst of inhibitory autophosphorylation at sites distinct from the autonomy site. Ca(2+)-independent autophosphorylation occurs within the calmodulin binding domain at thr305, thr306, and ser314" SIGNOR-17308 GSK3A protein P49840 UNIPROT SFPQ protein P23246 UNIPROT down-regulates phosphorylation 9606 20932480 t miannu "Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687" SIGNOR-168385 PTK6 protein Q13882 UNIPROT EPS8 protein Q12929 UNIPROT "up-regulates activity" phosphorylation Tyr535 LKTQPKKyAKSKYDF 9606 BTO:0000007 28214294 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-263191 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr177 ADAEKPFyVNVEFHH 9606 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 tyrosine 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-40611 AminoAcids stimulus SIGNOR-ST5 SIGNOR RAG2 protein P55895 UNIPROT up-regulates 9606 22790199 f 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-198192 CDS1 protein Q92903 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "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-267018 MAPK8 protein P45983 UNIPROT BCL2L11 protein O43521 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser69 GPLAPPAsPGPFATR 9606 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-160323 calcium(2+) smallmolecule CHEBI:29108 ChEBI CALM3 protein P0DP25 UNIPROT up-regulates "chemical activation" 10090 10448861 t miannu "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-266334 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 PRKACA protein P17612 UNIPROT NOLC1 protein Q14978 UNIPROT "up-regulates activity" phosphorylation Ser623 KGEKRASsPFRRVRE -1 12167624 t miannu "PKA-dependent Nopp140 phosphorylation is important for its role in agp gene activation. both Ser627 and Ser628 are phosphorylated by PKA." SIGNOR-250020 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT up-regulates phosphorylation 9606 10828059 t "The effect has been demonstrated using Q08499-4" llicata "The short pde4d1 isoenzyme is activated by erk2 phosphorylation this signifies that erk2 phosphorylated pde4d1 at a single site, ser491, that is cognate to the single erk2 phosphorylation site (ser579) found in pde4d3." SIGNOR-77559 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 TNF protein P01375 UNIPROT SCN4A protein P35499 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. VGSCs were up-regulated at both the mRNA and protein levels." SIGNOR-253481 KDM6A protein O15550 UNIPROT HOXC6 protein P09630 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-260028 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 SPAST protein Q9UBP0 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 9534 BTO:0000298 15716377 f Gianni "Using purified components, we also show that Spastin interacts directly with microtubules and is sufficient for severing. These studies suggest that defects in microtubule severing are a cause of axonal degeneration in human disease." SIGNOR-269045 BMPR1B protein O00238 UNIPROT SMAD5 protein Q99717 UNIPROT up-regulates 10090 BTO:0000165 10564272 f lperfetto "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-235625 ADCY6 protein O43306 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-265001 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 CSNK1D protein P48730 UNIPROT AXIN1 protein O15169 UNIPROT up-regulates phosphorylation Ser46 PASYSFCsGKGVGIK 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/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)" SIGNOR-87437 FFAR2 protein O15552 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-257397 SRC protein P12931 UNIPROT PTK2 protein Q05397 UNIPROT up-regulates phosphorylation Tyr861 PIGNQHIyQPVGKPD 9606 BTO:0000195 17289681 t "The effect has been demonstrated using P34152-3" gcesareni "We propose that fak/c-src bipartite enzyme is a sensor of cytoplasmic shrinkage, and that the phosphorylation on fak tyr-861 by src and subsequent reorganization of f-actin can initiate an anti-apoptotic signaling pathway that protects cells from hyperosmotic stress." SIGNOR-152971 TJP2 protein Q9UDY2 UNIPROT ARVCF protein O00192 UNIPROT "down-regulates activity" relocalization 9615 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. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression" SIGNOR-252122 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 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 MAPK1 protein P28482 UNIPROT RORA protein P35398 UNIPROT down-regulates phosphorylation Thr183 PGEAEPLtPTYNISA 9606 17512500 t "The effect has been demonstrated using P35398-4" gcesareni "We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity" SIGNOR-154914 MAPK14 protein Q16539 UNIPROT DDIT3 protein P35638 UNIPROT "up-regulates activity" phosphorylation Ser82 STSQSPHsPDSSQSS -1 8650547 t miannu "CHOP, a member of the C/EBP family of transcription factors, mediates effects of cellular stress on growth and differentiation. It accumulates under conditions of stress and 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)." SIGNOR-250096 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr252 HDGTVTHtFCGTIEY 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-55306 calcium(2+) smallmolecule CHEBI:29108 ChEBI CDH13 protein P55290 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-265831 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 RBBP7 protein Q16576 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-263836 ARHGAP11A protein Q6P4F7 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-260466 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 MAPK1 protein P28482 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Ser59 GGQESQPsPLALLAA 9606 BTO:0000452 19318349 t gcesareni "PKCalpha, which was activated in senescent cells by ROS strongly activated Erk1/2, and the SA-pErk1/2 in turn phosphorylated Sp1 on Ser(59). Sp1-enhanced transcription of p21(Sdi1) resulted in regulation of cellular senescence in primary human diploid fibroblast cells." SIGNOR-248075 RELA protein Q04206 UNIPROT IL6 protein P05231 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000018 17350185 t Luana "The IL-6 promoter was stimulated by NF-kB RelA protein. " SIGNOR-266088 CCKAR protein P32238 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-257303 PDPK1 protein O15530 UNIPROT PRKCB protein P05771 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "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." SIGNOR-126069 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser37 NVLSPLPsQAMDDLM 9606 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage. On activation, both of these kinases also phosphorylate multiple sites in the p53 N-terminal domain. These include Ser15, Thr18, Ser20, and Ser37, which are all DNA-damageinducible sites" SIGNOR-153475 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 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 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 HCRTR2 protein O43614 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-257350 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 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 MAP3K3 protein Q99759 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" binding 9606 BTO:0000298 9162092 t lperfetto "These data indicate that mkk3 is preferentially activated by mekk3, whereas mkk4 is activated both by mekk2 and mekk3." SIGNOR-48628 IFNGR1 protein P15260 UNIPROT JAK1 protein P23458 UNIPROT up-regulates binding 9606 17063185 t flangone "Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively" SIGNOR-150194 SMURF1 protein Q9HCE7 UNIPROT 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-105931 PRKCE protein Q02156 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 15355962 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-128718 CKB protein P12277 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-265787 SIX1 protein Q15475 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000887 9826681 f gcesareni "We have demonstrated by studies of transgenic mice the importance of the mef3 motif present in the myogeninpromoter for its activation and have characterized the mef3 binding activity as consisting of two skeletal-muscle specific members of the six family, six1 and six4." SIGNOR-62104 GNG2 protein P59768 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-154255 MMP25 protein Q9NPA2 UNIPROT MMP2 protein P08253 UNIPROT "up-regulates activity" cleavage Asn109 CGNPDVAnYNFFPRK -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-256345 NLK protein Q9UBE8 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates phosphorylation 9606 20118921 t gcesareni "Nlk-phosphorylated notch1icd is impaired in its ability to form a transcriptionally_ active_ ternary_ complex." SIGNOR-163697 TBXA2R protein P21731 UNIPROT GNA13 protein Q14344 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-257139 TARS1 protein P26639 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-270799 3-isobutyl-1-methylxanthine chemical CHEBI:48518 ChEBI CEBPB protein P17676 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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-43310 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 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "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-252453 PPARG protein P37231 UNIPROT ACADM protein P11310 UNIPROT "down-regulates activity" binding 9606 BTO:0001370 28974683 t Federica "This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation" SIGNOR-261264 AKT proteinfamily SIGNOR-PF24 SIGNOR EDC3 protein Q96F86 UNIPROT "down-regulates activity" phosphorylation Ser161 SFRRRHNsWSSSSRH 10029 BTO:0000246 20051463 t miannu "Together these data show that recombinant EDC3 co-immunoprecipitates with endogenous 14-3-3 isoforms in response to insulin in vivo and is phosphorylated at the putative 14-3-3 binding and AKT phosphorylation site Ser-161. Collectively, these data suggest that Ser-161 in EDC3 is phosphorylated in response to insulin principally by AKT and that this subsequently triggers 14-3-3 binding. Constitutive 14-3-3 binding to EDC3 alters p-body morphology and function" SIGNOR-262631 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 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 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 PFDN1 protein O60925 UNIPROT "Prefoldin co-chaperone" complex SIGNOR-C513 SIGNOR "form complex" binding 9606 32699605 t miannu "The correct folding is a key process for a protein to acquire its functional structure and conformation. Prefoldin is a well-known chaperone protein that regulates the correct folding of proteins.  Canonical prefoldin complex is a heterohexameric complex composed of two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4 and PFDN6)" SIGNOR-270932 RPS14 protein P62263 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-262438 TP53 protein P04637 UNIPROT CYCS protein P99999 UNIPROT up-regulates 9606 19007744 f "Translocation from Mitochondria to Cytosol" lperfetto "P53 translocation precedes changes of mitochondrial membrane potential, cytochrome c release and caspase activation" SIGNOR-140251 PRKAA1 protein Q13131 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-139158 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 USP9X protein Q93008 UNIPROT EPS15 protein P42566 UNIPROT "down-regulates activity" deubiquitination 9606 26748853 t gcesareni "We identify the endocytic protein Eps15 as one of the critical substrates of USP9X" SIGNOR-245052 ZAP70 protein P43403 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr113 SSFEEDDyESPNDDQ 9606 9047237 t lperfetto "Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient." SIGNOR-46855 ITGB3 protein P05106 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-253206 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 EIF2B4 protein Q9UI10 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-269127 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 PDPK1 protein O15530 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 9445476 t miannu "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." SIGNOR-188911 NMBR protein P28336 UNIPROT GNA13 protein Q14344 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-107028 MAPK9 protein P45984 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser307 TRRSRTEsITATSPA 9606 14579029 t gcesareni "Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632" SIGNOR-118881 KDM4B protein O94953 UNIPROT BBC3 protein Q9BXH1 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-263732 SP1 protein P08047 UNIPROT CD151 protein P48509 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20149781 f miannu "SP1 is required for basal activation and chromatin accessibility of CD151 promoter in liver cancer cells." SIGNOR-255195 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 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR SF3B1 protein O75533 UNIPROT unknown phosphorylation Thr313 HGSGWAEtPRTDRGG 9606 12105215 t lperfetto "We indeed found that sap155-(223_322) and sap155-(1_491) are excellent substrates for in vitrophosphorylation by cyclin e-cdk2 as well as cyclin b-cdk1" SIGNOR-216717 CSNK2A1 protein P68400 UNIPROT ACE protein P12821 UNIPROT "up-regulates activity" phosphorylation Ser1299 SHGPQFGsEVELRHS 9823 BTO:0001176 12386153 t lperfetto "CK2 coprecipitated with ACE from endothelial cells, and CK2 phosphorylated both ACE and a peptide corresponding to the cytoplasmic tail. Mutation of serine(1270) within the CK2 consensus sequence almost abolished ACE phosphorylation.|These results indicate that the CK2-mediated phosphorylation of ACE regulates its retention in the plasma membrane and may determine plasma ACE levels." SIGNOR-264425 CCR2 protein P41597 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-255117 MACROD2 protein A1Z1Q3 UNIPROT 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 ChEBI "down-regulates quantity" "chemical modification" 9606 32257385 t miannu "MACROD2 is a protein-coding gene located at a fragile site on human chromosome 20. The MACROD2 protein is a deacetylase involved in the removal of ADP-ribose from mono-ADP-ribosylated proteins" SIGNOR-269839 EEF1A1 protein P68104 UNIPROT Gln-tRNA(Gln) smallmolecule CHEBI:29166 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-269510 DGCR8 protein Q8WYQ5 UNIPROT "Microprocessor complex" complex SIGNOR-C356 SIGNOR "form complex" binding 9606 BTO:0000552 24581491 t 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-264849 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 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 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 PPP2CB protein P62714 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-248592 KIT protein P10721 UNIPROT PTPN11 protein Q06124 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0002882 22806893 t irozzo "SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation." SIGNOR-256140 PRKCA protein P17252 UNIPROT GABRR1 protein P24046 UNIPROT unknown phosphorylation Ser447 SQRSSYVsMRIDTHA -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-262754 PRKCZ protein Q05513 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr668 SYCGKRFtRSDELQR 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-160770 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT up-regulates phosphorylation Tyr354 LMLRLQDyEEKTKKA 9606 BTO:0000017 15647376 t lperfetto "Ezrin was initially identified as a substrate for tyrosine phosphorylation by egfr (bretscher, 1989) and phosphorylation of residues y145 and y353 were detected to high stoichiometry after egf treatment . Phosphorylation of ezrin at y353 has been delineated to signal survival during epithelial cell differentiation via the phosphatidylinositol 3-kinase (pi3k)/akt pathway." SIGNOR-133215 EGFR protein P00533 UNIPROT EZR protein P15311 UNIPROT unknown phosphorylation Tyr146 KEVHKSGyLSSERLI 9606 BTO:0000017 15647376 t lperfetto "Here we report the identification of the tyrosine phosphorylation sites in ezrin using bacterially expressed protein as a substrate for in vitro phosphorylation with the egf receptor. tyrosines 145 and 353 were identified as the sites of phosphorylation. but as of yet the role of ezrin phosphorylation at y145 is unknown." SIGNOR-133219 GIGYF2 protein Q6Y7W6 UNIPROT GRB10 protein Q13322 UNIPROT "up-regulates activity" binding 10090 20670374 t miannu "We demonstrated that, in cultured cells and mammalian brains, GIGYF2 interacts and colocalises with Grb10, promoting ligand‐induced ubiquitination of IGF‐1R, and thereby regulates receptor degradation" SIGNOR-260057 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 L-thyroxine smallmolecule CHEBI:18332 ChEBI 3,3',5'-triiodothyronine smallmolecule CHEBI:28774 ChEBI "up-regulates quantity" "precursor of" 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-266943 NR0B2 protein Q15466 UNIPROT NR1I3 protein Q14994 UNIPROT down-regulates binding 9606 15000748 t gcesareni "The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition." SIGNOR-123154 NDUFV2 protein P19404 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-262184 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 OXGR1 protein Q96P68 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-256913 EEF1B2 protein P24534 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-269390 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 TWIST1 protein Q15672 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-255534 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 L-aspartate(1-) smallmolecule CHEBI:29991 ChEBI N-carbamoyl-L-aspartate(2-) smallmolecule CHEBI:32814 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-267423 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR IKBKB protein O14920 UNIPROT down-regulates cleavage Asp546 ALQTDIVdLQRSPMG 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-256435 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT "up-regulates quantity" 9606 10653850 f miannu "IL-12 Synergizes With IL-18 or IL-1beta for IFN-gamma Production From Human T Cells. IL-12 and IL-18 acted in a synergistic manner for the development of T cells into IFN-γ-producing cells without their TCR. Here we show that IL-12 and IL-1beta synergistically induce T cells to proliferate and produce IFN-gamma without their TCR engagement. IL-12 stimulation induced an increase in the proportion of T cells positive for IL-18R engagement." SIGNOR-260967 MELK protein Q14680 UNIPROT CDC25B protein P30305 UNIPROT up-regulates phosphorylation Ser169 VLRNITNsQAPDGRR 9606 15908796 t lperfetto "We demonstrate that cdc25b is phosphorylated in vitro by peg3 on serine 169this phosphorylated form of cdc25b accumulates during mitosis, and is localized to the centrosomes" SIGNOR-137378 MAP2K7 protein O14733 UNIPROT MAPK9 protein P45984 UNIPROT up-regulates phosphorylation Tyr185 TNFMMTPyVVTRYYR 9606 11062067 t lperfetto "In the present study, we found that mkk7 phosphorylates sapk2a/p38 exclusively at tyr-182, albeit at a low rate. Therefore one possibility is that the interaction of mkk7 and/or sapk1/jnk with another cellular protein alters the conformation of one of these enzymes in such a way as to facilitate phosphorylation of tyr-185 by mkk7 in vivo." SIGNOR-83748 LCK protein P06239 UNIPROT DEF6 protein Q9H4E7 UNIPROT "up-regulates activity" phosphorylation Tyr133 NFLSEDKyPLIMVPD 9606 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-253367 ASXL1 protein Q8IXJ9 UNIPROT "Polycomb repressive complex 2" complex SIGNOR-C130 SIGNOR "up-regulates activity" binding 9606 BTO:0001271 22897849 t irozzo "These data led us to hypothesize that ASXL1 interacts with the PRC2 complex; co-immunoprecipitation studies revealed that ASXL1 associates with members of the PRC2 complex including EZH2 and SUZ12 but not with the PRC1 repressive complex. Importantly, ASXL1 downregulation resulted in loss of EZH2 recruitment to the HOXA locus indicating a role of ASXL1 in recruiting the PRC2 complex to known leukemogenic loci." SIGNOR-255923 ASIP protein P42127 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-268703 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 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 "Av/b3 integrin" complex SIGNOR-C177 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-269026 SCN1A protein P35498 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-253448 "MLL2 complex" complex SIGNOR-C88 SIGNOR ESR1 protein P03372 UNIPROT up-regulates binding 9606 16603732 t miannu "Eralpha directly binds to the mll2 complex through two lxxll motifs in a region of mll2 near the c terminus in a ligand-dependent manner. Disrupting the interaction between eralpha and the mll2 complex with small interfering rnas specific against mll2 or an mll2 fragment representing the interacting region with eralpha significantly inhibited the eralpha transcription activity." SIGNOR-145868 MYC protein P01106 UNIPROT GLS protein O94925 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001518 19219026 f 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-268038 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser633 GISQCGYsSTIVHVP 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250818 TNF protein P01375 UNIPROT SCN8A protein Q9UQD0 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-253482 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 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr51 SRKLQLKtLLLQIAK 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182061 CHRM5 protein P08912 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-256730 "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 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 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 XL765 chemical CHEBI:71958 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207869 GPR34 protein Q9UPC5 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-256831 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 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI 4-trimethylammoniobutanal smallmolecule CHEBI:18020 ChEBI "up-regulates quantity" "precursor of" 9606 11802770 t miannu "HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine." SIGNOR-269690 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine smallmolecule CHEBI:44811 ChEBI PTAFR protein P25105 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-257567 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 MAPK3 protein P27361 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation 9606 19115199 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-217613 MFGE8 protein Q08431 UNIPROT IL1B protein P01584 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 23454767 f Giorgia "We show that MFGE8 is an endogenous inhibitor of inflammasome-induced IL-1β production. MFGE8 inhibited necrotic cell–induced and ATP-dependent IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions in primed cells. In conclusion, we demonstrated that MFGE8 regulates innate immunity through inhibition of inflammasome-induced IL-1β production." SIGNOR-260649 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 PRKD1 protein Q15139 UNIPROT PRKD1 protein Q15139 UNIPROT unknown phosphorylation Ser742 GEKSFRRsVVGTPAY -1 10867018 t lperfetto "The last two autophosphorylation sites (Ser(744) and Ser(748)) are located in the activation loop but are only phosphorylated in the isolated PKD-catalytic domain and not in the full-length PKD; they may affect enzyme catalysis but are not involved in the activation of wild-type PKD by phorbol ester. | These results indicate that neither of the activation loop serines is involved in PDBu-induced activation but that they may be involved in catalysis or in maintaining the conformation of the enzyme prot" SIGNOR-249047 SMAD3 protein P84022 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates binding 9606 14638857 t gcesareni "Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd" SIGNOR-254325 ADRA2B protein P18089 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-256714 bromocriptine chemical CHEBI:3181 ChEBI DRD3 protein P35462 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-258367 ESR1 protein P03372 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 15808510 t gcesareni "Ikkalpha in conjunction with eralpha and aib1/src-3, is important in activating the transcription of estrogen-responsive genes, including cyclin d1." SIGNOR-135053 NCSTN protein Q92542 UNIPROT PSEN1 protein P49768 UNIPROT up-regulates binding 9606 BTO:0000975 14572442 t "Gamma secretase subunit. Leads to PS1/PS2 eterodimer complex stabilisation" gcesareni "Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2." SIGNOR-118852 RELA protein Q04206 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." SIGNOR-59542 SIRT2 protein Q8IXJ6 UNIPROT AFP protein P02771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 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; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity." SIGNOR-254487 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 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 ELE1-RET "fusion protein" SIGNOR-FP10 SIGNOR SHC1 protein P29353 UNIPROT "up-regulates activity" binding 9606 16946010 t miannu "RET/PTC is tumorigenic in thyroid follicular cells; it transforms thyroid cells in culture and gives rise to thyroid carcinomas in transgenic mice. effects of RET/PTC activation require signaling along the MAPK pathway and, more specifically, the presence of the functional BRAF kinase. all breakpoints in the RET gene occur within intron 11, leaving intact the TK domain of the receptor and enabling the RET/PTC oncoprotein to bind SHC via Y1062 and activate the RAS-RAF-MAPK cascade" SIGNOR-251985 KDM3B protein Q7LBC6 UNIPROT UCP1 protein P25874 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0005964 19194461 t miannu "We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression." SIGNOR-266638 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 MS4A2 protein Q01362 UNIPROT FCER1 complex SIGNOR-C200 SIGNOR "form complex" binding 9606 BTO:0000830 16470226 t "Alessandro Palma" "FcepsilonRI is a tetrameric receptor that comprises an alpha-chain, which is responsible for binding IgE, as well as a beta-chain and a disulphide-linked gamma-chain homo dimer, which are responsible for initiating signalling." SIGNOR-254960 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 CSNK2A1 protein P68400 UNIPROT MDC1 protein Q14676 UNIPROT up-regulates phosphorylation Ser376 LQESQAGsDTDVEEG 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-179879 RARA protein P10276 UNIPROT THRA protein P10827 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-133231 U0126.EtOH chemical CHEBI:90692 ChEBI MAP2K1 protein Q02750 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207603 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR up-regulates phosphorylation 9606 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-244776 E2F1 protein Q01094 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR up-regulates 9606 21524151 f lperfetto "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-245477 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 blinatumomab antibody DB09052 DRUGBANK CD19 protein P15391 UNIPROT "down-regulates activity" binding 9606 BTO:0000731 25883042 t miannu "Blinatumomab, a bispecific antibody construct targeting CD19, is the most advanced member of bispecific T-cell engager (BiTE®) molecules.Blinatumomab recently gained approval in the United States by the U.S. Food and Drug Administration for treatment of Philadelphia chromosome-negative B-precursor relapsed/refractory acute lymphoblastic leukemia." SIGNOR-259888 ADRA1A protein P35348 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-257279 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 SATB2 protein Q9UPW6 UNIPROT BCL11B protein Q9C0K0 UNIPROT "down-regulates quantity" "transcriptional regulation" 9606 31666685 t gianni "Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development" SIGNOR-268931 JNK proteinfamily SIGNOR-PF15 SIGNOR BCL2 protein P10415 UNIPROT "up-regulates activity" phosphorylation Ser70 RDPVARTsPLQTPAA -1 11323415 t Luana "JNK1 directly phosphorylates Bcl2 at Ser70 in vitro and co-localizes with Bcl2 in mitochondrial membranes in vivo." SIGNOR-261133 PRKCG protein P05129 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr436 FHRNHTAtVRSHAEN 9606 11123317 t amattioni "Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation." SIGNOR-85183 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 BBS2 protein Q9BXC9 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-262557 sabcomeline chemical CHEBI:134846 ChEBI CHRM4 protein P08173 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-258675 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 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 ZAP70 protein P43403 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 shc1 (iso2)." SIGNOR-59647 MAPK8 protein P45983 UNIPROT WDR62 protein O43379 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr1053 PSSSLPQtPEQEKFL 9606 BTO:0000007 30566428 t lperfetto "WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053" SIGNOR-271710 SSTR4 protein P31391 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-256680 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 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 CHEK2 protein O96017 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Thr68 SSLETVStQELYSIP 9606 BTO:0000007 11901158 t lperfetto "Thus, activation of chk2 in irradiated cells may occur through oligomerization of chk2 via binding of the thr-68-phosphorylated region of one chk2 to the fha domain of another. Oligomerization of chk2 may therefore increase the efficiency of trans-autophosphorylation resulting in the release of active chk2 monomers that proceed to enforce checkpoint control in irradiated cells." SIGNOR-116135 IGF1R protein P08069 UNIPROT CSK protein P41240 UNIPROT up-regulates 9606 10026153 f lperfetto "The results suggest that c-src and csk are involved in igf-ir and ir signaling and that the interaction of csk with the igf-ir may play a role in the decrease in c-src activity following igf-i stimulation" SIGNOR-64676 "neuropeptide FF receptor agonist" smallmolecule CHEBI:141000 ChEBI NPFFR1 protein Q9GZQ6 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-257549 Gbeta proteinfamily SIGNOR-PF4 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-270069 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 MAPK3 protein P27361 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Ser664 KKTSGPLsPPTGPPG 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-249457 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 NMBR protein P28336 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-256918 CTSG protein P08311 UNIPROT F2R protein P25116 UNIPROT "down-regulates activity" cleavage Phe43 ATLDPRSfLLRNPND -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-263562 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 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 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1034 AIETDKEyYTVKDDR 10090 11909529 t "The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP" SIGNOR-248395 PTPN6 protein P29350 UNIPROT JAK1 protein P23458 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0001271;BTO:0000785;BTO:0000661;BTO:0003076 14624462 t gcesareni "We find, for the first time, that shp-1 down-regulates the level of tyk2 kinase in h9 cells and of jak1 kinase in htb26 cells, by accelerating their degradation." SIGNOR-119197 NUP107 protein P57740 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-262090 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 CSNK2A1 protein P68400 UNIPROT CFTR protein P13569 UNIPROT down-regulates phosphorylation Thr1471 IAALKEEtEEEVQDT 9606 21930781 t lperfetto "Cftr possesses two ck2 phosphorylation sites (s422 and t1471) the t1471 residue, previously described as a site for cftr phosphorylation by ck2 (25), seems to be critical for cftr turnover and processing." SIGNOR-176627 PIM2 protein Q9P1W9 UNIPROT PK proteinfamily SIGNOR-PF80 SIGNOR "down-regulates activity" phosphorylation 9606 BTO:0000007 24142698 t "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-268148 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 CSNK2A2 protein P19784 UNIPROT PTEN protein P60484 UNIPROT "down-regulates activity" phosphorylation Thr366 ASSSTSVtPDVSDNE -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-251026 LPAR5 protein Q9H1C0 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-257284 SLX4 protein Q8IY92 UNIPROT ERCC4 protein Q92889 UNIPROT up-regulates binding 9606 SIGNOR-C50 24726326 t miannu "Slx4 is a tumor suppressor that stimulates the activity of the nuclease xpf-ercc1 in dna crosslink repair." SIGNOR-204890 873837-23-1 chemical CID:46930994 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190467 TAF1A protein Q15573 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-269566 Ub:E2 complex SIGNOR-C497 SIGNOR NEDD4 protein P46934 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-271300 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 FOXO proteinfamily SIGNOR-PF27 SIGNOR NOTCH1 protein P46531 UNIPROT "down-regulates quantity" "transcriptional regulation" 10090 BTO:0002314 24749067 f gcesareni "We demonstrate that FOXO3, perhaps by activating Notch signaling, promotes the quiescent state during SC self-renewal in adult muscle regeneration." SIGNOR-252940 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 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 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 PRKCZ protein Q05513 UNIPROT MARK3 protein P27448 UNIPROT down-regulates phosphorylation Thr564 RGTASRStFHGQPRE 9606 15084291 t lperfetto "Hpar-1a, t564, is phosphorylated in vivo and by apkc in vitro.This study establishes a novel functional link between two central determinants of cellular polarity, apkc and par-1, and suggests a model by which apkc may regulate par-1 in polarized cells" SIGNOR-124221 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1738 SPSYSPTsPSYSPTS -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-248777 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 RPS6KA1 protein Q15418 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser153 SWTRVFQsWWDRNLG 9606 BTO:0000007 10837486 t lperfetto "We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites." SIGNOR-249045 ITGB1BP1 protein O14713 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 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-257659 GPR35 protein Q9HC97 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-257283 ethanol chemical CHEBI:16236 ChEBI SLC44A2 protein Q8IWA5 UNIPROT "up-regulates quantity" 9606 BTO:0003065 21367571 f lperfetto "Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it" SIGNOR-260407 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 DMPK protein Q09013 UNIPROT SRF protein P11831 UNIPROT up-regulates phosphorylation Thr159 DNKLRRYtTFSKRKT 10090 12809504 t llicata "Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha. " SIGNOR-236982 ORC3 protein Q9UBD5 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-267565 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 MAPK3 protein P27361 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-120180 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 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-252035 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 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR UBE2D2 protein P62837 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-271357 ATM protein Q13315 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" phosphorylation Ser50 TSTMPNSsQSSHSSS 9606 BTO:0000007 10973490 t lperfetto "Phosphorylation and activation of chk2 are ataxia telangiectasia-mutated (atm) dependent in response to iratm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro." SIGNOR-81407 SYK protein P43405 UNIPROT TUBA4A protein P68366 UNIPROT "up-regulates activity" phosphorylation Tyr432 MAALEKDyEEVGIDS 9606 BTO:0000776 9490415 t lperfetto "Syk, Activated by Cross-linking the B-cell Antigen Receptor, Localizes to the Cytosol Where It Interacts with and Phosphorylates alpha-Tubulin on Tyrosine" SIGNOR-246626 NFY complex SIGNOR-C1 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-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-255746 pralatrexate chemical CHEBI:71223 ChEBI DHFR protein P00374 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0002207 19221750 t Luana "This study reports a head-to-head comparison of in vitro and in vivo activities of three antifolates: pralatrexate, methotrexate, and pemetrexed. A clear difference was demonstrated among the antifolates in regulation of enzymatic activity. Pralatrexate demonstrated a unique activity profile relative to methotrexate and pemetrexed" SIGNOR-257815 RELA protein Q04206 UNIPROT CREBBP protein Q92793 UNIPROT up-regulates binding 9606 SIGNOR-C6 10207072 t gcesareni "Both p53 and rela(p65) interact with the transcriptional coactivator proteins p300 and creb-binding protein (cbp), and we demonstrate that these results are consistent with competition for a limiting pool of p300/cbp complexes in vivo." SIGNOR-66953 UBXN2B protein Q14CS0 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-265042 MYOD1 protein P15172 UNIPROT SMARCD3 protein Q6STE5 UNIPROT up-regulates binding 9606 15870273 t lperfetto "This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion" SIGNOR-136130 TP53BP2 protein Q13625 UNIPROT PPP1R14A protein Q96A00 UNIPROT down-regulates binding 9606 8549741 t gcesareni "The phosphorylase phosphatase activity of pp1 was inhibited by p53bp2 at nanomolar concentrations." SIGNOR-39666 "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 CCKAR protein P32238 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-257035 PRKACA protein P17612 UNIPROT PPP1R9B protein Q96SB3 UNIPROT "down-regulates activity" phosphorylation Ser94 SERGVRLsLPRASSL 9606 BTO:0000007 12417592 t miannu "Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged." SIGNOR-250035 AARS1 protein P49588 UNIPROT diphosphate(3-) smallmolecule CHEBI:33019 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-270449 H2AC4 protein P04908 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-263874 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 GCHFR protein P30047 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates activity" binding 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-252203 CSNK2A1 protein P68400 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-250845 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 OPRM1 protein P35372 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-256711 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 SDHC protein Q99643 UNIPROT "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "form complex" binding 30030361 t lperfetto "Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites" SIGNOR-262186 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 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 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 UXT protein Q9UBK9 UNIPROT "URI1 prefoldin co-chaperone" complex SIGNOR-C514 SIGNOR "form complex" binding 9606 30484151 t miannu "In humans, the R2TP complex consists of orthologous proteins named RUVBL1, RUVBL2, RPAP3, and PIH1D1  and the PFDL module is composed of two α (UXT and URI1) and four β subunits (PFDN2, PFDN6, PDRG1, and one of them likely duplicated) as well as two additional members, the RNA polymerase II subunit POLR2E/RPB5, and WDR93" SIGNOR-270916 F2RL3 protein Q96RI0 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 22318735 t gcesareni "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-196015 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 Ub:E2 complex SIGNOR-C497 SIGNOR RC3H2 protein Q9HBD1 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-271006 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 lidocaine chemical CHEBI:6456 ChEBI SCN5A protein Q14524 UNIPROT "down-regulates activity" "chemical inhibition" 8355 BTO:0000964 8786356 t miannu "Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19)." SIGNOR-258499 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 SEMA3A protein Q14563 UNIPROT NRP1 protein O14786 UNIPROT down-regulates binding 9606 10196546 t gcesareni "Semaphorins a and e act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors." SIGNOR-66661 VAV2 protein P52735 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 10618391 t tpavlidou "Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo." SIGNOR-73874 TRAF6 protein Q9Y4K3 UNIPROT HK2 protein P52789 UNIPROT "down-regulates quantity" ubiquitination 9606 BTO:0000007 28980855 t "The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation." SIGNOR-260003 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 "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 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 KCNE3 protein Q9Y6H6 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-265589 ERBB2 protein P04626 UNIPROT ERBB2 protein P04626 UNIPROT down-regulates phosphorylation Tyr1112 DPSPLQRySEDPTVP 9606 BTO:0000149 1706616 t gcesareni "However, each of these peptides contains tyrosines that correspond to major autophosphorylation sites of the epidermal growth factor receptor, suggesting that, in addition to y1023 and y1248, y1139 and y1222 also serve as autophosphorylation sites of her2." SIGNOR-21211 MYC protein P01106 UNIPROT DKK1 protein O94907 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 17485441 f gcesareni "C-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity" SIGNOR-245355 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 AKT1 protein P31749 UNIPROT STK3 protein Q13188 UNIPROT down-regulates phosphorylation Thr384 GTMKRNAtSPQVQRP 9606 20086174 t llicata "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-163537 PHKG1 protein Q16816 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser602 INKKLDLsNVQSKCG -1 8999860 t miannu "Muscle phosphorylase kinase phosphorylates Ser237, Ser262, Ser285, Ser305, and Ser352 of human tau. in vitro phosphorylation of tau on Ser262 alone strongly reduced the ability of tau to bind microtubules whereas the phosphorylation of many Ser/Thr-Pro motif sites of tau showed moderate effects on the binding of tau to microtubules" SIGNOR-250285 NRF1 protein Q16656 UNIPROT BRK1 protein Q8WUW1 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23939472 f miannu "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." SIGNOR-261369 MAP2K4 protein P45985 UNIPROT JNK proteinfamily SIGNOR-PF15 SIGNOR "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-236110 Avacopan chemical CID:49841217 PUBCHEM C5AR2 protein Q9P296 UNIPROT "down-regulates activity" binding 9606 31734405 t lperfetto "CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients." SIGNOR-263474 MAPK1 protein P28482 UNIPROT AR protein P10275 UNIPROT down-regulates phosphorylation Ser516 VSRVPYPsPTCVKSE 9606 BTO:0001130 18511414 t gcesareni "Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126" SIGNOR-178718 EFNA3 protein P52797 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The eph family of receptors." SIGNOR-52309 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 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 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 MC5R protein P33032 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-256941 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 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 PXN protein P49023 UNIPROT Cell_migration phenotype SIGNOR-PH38 SIGNOR up-regulates 9606 18650496 f "VEGF pathway" Gianni "Through the interactions of its multiple protein-protein binding modules, many of which are regulated by phosphorylation, paxillin serves as a platform for the recruitment of numerous regulatory and structural proteins that together control the dynamic changes in cell adhesion, cytoskeletal reorganization and gene expression that are necessary for cell migration and survival." SIGNOR-261944 EFNA1 protein P20827 UNIPROT EPHA5 protein P54756 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-56910 GNAI3 protein P08754 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-38032 PPP2CB protein P62714 UNIPROT CHEK1 protein O14757 UNIPROT "down-regulates activity" dephosphorylation Ser317 ENVKYSSsQPEPRTG 9606 17015476 t "Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo." SIGNOR-248579 PAX6 protein P26367 UNIPROT PCSK1 protein P29120 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19034419 f miannu "PAX6 can bind to the promoter and directly upregulate production of prohormone convertase (PC)1/3, an enzyme essential for conversion of proinsulin to insulin." SIGNOR-254900 CLTA protein P09496 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-260678 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 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 CSNK2A1 protein P68400 UNIPROT IRS1 protein P35568 UNIPROT unknown phosphorylation Ser99 HFAIAADsEAEQDSW -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-250909 KTN1 protein Q86UP2 UNIPROT KIF5B protein P33176 UNIPROT up-regulates binding 9606 15316074 t miannu "This study demonstrated the effect of kinectin-kinesin interaction on lysosome dynamics and observed that the kinesin-binding domain of kinectin can significantly enhance the mt-stimulated atpase activity of kinesin." SIGNOR-128092 ATM protein Q13315 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-180751 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 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 P2RY2 protein P41231 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-256902 "glutamic acid" smallmolecule CHEBI:18237 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-264752 MC3R protein P41968 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-256748 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 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 JAK2 protein O60674 UNIPROT STAP2 protein Q9UGK3 UNIPROT "up-regulates activity" phosphorylation Tyr250 PFLLDEDyEKVLGYV 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-249371 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 CSNK2A1 protein P68400 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-250908 TEAD1 protein P28347 UNIPROT MSLN protein Q13421 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 17909009 f miannu "The presence of TEF-1 was required for MSLN protein overexpression as determined by TEF-1 knockdown experiments." SIGNOR-255395 ACTG1 protein P63261 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-261878 MAPK3 protein P27361 UNIPROT TOB1 protein P50616 UNIPROT down-regulates phosphorylation Ser154 SSVSSSPsPPFGHSA 9606 BTO:0000782 12151396 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-91059 FOXO3 protein O43524 UNIPROT CDKN1B protein P46527 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14981546 f "Induction of Foxo3a phosphorylation by FLT3-ITD receptors in Ba/F3 cells correlates with the suppression of Foxo-target genes p27Kip1 and the proapoptotic Bcl-2 family member Bim" SIGNOR-261527 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 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 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 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 LCK protein P06239 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 9606 BTO:0000007 9973379 t "Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218.the role of Y218 in CTLA-4 biology is not known at the present" SIGNOR-251371 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 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 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 AKT2 protein P31751 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates activity" phosphorylation Thr32 QSRPRSCtWPLPRPE 9606 16272144 t gcesareni "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.[...]These results indicate that phosphorylation at Thr32 and Ser197 is indispensable, whereas that at Ser262 is not critical, for regulation of the nuclear localization and transcriptional activity of FOXO4" SIGNOR-252870 JAK1 protein P23458 UNIPROT STAT2 protein P52630 UNIPROT "up-regulates activity" phosphorylation 9606 9020188 t lperfetto "The stat1 and stat2 proteins are present in the cytoplasm of untreated cells;upon stimulation with ifn-?, They become rapidly activated by tyrosine phosphorylation at a single site catalyzed by receptor associated jak (janus) kinases." SIGNOR-88285 WWTR1 protein Q9GZV5 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-256668 paclitaxel chemical CHEBI:45863 ChEBI TUBB1 protein Q9H4B7 UNIPROT "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-259347 WASHC3 protein Q9Y3C0 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-261017 doramapimod chemical CHEBI:40953 ChEBI MAPK14 protein Q16539 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-258208 "(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 GRM3 protein Q14832 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-193772 HDAC1 protein Q13547 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-268835 WDR18 protein Q9BV38 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-265471 GSK3B protein P49841 UNIPROT BCL2L12 protein Q9HB09 UNIPROT up-regulates phosphorylation Ser156 SESPRPCsLPIRPCY 9606 BTO:0000527 22262180 t lperfetto "Gsk3b phosphorylates bcl2l12 at s156. Ectopic expression of gfp-fused bcl2l12 or bcl2l12a in u87mg cells leads to repression of apoptotic markers and protects against staurosporine (sts) insults, indicating an antiapoptotic role for both bcl2l12 and bcl2l12a. In contrast, no anti-apoptotic ability was seen in bcl2l12(s156a)" SIGNOR-195512 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 Fibrin complex SIGNOR-C317 SIGNOR Fibrin_clot_formation phenotype SIGNOR-PH153 SIGNOR up-regulates binding 9606 BTO:0000131 18544683 t lperfetto "A fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel.|Fibrin clots were formed as described for turbidity experiments, in which the fibrinogen, calcium, and polyP (when included) were preincubated for 15 minutes before adding thrombin." SIGNOR-263531 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 FBXO3 protein Q9UK99 UNIPROT HIPK2 protein Q9H2X6 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0004573 18809579 t miannu "O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. " SIGNOR-271741 EGFR protein P00533 UNIPROT ASAP3 protein Q8TDY4 UNIPROT "up-regulates activity" phosphorylation Tyr34 FAAKMPRyRGAALAR 9606 BTO:0000599 23776207 t lperfetto "How ACAP4 regulates membrane dynamics and curvature in response to EGF stimulation is unknown. Here, we show that phosphorylation of the N-terminal region of ACAP4, named the Bin, Amphiphysin, and RSV161/167 (BAR) domain, at Tyr34 is necessary for EGF-elicited membrane remodeling. |EGF stimulation of cells causes phosphorylation of ACAP4 at Tyr34, which subsequently promotes ACAP4 homodimer curvature." SIGNOR-272234 BLOC1S2 protein Q6QNY1 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-265937 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 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 DPF3 protein Q92784 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-270690 BLOC-1 complex SIGNOR-C381 SIGNOR serotonin smallmolecule CHEBI:28790 ChEBI "up-regulates quantity" relocalization 9606 23805129 t lperfetto "The multidrug transporter MRP4, a multidrug resistance protein, is found on platelet dense granules and is proposed to transport adenine nucleotides into these granules (Jedlitschky et al., 2004). Uptake of serotonin from platelet cytosol into dense granules is mediated by vesicular monoamine transporter 2 (VMAT2). |VMAT2 also appears to mediate histamine transport into dense granules" SIGNOR-265999 HOXD12 protein P35452 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-241232 THRB protein P10828 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-267256 ASAP3 protein Q8TDY4 UNIPROT ARHGEF6 protein Q15052 UNIPROT "up-regulates activity" binding 9606 BTO:0000599 23776207 t lperfetto "ArfGAP With Coiled-Coil, Ankyrin Repeat And PH Domains 4 (ACAP4) is an ADP-ribosylation factor 6 (ARF6) GTPase-activating protein essential for EGF-elicited cell migration. |The crystal structure of the catalytic core of ACAP4 in a complex with ARF6 reveals the structural determinants underlying ACAP4 selectivity and specificity as an ARF6 GTPase-activating protein" SIGNOR-272235 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 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 LCK protein P06239 UNIPROT CD3G protein P09693 UNIPROT "up-regulates activity" phosphorylation 10090 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-259928 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 AMHR2 protein Q16671 UNIPROT BMPR1B protein O00238 UNIPROT up-regulates binding 9606 14746809 t gcesareni "See table2" SIGNOR-121596 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 H3C1 protein P68431 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-263721 TGFBR1 protein P36897 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" phosphorylation Ser465 SPSVRCSsMS 9534 BTO:0001538 9346908 t lperfetto "Recently, it was demonstrated that Smad2 interacts transiently with and is a direct substrate of the transforming growth factor-_ (TGF-_) type I receptor, T_RI. Phosphorylation sites on smad2 were localized to a carboxyl-terminal fragment containing three serine residues at positions 464, 465, and 467. In this report, we show that T_RI specifically phosphorylates Smad2 on serines 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-236107 ERK1/2 proteinfamily SIGNOR-PF1 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-270132 FGF12 protein P61328 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-253424 POU4F1 protein Q01851 UNIPROT SCN9A protein Q15858 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000931 24493753 f miannu "In neuroblastoma ND7 cells, a nuclear interaction between the developmentally regulated transcription factor Brn-3a and AR resulted in a complex which bound to multiple elements within the promoter region of SCN9A (Nav1.7) and upregulated channel expression." SIGNOR-253465 PML protein P29590 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 BTO:0001271 15093545 f gcesareni "The promyelocytic leukemia (pml) protein is a potent growth suppressor and proapototic factor" SIGNOR-256659 BMPR1A protein P36894 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 10090 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-75652 BIRC3 protein Q13489 UNIPROT RIPK1 protein Q13546 UNIPROT "up-regulates activity" ubiquitination Lys377 NEPSLQSkLQDEANY 9606 18570872 t amattioni "In this report, we show that ciap1 and ciap2 promote cancer cell survival by functioning as e3 ubiquitin ligases that maintain constitutive ubiquitination of the rip1 adaptor protein." SIGNOR-179104 STK26 protein Q9P289 UNIPROT ASAP3 protein Q8TDY4 UNIPROT "up-regulates activity" phosphorylation Thr545 HRFARRCtPEPQRLW 9606 BTO:0000007 28808054 t lperfetto "Here we show that MST4 phosphorylates ACAP4, an ARF6 GTPase-activating protein, at Thr545|Significantly, phosphorylation of Thr545 enables ACAP4 to interact with ezrin. Given the location of Thr545 between the GTPase-activating protein domain and the first ankyrin repeat, we reason that MST4 phosphorylation elicits a conformational change that enables ezrin-ACAP4 interaction." SIGNOR-272238 PRKCG protein P05129 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-249088 DDX28 protein Q9NUL7 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-261229 PCDHAC1 protein Q9H158 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-269037 DFFB protein O76075 UNIPROT DNA_fragmentation phenotype SIGNOR-PH22 SIGNOR up-regulates 9606 BTO:0000661 9422513 f "Cleavage of ICAD/DFF-45" amattioni "The specific cleavage of icad/dff-45 by caspase-3 relieves the inhibition and promotes the endonuclease activity of cad, resulting in apoptotic dna fragmentation" SIGNOR-54358 MPO-ANCA complex SIGNOR-C474 SIGNOR Neutrophil_activation phenotype SIGNOR-PH211 SIGNOR up-regulates 9606 BTO:0000133 2161532 f lperfetto "ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation." SIGNOR-270583 MTOR protein P42345 UNIPROT MAF1 protein Q9H063 UNIPROT down-regulates phosphorylation Ser75 SPSRLSKsQGGEEEG 9606 BTO:0000567 20543138 t fstefani "Maf1, a repressor that binds and inhibits pol iii, is phosphorylated in a mtor-dependent manner both in vitro and in vivo at serine 75" SIGNOR-166054 Ub:E2 complex SIGNOR-C497 SIGNOR DTX3L protein Q8TDB6 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-270952 SMO protein Q99835 UNIPROT TIAM1 protein Q13009 UNIPROT up-regulates binding 9606 BTO:0000785 23074268 t gcesareni "This latter work suggested that inactive smo prevents rac1 activation by interacting with the rac guanine nucleotide exchange factor (gef) t-lymphoma invasion and metastasis 1 (tiam1). This smo-tiam1 complex dissociates upon shh-mediated activation of smo, thus allowing tiam1 to activate rac1" SIGNOR-199192 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR NUP153 protein P49790 UNIPROT unknown phosphorylation 9606 19767751 t "inferred from 70% family members" 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-270159 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR AMPH protein P49418 UNIPROT unknown phosphorylation Ser272 EEPSPLPsPTASPNH -1 11113134 t llicata "Amphiphysin is phosphorylated by cdk5 in a region including serines 272, 276, and 285. Amphiphysin 1 is also phosphorylated by the cdc2/cyclin B kinase complex in the same region and undergoes mitotic phosphorylation in dividing cells. " SIGNOR-250644 MAP3K2 protein Q9Y2U5 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 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-107695 ROS stimulus SIGNOR-ST2 SIGNOR NFE2L2 protein Q16236 UNIPROT up-regulates 9606 BTO:0000018 22789539 f miannu "Nrf2 is a master transcriptional activator of cytoprotective genes. It activates transcription in response to electrophiles and reactive oxygen species (ROS) (Itoh et al., 1997, Uruno and Motohashi, 2011). Under normal conditions, Nrf2 is constantly ubiquitinated by Keap1 and degraded by the proteasome. Exposure to the stimuli inactivates Keap1 and stabilizes Nrf2." SIGNOR-267353 GGCX protein P38435 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 31539109 f miannu "GGCX can regulate osteoporosis via promoting the TGFβ/smad signaling pathway, facilitating BMSCs osteogenic differentiation, and inhibiting BMSCs adipogenic differentiation. The transfection of pcDNA-GGCX plasmid significantly promoted BMSC cell proliferation, increased calcified nodule formation, inhibited adipogenic differentiation, enhanced ALP activity, elevated RUNX2, and OPN mRNA expressions, and upregulated TGFβ1, Smad2, and Smad7 expressions (p < 0.05)." SIGNOR-261232 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 "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 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 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT "down-regulates activity" phosphorylation Thr118 TNLGEKLtDEEVDEM -1 26675311 t miannu "Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third." SIGNOR-266355 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR PTCH1 protein Q13635 UNIPROT down-regulates cleavage Asp1405 CPGYPETdHGLFEDP 9606 23074268 t gcesareni "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-256437 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR tRNA(Glu) smallmolecule CHEBI:29175 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-270379 ATAT1 protein Q5SQI0 UNIPROT TUBA3C protein P0DPH7 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272244 NLRX1 protein Q86UT6 UNIPROT PCBP2 protein Q15366 UNIPROT "up-regulates activity" binding 9606 28956771 t Giorgia "Moreover, poly(rC) binding protein 2 (PCBP2) interacts with NLRX1 to participate in the NLRX1-induced degradation of MAVS and the inhibition of antiviral responses during HCV infection." SIGNOR-260359 lovastatin chemical CHEBI:40303 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-258351 TCF3 protein P15923 UNIPROT CR2 protein P20023 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11739509 f miannu "We have previously described the presence of an intronic element that is required for both cell- and stage-specific expression of CR2. In this study, we report the identification of a cell type-specific repressor element within the proximal promoter. By supershift analysis this element binds members of the basic helix-loop-helix family of proteins, in particular E2A gene products. Mutational analysis demonstrates that binding of E2A proteins is critical for functioning of this repressor. Thus, E2A activity is key not only for early B cell development, but also for controlling CR2 expression, a gene expressed only during later stages of ontogeny." SIGNOR-255387 TP53 protein P04637 UNIPROT TNFRSF10B protein O14763 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 14585074 f "Nuclear p53" amattioni "Cd95l, cd95, and the trail death receptors are induced by the tumour suppressor p53" SIGNOR-113707 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 ERP44 protein Q9BS26 UNIPROT ITPR1 protein Q14643 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 15652484 t Simone "In this study, we found that ERp44, an ER lumenal protein of the thioredoxin family, directly interacts with the third lumenal loop of IP(3)R type 1 (IP(3)R1) and that the interaction is dependent on pH, Ca(2+) concentration, and redox state. In this study we demonstrated that ERp44 directly interacts with the L3V domain of IP3R1, thereby inhibiting its channel activity." SIGNOR-261046 STAT3 protein P40763 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 30029643 f "Taken together, our data show IL-15 can enhance the collagen deposition in vivo after muscle damage and this process can be prevented by blocking Jak-STAT pathway." SIGNOR-256257 Ub:E2 complex SIGNOR-C497 SIGNOR MAEA protein Q7L5Y9 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-271048 CSNK2A1 protein P68400 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2484 LVSFHDDsDEDLLHI 9606 8318012 t lperfetto "The two sites phosphorylated by ck ii in vivo and in vitro are ser82 and ser157." SIGNOR-37835 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10497236 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." lperfetto "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-217746 ATAT1 protein Q5SQI0 UNIPROT TUBA3D protein P0DPH8 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272246 RALGDS protein Q12967 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-220859 carbachol chemical CHEBI:3385 ChEBI CHRM1 protein P11229 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-258620 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 NLGN1 protein Q8N2Q7 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-264159 CRYAA protein P02489 UNIPROT Maintenance_of_lens_transparency phenotype SIGNOR-PH65 SIGNOR up-regulates 9606 22982024 f miannu "Aberrant protein interactions can lead to aggregation and insolubilization, such as occurs during cataract formation. Deamidation, a prevalent age-related modification in the lens of the eye, decreases stability of the major lens proteins, crystallins. Deamidation did not disrupt specific αA/βB2 interactions but favored aggregation before complex formation with αA. We conclude that deamidation contributes to cataract formation through destabilization of crystallins before they can be rescued by α-crystallin." SIGNOR-252156 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM37 protein O94972 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-271082 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 "lysophosphatidylserine 14:0(1-)" chemical CHEBI:72402 ChEBI P2RY10 protein O00398 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-257558 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 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser649 VPPSPSLsRHSSPHQ 11427888 t "Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II." SIGNOR-251240 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1190 DIYETDYyRKGGKGL 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-16243 Cell-Cell_contact stimulus SIGNOR-ST13 SIGNOR TJP2 protein Q9UDY2 UNIPROT up-regulates 9606 21529719 f milica "Another junction protein, the tight junction protein ZO-2, binds to YAP/TAZ, facilitating their nuclear translocation." SIGNOR-230703 DGC complex SIGNOR-C217 SIGNOR NRXN2 protein P58401 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-265449 MTOR protein P42345 UNIPROT RPTOR protein Q8N122 UNIPROT "up-regulates activity" phosphorylation Ser855 QRVLDTSsLTQSAPA 9606 BTO:0000007 19864431 t lperfetto "Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855))" SIGNOR-174882 APP protein P05067 UNIPROT GSK3A protein P49840 UNIPROT up-regulates 9606 BTO:0000938 16446437 f gcesareni "These results suggest a direct relationship between app proteolytic processing, but not amyloid-_, in gsk-3_ activation and tau phosphorylation in human neurons." SIGNOR-144057 CCT137690 chemical CID:25154041 PUBCHEM AURKC protein Q9UQB9 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190898 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 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 SRSF7 protein Q16629 UNIPROT NXF1 protein Q9UBU9 UNIPROT up-regulates binding 9606 18364396 t miannu "9g8 and srp20 also enhance the tap rna-binding activity" SIGNOR-161338 GSK3B protein P49841 UNIPROT CLASP2 protein O75122 UNIPROT "down-regulates activity" phosphorylation Ser533 QGCSREAsRESSRDT 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-264825 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 EIF1AX protein P47813 UNIPROT Ternary_GTP_eIF2_tRNA_complex complex SIGNOR-C452 SIGNOR "up-regulates activity" relocalization 9606 12514125 t lperfetto "Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA i Met ternary complex (TC) and ribosomal scanning. " SIGNOR-269147 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 "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 ANP32A protein P39687 UNIPROT CASP9 protein P55211 UNIPROT "up-regulates activity" 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-259082 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 MAPK1 protein P28482 UNIPROT ASB2 protein Q96Q27 UNIPROT "up-regulates activity" phosphorylation Ser371 RIRRSGVsPLHLAAE 24044920 t lperfetto "Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation." SIGNOR-272240 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 HUWE1 protein Q7Z6Z7 UNIPROT POLL protein Q9UGP5 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys27 ASSKVLAkIPRREEG 9606 BTO:0000567 22203964 t miannu "We found that Pol λ can be ubiquitinated by the E3 ligase Mule in vitro and in vivo and that this interaction is functionally connected to the phosphorylation-dependent stabilization of Pol λ by Cdk2/cyclinA. " SIGNOR-272904 SHH protein Q15465 UNIPROT PTCH1 protein Q13635 UNIPROT "down-regulates activity" binding 9606 14556242 t lperfetto "In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling.Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other." SIGNOR-118615 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 PAK1 protein Q13153 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 12198493 t gcesareni "In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152." SIGNOR-92065 GALR3 protein O60755 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-257114 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 ZMYND8 protein Q9ULU4 UNIPROT MMP1 protein P03956 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-262042 LPAR6 protein P43657 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-256868 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 CTDSP1 protein Q9GZU7 UNIPROT SMAD2 protein Q15796 UNIPROT "down-regulates activity" dephosphorylation Ser255 ELSPTTLsPVNHSLD 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-248797 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR RANGAP1 protein P46060 UNIPROT up-regulates phosphorylation Ser442 STFLAFPsPEKLLRL 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-216785 "tacrolimus (anhydrous)" chemical CHEBI:61049 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-269893 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 Ub:E2 complex SIGNOR-C497 SIGNOR RNF115 protein Q9Y4L5 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-271000 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 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 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 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3R1 protein P27986 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni "Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling" SIGNOR-191673 NOSIP protein Q9Y314 UNIPROT EPOR protein P19235 UNIPROT "up-regulates activity" ubiquitination 9534 BTO:0000298 12746455 t miannu "Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation. This receptor-associated ubiquitin ligase, RUL, co-precipitated with EpoR from mammalian cells and mediated ubiquitination of EpoR. RUL mediates EpoR ubiquitination in COS7 cells and is inducibly ubiquitinated after Epo treatment. This observation is consistent with the lack of effects on EpoR stability by RUL-mediated ubiquitination in COS7 cells (Fig. 4)." SIGNOR-271477 CDKN1B protein P46527 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0002392 22343731 f fcortellessa "The results of the MTT assay and growth curves revealed that the cells transfected with pEGFP-p27kip1 had a significant growth inhibition when compared with cells transfected with pEGFP-NC (Fig. 5B and D). These data indicated that overexpression of p27kip1 could arrest cell-cycle progression and decrease proliferation of SGC-7901 cells." SIGNOR-261687 1,1-dioxo-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3-one chemical CHEBI:93578 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-258891 CIITA protein P33076 UNIPROT RFX5 protein P48382 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 9177217 t 2 miannu "RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA." SIGNOR-240980 ZEB2 protein O60315 UNIPROT MEOX2 protein P50222 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20516212 t Luisa "ZEB2 represses GAX transcription through multiple up- stream consensus binding sites." SIGNOR-268951 ADSL protein P30566 UNIPROT 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58475 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-266608 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 MCU protein Q8NE86 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-270869 CDH13 protein P55290 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-265853 CXCL11 protein O14625 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-260971 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1931 SPTSPTYsPTSPKGS 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-203600 U0126 chemical CHEBI:90693 ChEBI MAPK7 protein Q13164 UNIPROT down-regulates 9606 11782488 f gcesareni "Bmk1activation by h2o2 was inhibited by both pd98059 and u0126, which were reported to inhibit mek5 as well as mek1/2." SIGNOR-113782 MAPK3 protein P27361 UNIPROT ASB2 protein Q96Q27 UNIPROT "up-regulates activity" phosphorylation Ser371 RIRRSGVsPLHLAAE 24044920 t lperfetto "Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation." SIGNOR-272241 ATAT1 protein Q5SQI0 UNIPROT TUBA1C protein Q9BQE3 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272247 Gbeta proteinfamily SIGNOR-PF4 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-270110 C1RL protein Q9NZP8 UNIPROT HP protein P00738 UNIPROT "up-regulates activity" cleavage Arg161 NPANPVQrILGGHLD 9534 BTO:0001538 15385675 t miannu "We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinity-purified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction." SIGNOR-256358 RUNX1 protein Q01196 UNIPROT ELANE protein P08246 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004850 14594802 f miannu "We find that LEF-1 and CBFalpha co-activate ELA2 expression." SIGNOR-254553 "NLRP3 inflammasome" complex SIGNOR-C225 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-256381 CAPRIN2 protein Q6IMN6 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 19619488 t gcesareni "A cytoplasmic protein in vertebrates, referred to as caprin-2, binds to lrp6 and facilitates lrp6 phosphorylation by gsk3" SIGNOR-187177 GNAQ protein P50148 UNIPROT PLCB1 protein Q9NQ66 UNIPROT up-regulates binding 9606 8245028 t gcesareni "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-37149 GATA6 protein Q92908 UNIPROT PLXNA2 protein O75051 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-253149 PRKCQ protein Q04759 UNIPROT RAPGEF2 protein Q9Y4G8 UNIPROT up-regulates phosphorylation Ser960 KKRVRRSsFLNAKKL 9606 BTO:0000782 18796635 t lperfetto "After t-cell activation, the direct phosphorylation of rapgef2 at ser960 by pkc- theta regulates rap1 activation as well as lfa-1 adhesiveness to icam-1. Pkc- theta and its effector rapgef2 are critical factors in tcr signaling to rap1" SIGNOR-181186 COL18A1 protein P39060 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-252269 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 GRM4 protein Q14833 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-264935 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 ATAT1 protein Q5SQI0 UNIPROT TUBA3E protein Q6PEY2 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272248 Oxotremorine chemical CHEBI:7851 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-258653 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 AKT1 protein P31749 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-252844 AKT1 protein P31749 UNIPROT 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-252860 MAP3K1 protein Q13233 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 17563747 t lperfetto "Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna." SIGNOR-236346 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 SPI1 protein P17947 UNIPROT OSCAR protein Q8IYS5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 16046394 f lperfetto "NFATc1 expression results in the activation of the OSCAR promoter, which was found to be further enhanced by co-expression of PU.1 and microphthalmia-associated transcription factor (MITF)." SIGNOR-271689 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 TACR1 protein P25103 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-257249 LRRK2 protein Q5S007 UNIPROT PRDX3 protein P30048 UNIPROT "down-regulates activity" phosphorylation Thr146 SHLAWINtPRKNGGL 9606 BTO:0000793 21850687 t miannu "Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells." SIGNOR-262891 CAPN2 protein P17655 UNIPROT GSK3B protein P49841 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-251613 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 2-[[2-[[1-[2-(dimethylamino)-1-oxoethyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide chemical CHEBI:93768 ChEBI IGF1R protein P08069 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-258116 GRPR protein P30550 UNIPROT GNAQ protein P50148 UNIPROT up-regulates binding 9606 BTO:0000189 17251915 t gcesareni "Gastrin-releasing peptide receptors (grpr) are coupled primarily to galfaq, and are highly expressed in many cancers, including small-cell lung cancer" SIGNOR-152679 LMX1B protein O60663 UNIPROT "LMX1B/SFPQ/PSPC1 complex" complex SIGNOR-C106 SIGNOR "form complex" binding 10090 23308148 t miannu "LMX1B is part of a transcriptional complex with PSPC1 and PSF. This complex was observed in vitro and in vivo." SIGNOR-223966 D-glucopyranose smallmolecule CHEBI:4167 ChEBI UDP(3-) smallmolecule CHEBI:58223 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-268472 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 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 EP300 protein Q09472 UNIPROT RUNX2 protein Q13950 UNIPROT "up-regulates quantity" acetylation 9606 20851880 t gcesareni "These results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300" SIGNOR-167966 olanzapine chemical CHEBI:7735 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-258511 MAPK8 protein P45983 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Ser178 PPLPGALsPLYGVPE 10116 BTO:0004316 12853963 t miannu "JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (Pax(S178A)) formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin moved rapidly and retained close contacts as the predominant adhesion." SIGNOR-250129 TRIM27 protein P14373 UNIPROT MAPK13 protein O15264 UNIPROT up-regulates 9606 12807881 f miannu "We found rfp-mediated activation of both exogenous and endogenous forms of the other stress-activated mapk, p38." SIGNOR-102028 RNF25 protein Q96BH1 UNIPROT NKD2 protein Q969F2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 18757723 t miannu "Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2." SIGNOR-271738 STOM protein P27105 UNIPROT SLC2A1 protein P11166 UNIPROT "down-regulates activity" binding 9606 10562431 t Giulio "Similar to the results obtained in the RBC, Glut1 and stomatin immunoprecipitated with each other in lysates of Clone 9 cells. The above results suggest that stomatin is closely associated with Glut1 in the plasma membrane and that overexpression of stomatin results in a depression in the basal rate of glucose transport." SIGNOR-261278 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 MID1IP1 protein Q9NPA3 UNIPROT ACACA protein Q13085 UNIPROT "up-regulates activity" binding 10029 BTO:0000457 20952656 t miannu "Recently, we reported the discovery that MIG12, a 183 amino acid protein, binds to ACC1 and ACC2, which induces polymerization and subsequently increases the enzymatic activity of the protein" SIGNOR-267111 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 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 MYF6 protein P23409 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" BTO:0001103 7532173 f "Simone Vumbaca" "Finally, MRF4 may be responsible for the final myogenic events of the fully differentiated myofiber" SIGNOR-255645 TCL1B protein O95988 UNIPROT AKT1 protein P31749 UNIPROT up-regulates binding 9606 BTO:0000782;BTO:0001271 10983986 t gcesareni "In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation." SIGNOR-81713 CEBPB protein P17676 UNIPROT Neurodegeneration phenotype SIGNOR-PH139 SIGNOR "up-regulates activity" 10090 BTO:0000078 32795415 f Gianni "In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures." SIGNOR-261926 ABCG1 protein P45844 UNIPROT HDL_assembly phenotype SIGNOR-PH61 SIGNOR up-regulates 9606 16054053 f miannu "ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. cholesterol efflux to HDL specifically requires ABCG1, whereas efflux to apoA1 requires ABCA1. These studies identify Abcg1 as a key gene involved in both cholesterol efflux to HDL and in tissue lipid homeostasis." SIGNOR-252111 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM39 protein Q9HCM9 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-270969 BRCA1 protein P38398 UNIPROT "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR "form complex" binding 25400280 t lperfetto "Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks." SIGNOR-263224 ID3 protein Q02535 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C129 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-241379 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 ETV2 protein O00321 UNIPROT Differentiation phenotype SIGNOR-PH37 SIGNOR up-regulates 10090 BTO:0001086 24583263 f irozzo "Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation." SIGNOR-256009 (-)-anisomycin chemical CHEBI:338412 ChEBI FOS protein P01100 UNIPROT up-regulates "chemical activation" 9606 Other t CellSignaling gcesareni SIGNOR-189626 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 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 AMPK complex SIGNOR-C15 SIGNOR FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249678 PCK2 protein Q16822 UNIPROT phosphonatoenolpyruvate smallmolecule CHEBI:58702 ChEBI "up-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-266557 ZC3H12A protein Q5D1E8 UNIPROT TAL1 protein P17542 UNIPROT "up-regulates quantity" "post transcriptional regulation" 9606 BTO:0000007 30842549 t "Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA" SIGNOR-259944 "TTM complex" complex SIGNOR-C305 SIGNOR "Shelterin complex" complex SIGNOR-C306 SIGNOR "up-regulates activity" relocalization 9606 BTO:0000007 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-263308 HIVEP2 protein P31629 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-261617 UBE2I protein P63279 UNIPROT SMAD4 protein Q13485 UNIPROT up-regulates sumoylation Lys159 APSSMMVkDEYVHDF 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-98997 vorinostat chemical CHEBI:45716 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-257922 PPM1F protein P49593 UNIPROT PAK2 protein Q13177 UNIPROT down-regulates dephosphorylation 9606 BTO:0000150;BTO:0000093 20016286 t gcesareni "Pop x2, a pp 2c serine/threonine phosphatase, is known to dephosphorylate pak and downregulate its activity." SIGNOR-162149 MAPK1 protein P28482 UNIPROT RAF1 protein P04049 UNIPROT "down-regulates activity" phosphorylation Ser29 FDGSSCIsPTIVQQF 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-249441 "Glycine cleavage system" complex SIGNOR-C437 SIGNOR glycine smallmolecule CHEBI:15428 ChEBI "down-regulates quantity" "chemical modification" 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-268238 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 ZNRF3 protein Q9ULT6 UNIPROT LRP6 protein O75581 UNIPROT down-regulates ubiquitination 9606 23151663 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-199656 SKI protein P12755 UNIPROT SMAD2/SMAD4 complex SIGNOR-C8 SIGNOR "down-regulates activity" binding 9606 BTO:0000848 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-253300 FLT3 protein P36888 UNIPROT HK2 protein P52789 UNIPROT "up-regulates activity" 9606 BTO:0002144 28194038 f "FLT3/ITD causes a significant increase in aerobic glycolysis through AKT-mediated upregulation of mitochondrial hexokinase (HK2), and renders the leukemia cells highly dependent on glycolysis and sensitive to pharmacological inhibition of glycolytic activity" SIGNOR-261322 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 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 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 JAG1 protein P78504 UNIPROT NOTCH2 protein Q04721 UNIPROT up-regulates binding 9606 18660822 t "Binding Calcium-dependent." gcesareni "Here we report the first x-ray structure of a functional fragment of a notch ligand, the dsl-egf3 domains of human jagged-1 (j-1dsl-egf3). The structure identifies a highly conserved face of the dsl domain and we show, by functional analysis of drosophila ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with notch." SIGNOR-179622 CCKBR protein P32239 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-257150 KDM5C protein P41229 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-264305 KPNA4 protein O00629 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-165314 NFKBIA protein P25963 UNIPROT RELA protein Q04206 UNIPROT "up-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-17691 CRIPAK protein Q8N1N5 UNIPROT PAK1 protein Q13153 UNIPROT up-regulates binding 9606 BTO:0000150 BTO:0000149 16278681 t gcesareni "We further found that cripak interacted with pak1 through the n-terminal regulatory domain and inhibited pak1 kinase in both in vitro and in vivo assays." SIGNOR-141467 STK11 protein Q15831 UNIPROT NUAK2 protein Q9H093 UNIPROT up-regulates phosphorylation Thr208 HQGKFLQtFCGSPLY 9606 14976552 t llicata "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-122717 CSNK2A1 protein P68400 UNIPROT GAP43 protein P17677 UNIPROT unknown phosphorylation Ser202 PPTETGEsSQAEENI -1 1828073 t llicata "Two serines located in the C-terminal end of neuromodulin, Ser-192 and Ser-193, were identified as the major casein kinase II phosphorylation sites." SIGNOR-250866 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 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 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 miR-132 mirna URS00001F4E81_9606 RNAcentral MECP2 protein P51608 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 10090 23132946 f irozzo "In human leukemic cells with MLL rearrangements (e.g., MONOMAC-6 and THP-1 cells), we found that ectopic expression of miR-495 could significantly inhibit cell growth/proliferation and increase apoptosis while decreasing cell viability." SIGNOR-256649 ATAT1 protein Q5SQI0 UNIPROT TUBA4A protein P68366 UNIPROT "up-regulates quantity by stabilization" acetylation Lys40 DGQMPSDkTIGGGDD -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272249 CSNK1D protein P48730 UNIPROT PSEN2 protein P49810 UNIPROT unknown phosphorylation Ser9 LTFMASDsEEEVCDE -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-250804 CDC25A protein P30304 UNIPROT CDK1 protein P06493 UNIPROT "up-regulates activity" dephosphorylation Tyr15 EKIGEGTyGVVYKGR 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-248480 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 CDK1 protein P06493 UNIPROT KIF2C protein Q99661 UNIPROT down-regulates phosphorylation Thr537 LGQNKAHtPFRESKL 9606 20368358 t llicata "We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation." SIGNOR-164761 JAK2 protein O60674 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates phosphorylation Tyr718 IPERDSRySQPLHEE 9606 19287004 t lperfetto "Previously we have shown that tyrosine 718 of ask1 when phosphorylated is critical for socs1 binding and socs1-mediated degradation of ask1we identified jak2 and shp2 as a tyr-718-specific kinase and phosphatase, respectively." SIGNOR-184600 "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR PAWR protein Q96IZ0 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 24992930 t miannu "Fbxo45 interacts with Par-4 in the cytoplasm and mediates its ubiquitylation and proteasomal degradation. Fbxo45 silencing results in stabilization of Par-4 with increased apoptosis.Fbxo45 forms an atypical ubiquitin ligase complex that contains Skp1 and the Ring-finger protein PAM (protein-associated with myc) also known as MYCBP2 (myc-binding protein 2)." SIGNOR-272224 BCL2L1 protein Q07817 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" binding -1 10949026 t lperfetto "Bad dimerizes with bcl-xl at the mitochondrial membrane where it exert its killing effects. Phosphorylation of bad promotes its binding to 14-3-3 protein, which may sequester bad from bcl-xl, thus promoting cell cells survival." SIGNOR-81125 AKT1 protein P31749 UNIPROT 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-252579 PRKG2 protein Q13237 UNIPROT 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 "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-186943 PTAFR protein P25105 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-257262 "mono(2-ethylhexyl) phthalate" chemical CHEBI:17243 ChEBI PPARD protein Q03181 UNIPROT "up-regulates activity" "chemical activation" 9606 19433246 t miannu "Phthalates are true ligands of PPARs. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic." SIGNOR-268746 L-thyroxine(1-) chemical CHEBI:60302 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-258051 sunitinib chemical CHEBI:38940 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 21423276 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-172917 CSNK2A2 protein P19784 UNIPROT PTPRC protein P08575 UNIPROT "up-regulates activity" phosphorylation Ser1009 DESSDDDsDSEEPSK 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-251031 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SOS1 protein Q07889 UNIPROT "down-regulates activity" phosphorylation Ser1167 ESAPAESsPSKIMSK 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-244584 HCK protein P08631 UNIPROT ADAM15 protein Q13444 UNIPROT unknown phosphorylation Tyr715 LVMLGASyWYRARLH 9606 11741929 t llicata "Hck, and to a lesser extent lck, phosphorylated the adam15 cytoplasmic domain in vitro in immune complex kinase assays." SIGNOR-112927 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 SKP2 protein Q13309 UNIPROT IDH1 protein O75874 UNIPROT "down-regulates quantity by destabilization" ubiquitination phosphorylation:Thr157 GKVEITYtPSDGTQK 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-267625 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 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 PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252657 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 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 CDK2 protein P24941 UNIPROT CHEK1 protein O14757 UNIPROT up-regulates phosphorylation Ser301 IQSNLDFsPVNSASS 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-175083 TRIM59 protein Q8IWR1 UNIPROT IRF3 protein Q14653 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-260373 streptozocin chemical CHEBI:9288 ChEBI SLC2A2 protein P11168 UNIPROT "down-regulates quantity" "chemical inhibition" 10090 9421374 t miannu "In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells." SIGNOR-259314 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2315 RSPQPVPsPRPQSQP 9606 17623675 t lperfetto "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-244634 CSNK1D protein P48730 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Thr18 EPPLSQEtFSDLWKL 9606 10606744 t gcesareni "Protein kinase ck1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15." SIGNOR-73270 FGF13 protein Q92913 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-253435 Ub:E2 complex SIGNOR-C497 SIGNOR ITCH protein Q96J02 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-271301 DPYSL2 protein Q16555 UNIPROT Microtubule_polimerization phenotype SIGNOR-PH106 SIGNOR up-regulates 9606 BTO:0000938 25040932 f lperfetto "In the non-phosphorylated state, CRMP2 binding to tubulin induces the promotion of tubulin polymerisation leading to dendrite outgrowth while" SIGNOR-264841 APC-c complex SIGNOR-C150 SIGNOR CDR2 protein Q01850 UNIPROT "down-regulates quantity by destabilization" ubiquitination 20383333 t lperfetto "Here we find that cdr2 is cell cycle regulated in tumor cells with protein levels peaking in mitosis. As cells exit mitosis, cdr2 is ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) and rapidly degraded by the proteasome. Previously we showed that cdr2 binds to the oncogene c-myc, and here we extend this observation to show that cdr2 and c-myc interact to synergistically regulate c-myc-dependent transcription during passage through mitosis." SIGNOR-252024 PRKCA protein P17252 UNIPROT HMGN1 protein P05114 UNIPROT down-regulates phosphorylation Ser21 KEEPKRRsARLSAKP 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-76282 RNF126 protein Q9BV68 UNIPROT CDKN1A protein P38936 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23026136 t miannu "E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation.We showed that RNF126 interacts with p21 and RNF126 overexpression increased p21 protein ubiquitination in an E3 ligase activity-dependent manner." SIGNOR-272033 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 ARHGAP4 protein P98171 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-260460 "SB 505124" chemical CHEBI:100922 ChEBI ACVR1C protein Q8NER5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206739 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 MCHR2 protein Q969V1 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-257067 POU5F1 protein Q01860 UNIPROT THY1 protein P04216 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-254931 FGF11 protein Q92914 UNIPROT SCN2A protein Q99250 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-253430 GATA1 protein P15976 UNIPROT HBG2 protein P69892 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-251804 SAV1 protein Q9H4B6 UNIPROT STK4 protein Q13043 UNIPROT "up-regulates quantity by stabilization" binding 9606 16930133 t "Hippo pathway" Gianni "Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation." SIGNOR-261958 KLF1 protein Q13351 UNIPROT CDKN2C protein P42773 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 17442339 t Luana "Thus, EKLF is a direct regulator of p18INK4c gene expression, and much of EKLF's role in driving erythroid cell differentiation may occur via p18INK4c." SIGNOR-266046 FAM8A1 protein Q9UBU6 UNIPROT SYVN1 protein Q86TM6 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 28827405 t miannu "FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp" SIGNOR-261348 ATAT1 protein Q5SQI0 UNIPROT TUBA4B protein Q9H853 UNIPROT "up-regulates quantity by stabilization" acetylation -1 29703898 t lperfetto "Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules" SIGNOR-272252 CDK1 protein P06493 UNIPROT RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Ser266 QYLGSIAsPSVHPAT 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-138912 GHSR protein Q92847 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-257380 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 17419683 t gcesareni "Binding of sonic hedgehog (shh) to patched (ptc) relieves the latter's tonic smoothened (smo), a receptor that spans the cell membrane seven times. Ptch exists in vertebrates as two isoforms, ptch1 and ptch2, which seem to be equivalent in terms of binding the three hh isoforms." SIGNOR-154285 GABRD protein O14764 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-263773 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Thr444 RFIGSPRtPVSPVKF 9606 BTO:0000887;BTO:0001103 11705993 t gcesareni "The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain." SIGNOR-111511 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 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 TPO protein P07202 UNIPROT TG protein P01266 UNIPROT "up-regulates activity" "catalytic activity" 9606 23349248 t miannu "After transport through the apical membrane, I− is covalently bound to the tyrosyl residues of Tg by thyroid peroxidase (TPO)." SIGNOR-259914 TERF1 protein P54274 UNIPROT "Shelterin complex" complex SIGNOR-C306 SIGNOR "form complex" binding 9606 15383534 t lperfetto "Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins|Gel filtration reveals a complex consisting of POT1 , RAP1, TRF1, ACD, TERF2 and TINF2 proteins." SIGNOR-263316 DUSP1 protein P28562 UNIPROT Gbeta proteinfamily SIGNOR-PF4 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-269910 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser15 PSVEPPLsQETFSDL 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-74823 HDAC1 protein Q13547 UNIPROT FLI1 protein Q01543 UNIPROT up-regulates deacetylation Lys380 PTESSMYkYPSDISY 9606 24058639 t miannu "Hdac1 interacts with fli1 and mediates its deacetylation / our previous studies have shown that pcaf-dependent acetylation of fli1 at lysine 380 decreases its protein stability / p300 promotes the interaction of fli1 with hdac1 and increases the dna binding ability of fli1 through deacetylation of lysine 380" SIGNOR-202689 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RUNX1 protein Q01196 UNIPROT up-regulates phosphorylation Thr273 SPSVHPAtPISPGRA 9606 BTO:0002181 16046550 t "The effect has been demonstrated using Q01196-8" lperfetto "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-244715 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 ATIC protein P31939 UNIPROT (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 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-267326 OPRD1 protein P41143 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-256683 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 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 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 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 ROCK1 protein Q13464 UNIPROT LIMK2 protein P53671 UNIPROT up-regulates phosphorylation Thr505 NDRKKRYtVVGNPYW 9606 11018042 t lperfetto "Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase" SIGNOR-82755 "Complement C1 complex" complex SIGNOR-C309 SIGNOR 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-263427 "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 GPR17 protein Q13304 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-257087 naltrexone chemical CHEBI:7465 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-258936 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM22 protein Q8IYM9 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-271080 E protein P59637 UNIPROT SDCBP protein O00560 UNIPROT "up-regulates activity" relocalization 9534 25122212 t Luana "Overall, these results support the hypothesis that the interaction of E protein PBM with syntenin facilitates the recruitment of syntenin in the cytosol and leads to p38 MAPK activation." SIGNOR-260752 MAPK3 protein P27361 UNIPROT 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-263008 mRNA_capping phenotype SIGNOR-PH178 SIGNOR "messenger RNA" smallmolecule CHEBI:33699 ChEBI "up-regulates quantity by stabilization" "chemical modification" 9606 19224921 f lperfetto "Because only mRNA molecules that have been correctly spliced, capped at the 5′ extremity, and processed at the 3′ extremity can be used as templates for translation, processing of mRNA precursors plays a critical role in the regulation of gene expression. 3′ processing of pre-mRNAs comprises two steps (reviewed in Ref. 4): cleavage and polyadenylation." SIGNOR-268317 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 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 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 "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 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) smallmolecule CHEBI:58467 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-267324 CHKA protein P35790 UNIPROT PLIN2 protein Q99541 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr232 TKLHSRAyQQALSRV 9606 BTO:0000527 34929314 t lperfetto "In addition, as a protein kinase, CHKalpha2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth " SIGNOR-267649 MAP3K7 protein O43318 UNIPROT MAP3K14 protein Q99558 UNIPROT "up-regulates activity" phosphorylation 10094049 t lperfetto "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway." SIGNOR-262833 PROC protein P04070 UNIPROT F5 protein P12259 UNIPROT "down-regulates activity" cleavage Arg534 KSRSLDRrGIQRAAD -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-263629 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 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 MICU1 protein Q9BPX6 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 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-270859 MICU2 protein Q8IYU8 UNIPROT MCU_MICUB_variant complex SIGNOR-C499 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-270860 AFDN protein P55196 UNIPROT RIN1 protein Q13671 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-220926 QRICH1 protein Q2TAL8 UNIPROT WARS1 protein P23381 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-269410 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 CDK5 protein Q00535 UNIPROT TPPP protein O94811 UNIPROT "down-regulates activity" phosphorylation Ser160 GVTKAISsPTVSRLT -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-262931 "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-270432 "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 PRKCA protein P17252 UNIPROT PDE3A protein Q14432 UNIPROT up-regulates phosphorylation Ser428 IPKRLRRsLPPGLLR 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-184452 CYCS protein P99999 UNIPROT APAF1 protein O14727 UNIPROT "up-regulates activity" binding 9606 15829969 t lperfetto "During apoptosis, Apaf-1 binds to cytochrome c and in the presence of ATP/dATP forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9." SIGNOR-135384 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR MYOD1 protein P15172 UNIPROT down-regulates phosphorylation Ser200 YSGDSDAsSPRSNCS 9606 21902831 t lperfetto "Phosphorylation of myod at s200 is common to other cdks, such as the mitotic cyclin b/cdk1, which may prevent inappropriate myod accumulation during mitosis." SIGNOR-216860 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 HAP1 protein P54257 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-234602 RPS6KA5 protein O75582 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-138479 VXJPSOQJNUZHDN-YJFQKBDPSA-N smallmolecule CID:118708139 PUBCHEM NMUR1 protein Q9HB89 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-257591 HSP90AA1 protein P07900 UNIPROT CBLL1 protein Q75N03 UNIPROT "up-regulates quantity" binding 9606 BTO:0000007 31952268 t miannu "By immunoprecipitation, we present evidence that Hakai interacts with Hsp90 chaperone complex in several epithelial cells and demonstrate that is a novel Hsp90 client protein. Interestingly, by overexpressing and knocking-down experiments with Hakai, we identified Annexin A2 as a Hakai-regulated protein. Interestingly, geldanamycin-induced Hakai degradation is accompanied by an increased expression of E-cadherin and Annexin A2. Hsp90 participates in the correct folding of its client proteins, allowing them to maintain their stability and activity." SIGNOR-271474 MT-ND6 protein P03923 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-262149 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 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 HOTAIR ncrna URS000075C808_9606 RNAcentral MEX3B protein Q6ZN04 UNIPROT "up-regulates activity" binding 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-272092 NR3C1 protein P04150 UNIPROT KAT2B protein Q92831 UNIPROT "up-regulates activity" relocalization 32917954 t SimoneGraziosi "NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase" SIGNOR-269233 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 PSEN1 protein P49768 UNIPROT gamma-secretase complex SIGNOR-C98 SIGNOR up-regulates cleavage 9606 10593990 t "Gamma secretase subunit that leads a proteolitic cleavage through Asp257 and Asp385 after transport to cell surface." lperfetto "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-217743 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 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 AKT2 protein P31751 UNIPROT HTRA2 protein O43464 UNIPROT down-regulates phosphorylation Ser212 RVRVRLLsGDTYEAV 9606 17311912 t lperfetto "Akt attenuation of the serine protease activity of htra2/omi through phosphorylation of serine 212" SIGNOR-153327 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 CAV1 protein Q03135 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-264454 GSK3B protein P49841 UNIPROT LGALS3 protein P17931 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-261903 CSNK1E protein P49674 UNIPROT YAP1 protein P46937 UNIPROT down-regulates phosphorylation Ser403 ESTDSGLsMSSYSVP 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-230733 E2F4 protein Q16254 UNIPROT PPARG protein P37231 UNIPROT down-regulates "transcriptional regulation" 9606 12110166 f "During terminal adipocyte differentiation" fspada "we show here that e2f1 induces ppar gamma transcription during clonal expansion, whereas e2f4 represses pparg amma expression during terminal adipocyte differentiation" SIGNOR-210050 MAP1LC3B protein Q9GZQ8 UNIPROT SQSTM1 protein Q13501 UNIPROT up-regulates binding 9606 17580304 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-156356 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK14 protein Q16539 UNIPROT up-regulates "chemical activation" 9606 Other t "CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb" gcesareni SIGNOR-189699 FCAR protein P24071 UNIPROT Cytokine_production phenotype SIGNOR-PH166 SIGNOR up-regulates 9606 BTO:0000130;BTO:0000801;BTO:0000876;BTO:0000399 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-264860 ROCK1 protein Q13464 UNIPROT MYLK protein Q15746 UNIPROT up-regulates binding 9606 11283607 t gcesareni "Rock proteins are known to regulate mlc-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated mlc concomitant with rock i cleavage." SIGNOR-106552 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 IL6ST protein P40189 UNIPROT T_cell_activation phenotype SIGNOR-PH73 SIGNOR up-regulates 9606 32234467 f miannu "Interleukin-6 (IL-6) is an important member of the cytokine network and plays a central role in acute inflammation. IL-6 binds to its receptor IL-6R to form a complex, and then binds to the membrane protein gp130 to initiate intracellular signal transduction. IL-6 is the terminal helper factor of cytotoxic T lymphocyte (CTL), which can induce CTL activity and make immature thymocytes develop into CTL. In addition, IL-6 is a pro-inflammatory regulator of T cells." SIGNOR-261028 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 AKT1 protein P31749 UNIPROT MDM4 protein O15151 UNIPROT "up-regulates quantity by stabilization" 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-252517 "lysophosphatidic acid" smallmolecule CHEBI:132742 ChEBI LPAR4 protein Q99677 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-257531 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 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 "Uridylate-specific endoribonuclease" protein P0C6X7-PRO_0000037321 UNIPROT IFIH1 protein Q9BYX4 UNIPROT "down-regulates activity" 9606 28158275 f miannu "Here we show that the coronavirus endonuclease (EndoU) activity is key to prevent early induction of double-stranded RNA (dsRNA) host cell responses. Replication of EndoU-deficient coronaviruses is greatly attenuated in vivo and severely restricted in primary cells even during the early phase of the infection. Collectively our results demonstrate that the coronavirus EndoU efficiently prevents simultaneous activation of host cell dsRNA sensors, such as Mda5, OAS and PKR. It is thus tempting to propose that viral dsRNA represents the natural substrate of the coronavirus EndoU. However, it remains to be determined which kind of viral dsRNA is cleaved by the EndoU or triggers Mda5, OAS, and PKR activation." SIGNOR-260245 ATP smallmolecule CHEBI:15422 ChEBI "3',5'-cyclic AMP" smallmolecule CHEBI:17489 ChEBI "up-regulates quantity" "precursor of" 9606 11376933 t miannu "To date, ten different mammalian isoforms of adenylyl cyclase (AC) have been cloned and characterized. Each isoform has its own distinct tissue distribution and regulatory properties, providing possibilities for different cells to respond diversely to similar stimuli. The product of the enzymatic reaction catalyzed by ACs, cyclic AMP (cAMP) has been shown to play a crucial role for a variety of fundamental physiological cell functions ranging from cell growth and differentiation, to transcriptional regulation and apoptosis." SIGNOR-267842 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 CARM1 protein Q86X55 UNIPROT MAPK12/CARM1 complex SIGNOR-C218 SIGNOR "form complex" binding BTO:0001103 29681515 t apalma "Basal localization of the p38γ/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through β1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38γ/β1-syntrophin interactions are abrogated" SIGNOR-255980 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 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRM6 protein O15303 UNIPROT "up-regulates activity" "chemical activation" 9606 25042998 t miannu "Glutamate is the major excitatory neurotransmitter in the central nervous system. Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate." SIGNOR-264076 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 PRKACB protein P22694 UNIPROT NGFR protein P08138 UNIPROT up-regulates phosphorylation Ser303 PEGEKLHsDSGISVD 9606 BTO:0000938 12682012 t llicata "Pka phosphorylates the p75 receptor and regulates its localization to lipid rafts. activation of camp?PKA Is required for translocation of p75ntr to lipid rafts, and for biochemical and biological activities of p75ntr, such as inactivation of rho and the neurite outgrowth." SIGNOR-99755 PRKCA protein P17252 UNIPROT GMFB protein P60983 UNIPROT unknown phosphorylation Ser72 QPRFIVYsYKYQHDD -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-248959 SP1 protein P08047 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-253872 CAMK2A protein Q9UQM7 UNIPROT LRRC7 protein Q96NW7 UNIPROT unknown phosphorylation Ser1439 IQTKGQRsMDGYPEQ 11160423 t llicata "In contrast, phosphorylation of densin-180 by CaMKII at serine-1397 only slightly decreases its affinity for CaMKII. The specific interaction of densin-180 with holoenzymes of CaMKII containing only alpha-subunit and the increased affinity of CaMKII for densin-180 after autophosphorylation suggest that densin-180 may be involved in localization of activated CaMKII synthesized in dendrites." SIGNOR-250634 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 AMPK complex SIGNOR-C15 SIGNOR 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-209929 CCKBR protein P32239 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-257363 XRCC4 protein Q13426 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 10854421 f miannu "The DNA-dependent protein kinase (DNA-PK), consisting of Ku and the DNA-PK catalytic subunit (DNA-PKcs), and the DNA ligase IV-XRCC4 complex function together in the repair of DNA double-strand breaks by non-homologous end joining." SIGNOR-264530 HOXC10 protein Q9NYD6 UNIPROT LAMB2 protein P55268 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9534 BTO:0000298 10835276 t Luana "The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells." SIGNOR-261645 "Elongin E3-Cul-5" complex SIGNOR-C531 SIGNOR CLEC1B protein Q9P126 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19785988 t miannu "In this study, we reported that RACK1, the receptor for activated C-kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression.Previous reports indicated that RACK1 mediated ubiquitin–proteasome degradation of HIF-1a and BimEL by recruiting Elongin-C/B ubiquitin ligase complex" SIGNOR-272783 SMAD5 protein Q99717 UNIPROT SMAD6 protein O43541 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268940 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 PTPRJ protein Q12913 UNIPROT RET protein P07949 UNIPROT "down-regulates activity" dephosphorylation Tyr905 DVYEEDSyVKRSQGR 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-248701 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 GSK3A protein P49840 UNIPROT GRB14 protein Q14449 UNIPROT "down-regulates activity" phosphorylation Ser366 GCSSQSIsPMRSISE -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-264872 MAPK1 protein P28482 UNIPROT TPR protein P12270 UNIPROT up-regulates phosphorylation Thr2116 VGRGLQLtPGIGGMQ 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-181018 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR IL18 protein Q14116 UNIPROT "up-regulates activity" cleavage Asp76 MTDSDCRdNAPRTIF 9606 BTO:0001370 9334240 t lperfetto "Involvement of caspase-1 and caspase-3 in the production and processing of mature human interleukin 18 in monocytic THP.1 cells.|Further analyses of the partially purified enzymes revealed that one is caspase-1, which cleaves prohIL-18 at the Asp36-Tyr37 site to generate the mature hIL-18, and the other is caspase-3, which cleaves both precursor and mature hIL-18 at Asp71-Ser72 and Asp76-Asn77 to generate biologically inactive products." SIGNOR-256379 "sphingosine 1-phosphate(1-)" smallmolecule CHEBI:60119 ChEBI S1PR2 protein O95136 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-257578 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 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 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 citrate(3-) smallmolecule CHEBI:16947 ChEBI D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "up-regulates quantity" "precursor of" 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-266241 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO proteinfamily SIGNOR-PF27 SIGNOR "down-regulates quantity by destabilization" phosphorylation Ser253 APRRRAVsMDNSNKY 9606 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-252821 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 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 SETD5 protein Q9C0A6 UNIPROT Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 32299058 f "The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression" SIGNOR-268627 "NMDA receptor_2A" complex SIGNOR-C347 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-266599 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 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "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-249684 PFKFB4 protein Q16877 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT "up-regulates activity" phosphorylation Ser857 PPYNRAVsLDSPVSV 9606 BTO:0000007 29615789 t "PFKFB4, a regulatory enzyme that synthesizes an allosteric stimulator of glycolysis2, was found to be a robust stimulator of SRC-3 that co-activates estrogen receptor (ER). PFKFB4 phosphorylates SRC-3 at serine 857 (S857) enhancing its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient SRC-3 mutant S857A (SRC-3S857A) significantly abolishes SRC-3-mediated transcriptional output" SIGNOR-267269 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 FLT3 protein P36888 UNIPROT STAT5A protein P42229 UNIPROT "up-regulates activity" phosphorylation Tyr694 LAKAVDGyVKPQIKQ 10090 BTO:0002882 17356133 t gcesareni "in vitro kinase assays revealed that STAT5 is a direct target of Flt3" SIGNOR-245069 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 JAK2 protein O60674 UNIPROT ITGB2 protein P05107 UNIPROT "up-regulates activity" phosphorylation 9606 25624455 t miannu "PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role." SIGNOR-254738 "Host translation inhibitor nsp1" protein P0DTD1-PRO_0000449619 UNIPROT RPS3 protein P23396 UNIPROT "down-regulates activity" binding -1 33188728 t miannu "Nsp1 Locks the 40S in a Conformation Incompatible with mRNA Loading and Disrupts Initiation Factor Binding. Molecular interactions between C-Nsp1 and 40S ribosome components, including uS3, h18, and uS5." SIGNOR-262507 OGDHL protein Q9ULD0 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-267833 Saracatinib chemical CID:10302451 PUBCHEM SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206691 MAPK14 protein Q16539 UNIPROT EIF4EBP1 protein Q13541 UNIPROT down-regulates 9606 11777913 f 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-113566 NARS1 protein O43776 UNIPROT AMP smallmolecule CHEBI:456215 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-270458 PRKN protein O60260 UNIPROT SYT11 protein Q9BT88 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 12925569 t miannu "Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Parkin-mediated ubiquitination also enhances the turnover of sytXI." SIGNOR-272672 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 CEBPD protein P49716 UNIPROT MSTN protein O14793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 24011072 f miannu "To identify whether p-Stat3 acts through C/EBPŒ¥ to stimulate myostatin, we knocked down C/EBPŒ¥ using siRNA. In this case, the IL-6-induced increase in myostatin expression was blocked when C/EBPŒ¥was suppressed even though p-Stat3 was increased" SIGNOR-255332 TET2 protein Q6N021 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000738 25601757 f irozzo "Cell proliferation was stimulated by the knockdown of either TET2 or WT1 gene in KG-1 cells, but not additively by the co-depletion of both genes. Collectively, these results suggest that TET2 and WT1 function in the same pathway to inhibit leukemia cell proliferation and colony formation." SIGNOR-255704 RUNX2 protein Q13950 UNIPROT MMP2 protein P08253 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-255082 PCM1 protein Q15154 UNIPROT CETN1 protein Q12798 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-94947 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 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 CYP26A1 protein O43174 UNIPROT "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI "down-regulates quantity" "chemical modification" 9606 31963453 t lperfetto "Cytochrome P450 (CYP) subfamily 26 of enzymes degrade the excess of RA to avoid detrimental effects [17]. Among the three subtypes (CYP26A1, CYP26B1, and CYP26C1), CYP26A1 is particularly important during embryonic development" SIGNOR-265139 IL1RAP protein Q9NPH3 UNIPROT TOLLIP protein Q9H0E2 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-251979 RORA protein P35398 UNIPROT ITPR1 protein Q14643 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-266847 "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 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 PIM1 protein P11309 UNIPROT FLT3 protein P36888 UNIPROT "up-regulates quantity" phosphorylation Tyr591 SSDNEYFyVDFREYE 9606 BTO:0005720 24040307 t "Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication[...]Pim-1 inhibition also decreased phosphorylation of FLT3 at tyrosine 591 and of STAT5, and expression of Pim-1 itself, consistent with inhibition of the FLT3-ITD-STAT5 signaling pathway." SIGNOR-259927 "Neurokinin B" smallmolecule CHEBI:80312 ChEBI TACR3 protein P29371 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-257588 DMTF1 protein Q9Y222 UNIPROT ADM protein P35318 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004532 19816943 f 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-261581 CDK2 protein P24941 UNIPROT DNMT1 protein P26358 UNIPROT up-regulates phosphorylation Ser154 AKPEPSPsPRITRKS 9606 21565170 t gcesareni "We report that cyclin-dependent kinases (cdks) 1, 2 and 5 can phosphorylate ser154 of human dnmt1 in vitro. Further evidence of phosphorylation of endogenous dnmt1 at position 154 by cdks is also found in 293 cells treated with roscovitine, a specific inhibitor of cdk1, 2 and 5" SIGNOR-173681 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 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 MED30 protein Q96HR3 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-266673 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 DLK1 protein P80370 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 9606 22640926 f fspada "We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis." SIGNOR-197634 DCAF11 protein Q8TEB1 UNIPROT GEN1 protein Q17RS7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 31409866 t miannu "(WDR23) isoforms differentially ubiquitinate (GEN1). In the presence of the necessary components for a successful ubiquitination reaction (CUL4A-DDB1-WDR23 complex, UBE1, UBE2D1, ubiquitin, and ATP) GEN1 receives the addition of ubiquitin in a time dependent manner." SIGNOR-272258 FBXW2 protein Q9UKT8 UNIPROT MSX2 protein P35548 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 31548378 t miannu " Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation." SIGNOR-272259 FBXW2 protein Q9UKT8 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 31548378 t miannu " Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation." SIGNOR-272260 THOC5 protein Q13769 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-268506 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 NOC3L protein Q8WTT2 UNIPROT Adipogenesis phenotype SIGNOR-PH26 SIGNOR up-regulates 10090 BTO:0000011 15564382 f "Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation" SIGNOR-253060 AURKA protein O14965 UNIPROT DLGAP5 protein Q15398 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser627 VKLFSGLsVSSEGPS 9606 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-262649 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 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 PRPS1 protein P60891 UNIPROT "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "down-regulates quantity" "chemical modification" 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-267078 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR MSX2 protein P35548 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 31548378 t miannu " Mechanistic studies revealed that MSX2 is a new substrate of SCFFBXW2 E3 ubiquitin ligase.  Taken together, our combined results showed that MSX2 is a substrate of the SCFFBXW2 E3 ligase, which ubiquitylates it and targets it for proteasome degradation." SIGNOR-272261 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 MAPK1 protein P28482 UNIPROT 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-262521 ibrutinib chemical CHEBI:76612 ChEBI BTK protein Q06187 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189641 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" phosphorylation Thr453 SGPIIIRtPTVGPNG 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-249480 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 10929711 t gcesareni "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. mitochondrial survivin associated with smac/diablo, delaying its release." SIGNOR-80212 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 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 DEPTOR protein Q8TB45 UNIPROT mTORC2 complex SIGNOR-C2 SIGNOR "down-regulates activity" binding 9606 BTO:0000007 19446321 t "DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival" SIGNOR-251659 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 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 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191145 RASGEF1A protein Q8N9B8 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-183826 FBXO3 protein Q9UK99 UNIPROT EP300 protein Q09472 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0004573 18809579 t miannu "O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway. " SIGNOR-271742 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 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 RNF167 protein Q9H6Y7 UNIPROT VAMP3 protein Q15836 UNIPROT "down-regulates quantity by destabilization" ubiquitination Lys77 KYWWKNCkMWAIGIT 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-272095 ITGB4 protein P16144 UNIPROT PIK3CG protein P48736 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-54703 CTBP1 protein Q13363 UNIPROT BHLHE41 protein Q9C0J9 UNIPROT up-regulates binding 9606 16287852 t gcesareni "We identify the ctip and ctbp corepressors as novel components of the human rbp-jkappa/sharp-corepressor complex and show that ctip binds directly to the sharp repression domain. Functionally, ctip and ctbp augment sharp-mediated repression." SIGNOR-141613 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 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 POU5F1 protein Q01860 UNIPROT LEFTY2 protein O00292 UNIPROT "up-regulates quantity by expression" "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-254940 PBX1 protein P40424 UNIPROT HOXB1 protein P14653 UNIPROT "up-regulates activity" binding -1 10052460 t 2 miannu "Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1–Pbx1–DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA." SIGNOR-241219 SEC23IP protein Q9Y6Y8 UNIPROT SEC23A protein Q15436 UNIPROT "up-regulates activity" binding 10090 BTO:0000142 10400679 t lperfetto "The results showed that the N-terminal region of p125 is important for the interaction with Sec23p. We confirmed the interaction between the two proteins by a yeast two-hybrid assay. Overexpression of p125, like that of mammalian Sec23p, caused disorganization of the endoplasmic reticulum-Golgi intermediate compartment and Golgi apparatus, suggesting its role in the early secretory pathway." SIGNOR-265307 "BRCC ubiquitin ligase complex" complex SIGNOR-C295 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 24832651 f lperfetto "The exact function of the BRCC complex in HR is not entirely elucidated, but its E3 ligase activity may promote the mobilization and stabilization of the complex at broken chromatin sites were the complex can stabilize the formation of RAD51 filaments thus facilitating the repair process" SIGNOR-263204 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 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 RPS6K proteinfamily SIGNOR-PF26 SIGNOR CCT2 protein P78371 UNIPROT up-regulates phosphorylation Ser260 GSRVRVDsTAKVAEI 9606 21440620 t lperfetto "Furthermore, both the s260a and s260d mutants showed a decreased folding capacity as compared to cells expressing the wild-type cct_ subunit ( fig.?_5e), suggesting that a cyclic phosphorylation of the s260 site by s6k1 is likely to be important for chaperonin function and that mutation of this site interferes with this process." SIGNOR-252780 dacomitinib chemical CHEBI:132268 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205936 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR "up-regulates activity" 25309941 f "Following GSK3β activation, NF-κB is translocated from the cytoplasm to the nucleus and binds transcriptional sites with CBP leading to an increase in the transcription of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6)." SIGNOR-255485 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 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-251599 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1927 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-120068 "Ub:E1 (UBA6 substrate)" complex SIGNOR-C496 SIGNOR BIRC6 protein Q9NR09 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-271352 PKA proteinfamily SIGNOR-PF17 SIGNOR NOXA1 protein Q86UR1 UNIPROT "down-regulates activity" phosphorylation Ser172 DQVQRRGsLPPRQVP 9606 BTO:0003250 20943948 t lperfetto "On the other hand, our group has shown that protein kinase A (PKA) inhibits Nox1 activity in colon epithelial cells by phosphorylating NoxA1 at two distinct sites, Ser172 and Ser461" SIGNOR-264712 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 trametinib chemical CHEBI:75998 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192826 SIRT5 protein Q9NXA8 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31608237 f Monia "In SIRT5 silenced Mero-14 cells, beclin-1 protein levels were downregulated upon rotenone and resveratrol treatment. In summary, in most cases, where significant effects were detected, SIRT1, SIRT3, and SIRT5 had positive effects on beclin1 and LC3II/LC3I ratio" SIGNOR-261206 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 STK39 protein Q9UEW8 UNIPROT MAPK14 protein Q16539 UNIPROT up-regulates binding 9606 14563843 t gcesareni "Spak, a ste20/sps1-related kinase that activates the p38 pathway. p38, one of the three major mapks, can be coimmunoprecipitated with spak and with nkcc1 in an activity-dependent manner. The amount of p38 coimmunoprecipitated with the kinase and the cotransporter significantly decreases upon cellular stress," SIGNOR-118848 CyclinE/CDK2 complex SIGNOR-C16 SIGNOR MCM3 protein P25205 UNIPROT up-regulates phosphorylation Thr722 EEMPQVHtPKTADSQ 9606 21965652 t lperfetto "In this study, we demonstrate that mcm3 is a substrate of cyclin e/cdk2 and can be phosphorylated by cyclin e/cdk2 at thr-722." SIGNOR-216694 CyclinB/CDK1 complex SIGNOR-C17 SIGNOR ECT2 protein Q9H8V3 UNIPROT up-regulates phosphorylation Thr846 RAFSFSKtPKRALRR 9606 BTO:0001938 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-216928 PSMA1 protein P25786 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-263363 RPS6KB1 protein P23443 UNIPROT POLDIP3 protein Q9BY77 UNIPROT unknown phosphorylation Ser385 PRRVNSAsSSNPPAE 9606 15341740 t llicata "Here we identify skar as a novel and specific binding partner and substrate of s6k1 but not s6k2. We find that serines 383 and 385 of human skar are insulin-stimulated and rapamycin-sensitive s6k1 phosphorylation sites." SIGNOR-128499 CDC7 protein O00311 UNIPROT MCM7 protein P33993 UNIPROT up-regulates phosphorylation 9606 21070963 t gcesareni "We propose that phosphorylation of mcm4/6 s/tp sites, which are already phosphorylated in g1, allows initial mcm2-7 phosphorylation by ddk and initiation from the first origins of replication ( fig. 7ai )." SIGNOR-169506 LYN protein P07948 UNIPROT HCLS1 protein P14317 UNIPROT "up-regulates activity" phosphorylation Tyr378 EPEPENDyEDVEEMD 9606 9104825 t "Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252" SIGNOR-251400 SRC protein P12931 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr42 DSMKDEEyEQMVKEL 9606 9792645 t llicata "C-src phosphorylates IkappaB On tyrosine 42|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation." SIGNOR-60879 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 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 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 HMGB1 protein P09429 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-240113 CREBRF protein Q8IUR6 UNIPROT HERPUD1 protein Q15011 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 16940180 t Luana "Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element." SIGNOR-261575 SGK3 protein Q96BR1 UNIPROT GSK3B protein P49841 UNIPROT "down-regulates activity" phosphorylation Ser9 SGRPRTTsFAESCKP 9606 BTO:0000007 12054501 t lperfetto "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction" SIGNOR-249166 LAT protein O43561 UNIPROT VAV1 protein P15498 UNIPROT "up-regulates activity" binding 9606 phosphorylation:Tyr255;Tyr220 EEEGAPDyENLQELN;SLDGSREyVNVSQEL 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-246045 CADPS2 protein Q86UW7 UNIPROT STX1A protein Q16623 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-264337 SHH protein Q15465 UNIPROT CP protein P00450 UNIPROT down-regulates binding 9606 14556242 t gcesareni "Two genes were newly identified to be shh responsive in neuroepithelial cell line mns-70: the metal-binding protein ceruloplasmin (cp) and the serine protease inhibitor inter-alpha-trypsine inhibitor heavy chain h3 (itih3). cp appeared to be regulated by gli-independent pathways." SIGNOR-118612 LPAR3 protein Q9UBY5 UNIPROT GNA13 protein Q14344 UNIPROT up-regulates binding 9606 15856019 t gcesareni "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-135846 MYC protein P01106 UNIPROT ENO1 protein P06733 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-259989 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 PRKG1 protein Q13976 UNIPROT PPP1R17 protein O96001 UNIPROT up-regulates phosphorylation Thr119 KKPRRKDtPALHMSP 9606 BTO:0001011 10051666 t miannu "Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1." SIGNOR-263147 KLHL3 protein Q9UH77 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000567 23387299 t miannu "CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms." SIGNOR-272101 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 DYRK1A protein Q13627 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser519 SGYSSPGsPGTPGSR 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-171030 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 "tubastatin A" chemical CHEBI:94186 ChEBI HDAC6 protein Q9UBN7 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207450 PHB2 protein Q99623 UNIPROT MYOD1 protein P15172 UNIPROT down-regulates binding 10090 BTO:0000165 BTO:0000887 15173318 t lperfetto "Phb2 interacts with both myod and mef2, and represses both myod- and mef2-dependent gene transcription. Furthermore, binding of phb2 to both myod and mef2 significantly decreases upon myogenic differentiation." SIGNOR-235843 KDM4C protein Q9H3R0 UNIPROT H3-4 protein Q16695 UNIPROT "down-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 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-263867 RUVBL1 protein Q9Y265 UNIPROT "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "form complex" binding 9606 29662061 t miannu " Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. " SIGNOR-270928 SNRPD2 protein P62316 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-270636 SNAPIN protein O95295 UNIPROT SNAP25 protein P60880 UNIPROT "up-regulates activity" binding 9606 BTO:0000793 18167355 t miannu "In the present study, we used yeast two-hybrid analysis to identify a new binding partner of torsinA, the SNARE-associated protein snapin. We have reported that snapin shows a robust interaction with wild type and mutant torsinA. we have demonstrated that this portion of torsinA and/or the adjacent linker region has the additional role of recruiting snapin. we found that snapin, which binds SNAP-25 (synaptosome-associated protein of 25,000 Da) and enhances the association of the SNARE complex with synaptotagmin, is an interacting partner for both wild type and mutant torsinA." SIGNOR-261171 GTF2H1 protein P32780 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-269316 TUT1 protein Q9H6E5 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR up-regulates 9606 21102410 f miannu "Star-PAP is a poly (A) polymerase (PAP) that is putatively required for 3'-end cleavage and polyadenylation of a select set of pre-messenger RNAs (mRNAs)" SIGNOR-272322 CDK1 protein P06493 UNIPROT UBE2A protein P49459 UNIPROT up-regulates phosphorylation Ser120 LDEPNPNsPANSQAA 9606 11953320 t llicata "Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity." SIGNOR-116504 LCK protein P06239 UNIPROT CD5 protein P06127 UNIPROT "up-regulates activity" phosphorylation Tyr453 ASHVDNEySQPPRNS 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-106799 PTEN protein P60484 UNIPROT ABTB1 protein Q969K4 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-260050 KLHL3 protein Q9UH77 UNIPROT WNK4 protein Q96J92 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23453970 t miannu "Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein." SIGNOR-272105 MKRN1 protein Q9UHC7 UNIPROT CDKN2A protein Q8N726 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0002552 23104211 t miannu "Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation.The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro." SIGNOR-272036 MAPK8 protein P45983 UNIPROT STAT6 protein P42226 UNIPROT down-regulates phosphorylation Ser707 IPPYQGLsPEESVNV 9606 21123173 t llicata "Deactivation of stat6 through serine 707 phosphorylation by jnk." SIGNOR-170153 KLHL3 protein Q9UH77 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 23453970 t miannu "Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein." SIGNOR-272106 CHUK protein O15111 UNIPROT TAX1BP1 protein Q86VP1 UNIPROT "up-regulates activity" phosphorylation Ser593 NYKELKRsLENPAER 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-175058 NOTCH1 protein P46531 UNIPROT HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19165418 f lperfetto "Several lines of evidence have suggested that these genes are indeed direct notch target genes: a) the promoters of hes1, hes5 and hes7 as well as hey1, hey2 and heyl subfamily of hes, related with yrpw motif) can be activated by a constitutive active form of notch1." SIGNOR-183507 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 "cyclosporin A" chemical CHEBI:4031 ChEBI PPP3CC protein P48454 UNIPROT down-regulates "chemical inhibition" 9606 15276472 t gcesareni "Calcineurin catalytic activity is inhibited by the immunosuppressive drugs cyclosporine and fk506 through complexes with immunophilin proteins." SIGNOR-127231 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 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR WNK4 protein Q96J92 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23453970 t miannu "Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein." SIGNOR-272107 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 KLHL2 protein O95198 UNIPROT WNK1 protein Q9H4A3 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272119 KLHL2 protein O95198 UNIPROT WNK2 protein Q9Y3S1 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272120 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT down-regulates dephosphorylation Ser20 PLSQETFsDLWKLLP 9606 20562916 t miannu "We found that dusp26 promotes the resistance of human neuroblastoma to doxorubicin-induced apoptosis by acting as a p53 phosphatase to downregulate p53 tumor suppressor function in neuroblastoma cells. / we found that dusp26 binds to p53 and dephosphorylates p53 at ser20 and ser37." SIGNOR-166258 GATA6 protein Q92908 UNIPROT MYC protein P01106 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-253152 bremazocine chemical CHEBI:3171 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-258779 TP53 protein P04637 UNIPROT FAS protein P25445 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000150 9841917 t "Nuclear p53" amattioni "In an attempt to understand how CD95 expression is regulated by p53, we identified a p53-responsive element within the first intron of the CD95 gene, as well as three putative elements within the promoter. The intronic element conferred transcriptional activation by p53 and cooperated with p53-responsive elements in the promoter of the CD95 gene. wt p53 bound to and transactivated the CD95 gene," SIGNOR-62376 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser204 NHSMDAGsPNLSPNP 9606 BTO:0001939 15520018 t miannu "Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways." SIGNOR-250113 IKBKB protein O14920 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates activity" phosphorylation Ser312 TESITATsPASMVGG -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-251293 SEMA7A protein O75326 UNIPROT "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 10090 17377534 t lperfetto "Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin." SIGNOR-253249 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 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 KLHL2 protein O95198 UNIPROT WNK3 protein Q9BYP7 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272121 HOXB8 protein P17481 UNIPROT PBX3 protein P40426 UNIPROT "up-regulates activity" binding 9606 BTO:0001545 11571641 t miannu "the ability of HoxB8 to heterodimerizes with endogenous Pbx proteins on DNA alters gene transcription in a manner that prevents progression through an intrinsic genetic differentiation program. In conjunction with Pbx, HoxB8 could alter transcription of Pbx target genes by direct or indirect mechanisms." SIGNOR-223149 TBK1 protein Q9UHD2 UNIPROT STING1 protein Q86WV6 UNIPROT "up-regulates activity" phosphorylation Ser358 VPSTSTMsQEPELLI 9606 BTO:0000007 18818105 t miannu "MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity. Consistent with its inability to activate IRF-E, the mutation of S358 to alanine impaired the ability of MITA to interact with TBK1 and to enhance the interaction between TBK1 and IRF3" SIGNOR-263136 SNAI2 protein O43623 UNIPROT CXCR4 protein P61073 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." SIGNOR-255171 CHEK1 protein O14757 UNIPROT FANCE protein Q9HB96 UNIPROT up-regulates phosphorylation Ser374 LFLGRILsLTSSASR 9606 17296736 t llicata "Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway." SIGNOR-153023 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 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 Odanacatib chemical CID:10152654 PUBCHEM CTSK protein P43235 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195007 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 RPS6KA2 protein Q15349 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 BTO:0000007 10837486 t lperfetto "We report here that the phosphorylation of BAD at Ser-155 within the BH3 domain is a second phosphorylation-dependent mechanism that inhibits the death-promoting activity of BAD. Protein kinase A, RSK1, and survival factor signaling stimulate phosphorylation of BAD at Ser-155, blocking the binding of BAD to Bcl-XL. RSK1 phosphorylates BAD at both Ser-112 and Ser-155 and rescues BAD-mediated cell death in a manner dependent upon phosphorylation at both sites." SIGNOR-249044 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR WNK2 protein Q9Y3S1 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272125 BMP2 protein P12643 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates 9606 21793042 f gcesareni "Upon bmp binding to the bmpr-ii, bmpr-i is recruited to form an activated quaternary complex, which then phosphorylates and activates intracellular smad proteins. Receptor smads bind to a co-smad and translocate to the nucleus to serve as transcription factors." SIGNOR-175273 PRKCB protein P05771 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 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-89182 RBM10 protein P98175 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0001938 30403180 f irozzo "Cell apoptosis is an important event in cancer progression. Overexpression of RBM10 dramatically induced U2OS cell apoptosis compared with negative control cells." SIGNOR-259150 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 PRKAA1 protein Q13131 UNIPROT FOXO3 protein O43524 UNIPROT "up-regulates activity" phosphorylation Ser413 GLMQRSSsFPYTTKG 9606 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-249677 AKT1 protein P31749 UNIPROT TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Thr1462 GLRPRGYtISDSAPS 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-235515 PRTN3 protein P24158 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Lys72 SASVLTGkLTTVFLP -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-263594 DVL3 protein Q92997 UNIPROT FRAT1 protein Q92837 UNIPROT up-regulates binding 9606 BTO:0000567 BTO:0000671 12556519 t gcesareni "These results indicate that cki epsilon-dependent phosphorylation of dvl enhances the formation of a complex of dvl-1 with frat-1 and that this complex leads to the activation of the wnt signaling pathway." SIGNOR-97877 F2R protein P25116 UNIPROT KLF6 protein Q99612 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-254849 CSNK2A1 protein P68400 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Ser1004 SEHDSDEsSDDDSDS 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-65269 FYN protein P06241 UNIPROT CDK5 protein Q00535 UNIPROT "up-regulates activity" phosphorylation Tyr15 EKIGEGTyGTVFKAK 9606 14757045 t "Constitutively active Fyn phosphorylated Tyr15 of Cdk5. Fyn Facilitates Kinase Activity of Cdk5 Via Tyr15 Phosphorylation" SIGNOR-251156 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 IGF1R protein P08069 UNIPROT PDPK1 protein O15530 UNIPROT up-regulates phosphorylation Tyr376 DEDCYGNyDNLLSQF 9606 20643654 t lperfetto "Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr373/376, and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr9 and then Tyr373/376" SIGNOR-166714 ACTL6A protein O96019 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-269789 AKT proteinfamily SIGNOR-PF24 SIGNOR PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser483 IRRPRNYsVGSRPLK 9606 BTO:0000567 BTO:0000562 12853467 t lperfetto "These findings suggest that pkb-dependent binding of 14-3-3s to phospho-ser483 of cardiac pfk-2 mediates the stimulation of glycolysis by growth factor." SIGNOR-103462 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 FBXO25 protein Q8TCJ0 UNIPROT ELK1 protein P19419 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23940030 t miannu "The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells." SIGNOR-272127 FBXO25 protein Q8TCJ0 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 23940030 t miannu "The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells." SIGNOR-272128 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 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR ELK1 protein P19419 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 23940030 t miannu "The F-box protein FBXO25 promotes the proteasome-dependent degradation of ELK-1 protein. FBXO25 is one of the 69 known human F-box proteins that serve as specificity factors for a family of ubiquitin ligases composed of SKP1, Rbx1, Cullin1, and F-box protein (SCF1) that are involved in targeting proteins for degradation across the ubiquitin proteasome system. FBXO25 interacted with and mediated the ubiquitination and proteasomal degradation of ELK-1 in HEK293T cells." SIGNOR-272129 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-267794 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO3 protein O43524 UNIPROT "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-249645 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 DRD3 protein P35462 UNIPROT GNB5 protein O14775 UNIPROT "up-regulates activity" binding 9606 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-264994 ABL1 protein P00519 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Tyr219 SIQGHNDyMCPATNQ 9606 BTO:0000150 20101225 t gcesareni "Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes." SIGNOR-163562 MCF2 protein P10911 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-260556 CADPS protein Q9ULU8 UNIPROT STX1A protein Q16623 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-264336 AKT1 protein P31749 UNIPROT METTL1 protein Q9UBP6 UNIPROT down-regulates phosphorylation Ser27 YYRQRAHsNPMADHT 9606 3627513 t lperfetto "The trna methylase mettl1 is phosphorylated and inactivated by pkb and rsk in vitro and in cells" SIGNOR-24994 ARHGAP29 protein Q52LW3 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-260484 TNF protein P01375 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 16813528 f lperfetto "These observations suggest that tnf-alpha activates p38 map kinase during the inflammatory response at the injured growth plate, and tnf-alpha-p38 signaling seems to be required for marrow mesenchymal cell proliferation and migration at the growth plate injury site and in cell culture." SIGNOR-147369 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 PGM2 protein Q96G03 UNIPROT "alpha-D-glucose 1-phosphate(2-)" smallmolecule CHEBI:58601 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-267933 NOTCH proteinfamily SIGNOR-PF30 SIGNOR HES1 protein Q14469 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 32195003 f "Notch signaling is initiated by the interaction of Notch ligands and receptors on adjacent cells, which further triggers two proteolytic cleavage events. The first cleavage releases a functional extracellular domain (NECD); the second cleavage, mediated by γ-secretase, releases the intracellular domain (NICD) into the cytoplasm. The NICD then translocates to the nucleus, binds to the transcription factor CBF/Su (H)/LAG-2 (CSL), and recruits Mastermind-like protein 1 and p300/CBP to induce transcription of Notch target genes, including Hes1, p21, Akt, cyclin D1, and mTOR" SIGNOR-261534 CASP6 protein P55212 UNIPROT N protein P59595 UNIPROT "up-regulates activity" cleavage Asp400 VTLLPAAdMDDFSRQ 9534 BTO:0001444 18155731 t Luana "Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403" SIGNOR-260211 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 Glutaminolysis phenotype SIGNOR-PH119 SIGNOR mTORC1 complex SIGNOR-C3 SIGNOR "up-regulates activity" 9606 BTO:0000567 22749528 f Luana "Glutaminolysis Is Required for the Activation of mTORC1 by Leucine and Glutamine" SIGNOR-268007 COPS5 protein Q92905 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-270775 Gbeta proteinfamily SIGNOR-PF4 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-270091 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 PAX7-FOXO1 "fusion protein" SIGNOR-FP11 SIGNOR JARID2 protein Q92833 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23435416 t lperfetto "JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells| we demonstrated that JARID2 is a direct transcriptional target of the PAX3-FOXO1 fusion protein.| Therefore, JARID2 is a downstream effector of PAX3-FOXO1 that maintains an undifferentiated myogenic phenotype that is characteristic of RMS" SIGNOR-249597 ESRRA protein P11474 UNIPROT CYP19A1 protein P11511 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000154 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-253794 FOXS1 protein O43638 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9913 18288644 t Luana "Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4." SIGNOR-261610 FBXL5 protein Q9UKA1 UNIPROT SNAI1 protein O95863 UNIPROT "down-regulates quantity by destabilization" binding -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. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C)." SIGNOR-272135 TGFB1 protein P01137 UNIPROT ACTA2 protein P62736 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 20846954 f Regulation miannu "We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes." SIGNOR-251923 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 CDC14B protein O60729 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser315 LPNNTSSsPQPKKKP 9606 10644693 t "The human Cdc14 phosphatases interact with and dephosphorylate the tumor suppressor protein p53|. Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34Cdc2/clb phosphorylation site (p53-phosphor-Ser315)|Earlier studies showed that Ser315 phosphorylation increases the sequence-specific DNA binding capacity of p53, suggesting that Ser315 phosphorylation is an activating modification" SIGNOR-248332 CDK5 protein Q00535 UNIPROT RB1 protein P06400 UNIPROT down-regulates phosphorylation Ser811 IYISPLKsPYKISEG 9606 15741232 t gcesareni "Phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a cdk5 inhibitor, roscovitine, which does not inhibit the usual rb cyclin-d kinases cdk4 and cdk6. Furthermore, analyses of levels and subcellular localization of cdk-related cyclins did not reveal any change following cdk5 activation, arguing for a direct effect of cdk5 activity on rb protein. Rb phosphorylation was visualized using phosphorylation-dependent antibodies (p-rbser795 and p-rbser807/811)." SIGNOR-134468 STUB1 protein Q9UNE7 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates ubiquitination 9606 14701756 t gcesareni "These results suggest that chip can interact with the smad1/smad4 proteins and block bmp signal transduction through the ubiquitin-mediated degradation of smad proteins." SIGNOR-120731 CDK5 protein Q00535 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-198115 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 MAP3K5 protein Q99683 UNIPROT MAP3K6 protein O95382 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 17210579 t Manara "C-terminal region of ASK1 binds to ASK2 and inhibits the degradation of ASK2" SIGNOR-260831 PRKACA protein P17612 UNIPROT PLN protein P26678 UNIPROT "up-regulates activity" phosphorylation Ser16 RSAIRRAsTIEMPQQ 10090 10988285 t miannu "Phospholamban (PLB) can be phosphorylated at Ser(16) by cyclic AMP-dependent protein kinase. phosphorylation of Ser(16) is sufficient for mediating the maximal cardiac responses to beta-adrenergic stimulation." SIGNOR-250030 LCK protein P06239 UNIPROT CD3E protein P07766 UNIPROT "up-regulates activity" phosphorylation Tyr188 PPVPNPDyEPIRKGQ 9534 BTO:0004055 11855827 t "Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways." SIGNOR-251368 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 SAE1 protein Q9UBE0 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-263003 SMARCD2 protein Q92925 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-270693 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr896 EPKSPGEyVNIEFGS 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-236745 Ub:E2 complex SIGNOR-C497 SIGNOR MARCHF8 protein Q5T0T0 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-271098 entinostat chemical CHEBI:132082 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-257962 MYC protein P01106 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664;BTO:0004465 26179066 t lperfetto "In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer." SIGNOR-272143 MYC protein P01106 UNIPROT BCR protein P11274 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000664;BTO:0004465 26179066 t lperfetto "In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer." SIGNOR-272144 AKT2 protein P31751 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-158627 PRKCE protein Q02156 UNIPROT GABRG2 protein P18507 UNIPROT "down-regulates activity" phosphorylation Ser366 FVSNRKPsKDKDKKK -1 17875639 t miannu "Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol." SIGNOR-263174 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 MAPK13 protein O15264 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser25 QAFELILsPRSKESV 9606 BTO:0000782;BTO:0001271 8125092 t gcesareni "Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase." SIGNOR-36362 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 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 PTPRG protein P23470 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0000876 25624455 t miannu "Deeper examination shows that JAKs are critically involved in integrin-mediated monocyte adhesion and that PTPRG activation leads to JAK2 dephosphorylation on the critical 1007–1008 phosphotyrosine residues, implying JAK2 inhibition and thus explaining the antiadhesive role of PTPRG." SIGNOR-254689 ABL1 protein P00519 UNIPROT GPX1 protein P07203 UNIPROT "up-regulates activity" phosphorylation Tyr98 EILNSLKyVRPGGGF 9606 12893824 t lperfetto "GPx1 also functions as a substrate for c-Abl- and Arg-mediated phosphorylation on Tyr-96. The results further show that c-Abl and Arg stimulate GPx activity and that these kinases contribute to GPx-mediated protection of cells against oxidative stress." SIGNOR-104324 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 ARF4 protein P18085 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-272151 ATP5IF1 protein Q9UII2 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-261400 DAB2 protein P98082 UNIPROT LRP6 protein O75581 UNIPROT down-regulates binding 9606 22491013 t gcesareni "Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin." SIGNOR-196925 6-[2-tert-butyl-5-(6-methyl-2-pyridinyl)-1H-imidazol-4-yl]quinoxaline chemical CHEBI:91391 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206715 CACNA1C protein Q13936 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-264325 IL23A protein Q9NPF7 UNIPROT IL23R protein Q5VWK5 UNIPROT up-regulates binding 9606 BTO:0000782 12023369 t gcesareni "We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r." SIGNOR-87805 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT up-regulates phosphorylation Ser280 TVHGLPTsPDRPGST 9606 BTO:0000782;BTO:0000801 17095509 t gcesareni "We found that in these cells, lipopolysaccharide stimulates the expression of mhc ii genes via the activation of erk1/2, which is mediated by toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of ciita isoform 1 that leads to its monoubiquitylation." SIGNOR-150545 ARF5 protein P84085 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-272152 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 ATM protein Q13315 UNIPROT RPA2 protein P15927 UNIPROT up-regulates phosphorylation Thr21 YGGAGGYtQSPGGFG 9606 14872059 t lperfetto "Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro." SIGNOR-121861 triazolopyridazine chemical CHEBI:48384 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-263803 ATP smallmolecule CHEBI:15422 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√¢‚Ǩ¬≤-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S)." SIGNOR-268079 ATF6 protein P18850 UNIPROT XBP1 protein P17861-2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31226023 t 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-260184 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 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser1463 IVNYSRAsINSLLSD 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-272268 Degranulation phenotype SIGNOR-PH92 SIGNOR IL6 protein P05231 UNIPROT "up-regulates quantity" 9606 BTO:0000830 24232182 f apalma "Particularly, damage-activated mast cells almost instantly begin to secrete TNFa, histamine and tryptase and then initiate the de novo synthesis of other cytokines, such as interleukin (IL)6" SIGNOR-255349 NCK1 protein P16333 UNIPROT ABL1 protein P00519 UNIPROT "down-regulates activity" binding 9606 11494134 t lperfetto "We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites" SIGNOR-109672 CSNK2A1 protein P68400 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" phosphorylation Ser133 NAIRYIEsLQELLRE -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-250922 PKA proteinfamily SIGNOR-PF17 SIGNOR ARHGAP17 protein Q68EM7 UNIPROT "down-regulates activity" phosphorylation Ser702 LSAPRRYsSSLSPIQ 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex." SIGNOR-272156 GNAI1 protein P63096 UNIPROT TNFAIP8 protein O95379 UNIPROT "up-regulates activity" binding 9606 20607800 t "TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation" SIGNOR-256491 PRKCZ protein Q05513 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser323 MVGGKPGsFRVRASS 9606 15069075 t gcesareni "Thus, pkc-zeta might promote feedback ir/irs-1 complex formation and irs-1 tyrosine phosphorylation through phosphorylation of ser318." SIGNOR-123738 D2HGDH protein Q8N465 UNIPROT 2-oxoglutarate(2-) smallmolecule CHEBI:16810 ChEBI "up-regulates quantity" 26178471 f lperfetto "Here we show that wild-type D2HGDH elevates α-KG levels" SIGNOR-253131 TRIP10 protein Q15642 UNIPROT ARHGAP17 protein Q68EM7 UNIPROT "down-regulates activity" binding 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |ARHGAP17 is a Rho GTPase-activating protein of Rac1 and is bound to the SH3 domain of CIP4 via its SH3 binding region in resting platelets. Endothelial PGI2 stimulates the activation of PKA and leads to the phosphorylation of Ser-702 in ARHGAP17, which results in the dissociation of the ARHGAP17-CIP4 complex." SIGNOR-272158 Ub:E2 complex SIGNOR-C497 SIGNOR HERC4 protein Q5GLZ8 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-271307 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 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK4 protein Q16099 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-264473 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 AKT2 protein P31751 UNIPROT ATP7A protein Q04656 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser1466 YSRASINsLLSDKRS 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-272270 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 MAPK12 protein P53778 UNIPROT SNTA1 protein Q13424 UNIPROT up-regulates phosphorylation Ser193 GWDSPPAsPLQRQPS 9606 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-67061 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 SMARCD3 protein Q6STE5 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-270692 RNF41 protein Q9H4P4 UNIPROT PRKN protein O60260 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 18541373 t miannu "Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate." SIGNOR-272639 PKC proteinfamily SIGNOR-PF53 SIGNOR ARHGEF6 protein Q15052 UNIPROT "down-regulates activity" phosphorylation Ser684 GSSTRKDsIPQVLLP 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex." SIGNOR-272161 PKA proteinfamily SIGNOR-PF17 SIGNOR ARHGEF6 protein Q15052 UNIPROT "down-regulates activity" phosphorylation Ser640 RKTERKPsEEEYVIR 9606 BTO:0000132 26507661 t lperfetto "ARHGEF6 is a Rho guanine nucleotide exchange factor for Rac1 and constitutively bound to GIT1. NO and PGI2 activate PKG and PKA, respectively and both kinases phosphorylate ARHGEF6 on Ser-684 and possibly on Ser-640. Phosphorylation of ARHGEF6 results in the assembly of a GIT1-ARHGEF6–14-3-3 complex. These changes might contribute to PGI2- and NO-mediated Rac1 inhibition." SIGNOR-272163 BCL2L11 protein O43521 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 9606 BTO:0000007 18498746 t lperfetto "Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly." SIGNOR-178679 SRC protein P12931 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "down-regulates activity" phosphorylation 9606 30889378 t miannu "SRC can directly phosphorylate and inhibit LATS" SIGNOR-259056 "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 PPP1CB protein P62140 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "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-248575 PRKDC protein P78527 UNIPROT POU2F1 protein P14859 UNIPROT down-regulates phosphorylation Thr226 LQAQNLLtQLPQQSQ 9606 9368058 t lperfetto "Through a similar strategy, t226 and s232 were characterized as the dna-pk phosphorylation sites" SIGNOR-53262 KAT2A protein Q92830 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-269595 FBXO45 protein P0C2W1 UNIPROT ZEB1 protein P37275 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272179 FBXO45 protein P0C2W1 UNIPROT ZEB2 protein O60315 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272180 N-[3-[[5-iodo-4-[3-[[oxo(thiophen-2-yl)methyl]amino]propylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide chemical CHEBI:91439 ChEBI IKBKE protein Q14164 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190792 PRKACA protein P17612 UNIPROT TNNI3 protein P19429 UNIPROT "up-regulates activity" phosphorylation Ser24 APIRRRSsNYRAYAT 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-134609 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 FBXO45 protein P0C2W1 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272183 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 MYCBP2 protein O75592 UNIPROT "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR "form complex" binding 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272184 SREBF1 protein P36956 UNIPROT SND1 protein Q7KZF4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 29296233 t irozzo "These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression." SIGNOR-259137 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 SKP1 protein P63208 UNIPROT "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR "form complex" binding 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272185 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 "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR ZEB1 protein P37275 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272186 INO80D protein Q53TQ3 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-270843 CDK5 protein Q00535 UNIPROT PRKN protein O60260 UNIPROT down-regulates phosphorylation Ser131 HTDSRKDsPPAGSPA 9606 BTO:0000142 17327227 t llicata "Phosphorylation by cdk5 decreased the auto-ubiquitylation of parkin both in vitro and in vivo." SIGNOR-153445 PRKACA protein P17612 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). These data, indicate that S422 and/or S423 are the major sites of PKA-mediated phosphorylation of the 1 GABA receptor.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-262750 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 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 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 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 CNBP protein P62633 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 23774591 t Luana "These data verified that the binding of CNBP with c-myc promoter G-quadruplex can indeed down-regulate its associated gene expression for a certain period of time. This result with human CNBP is somehow consistent with previous reports that c-myc G-quadruplex serves as a silencer of c-myc transcription [7] and CNBP promotes the formation of c-myc G-quadruplex." SIGNOR-261571 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 "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR SNAI1 protein O95863 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272188 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" phosphorylation Tyr493 LGADDSYyTARSAGK 9606 BTO:0000661 7961936 t "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." SIGNOR-251395 "Skp1-Pam E3" complex SIGNOR-C537 SIGNOR SNAI2 protein O43623 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272189 E2F1 protein Q01094 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000584 22537161 f lperfetto "Nicotine, IFN-γ and retinoic acid mediated induction of MUC4 in pancreatic cancer requires E2F1 and STAT-1 transcription factors and utilize different signaling cascades" SIGNOR-254133 Ub:E2 complex SIGNOR-C497 SIGNOR RNF19B protein Q6ZMZ0 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-271173 MAPK12 protein P53778 UNIPROT Satellite_cells_self-renewal phenotype SIGNOR-PH100 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0002314 BTO:0001103 29681515 f apalma "[...] we observed a significant diminution in the number of symmetric satellite stem cell (YFP–) divisions in p38 gamma siRNA-treated fibers, suggesting that p38 gamma is required for symmetric stem cell maintenance. Thus, loss of p38gamma greatly skewed the ratio of asymmetric to symmetric satellite stem cell divisions to favor asymmetric divisions and myogenic commitment at the expense of self-renewal" SIGNOR-255902 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR LNPK protein Q9C0E8 UNIPROT "up-regulates activity" polyubiquitination 9606 BTO:0000007 32433973 t miannu "  Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC3" SIGNOR-272199 PIWIL1 protein Q96J94 UNIPROT APC-c complex SIGNOR-C150 SIGNOR up-regulates binding 9606 BTO:0003081 32203416 t miannu "PIWIL1 leads to the constitutive activation of APC/C in PDAC cells. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. Collectively, these results demonstrate that Pinin is an authentic substrate of APC/CPIWIL1 in PDAC cells." SIGNOR-272202 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 CDKN1A protein P38936 UNIPROT CyclinE/CDK2 complex SIGNOR-C16 SIGNOR "down-regulates activity" binding 9606 BTO:0000093 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-245462 ROCK1 protein Q13464 UNIPROT MYL12A protein P19105 UNIPROT "up-regulates activity" phosphorylation Thr18 KKRPQRAtSNVFAMF 9606 12185584 t miannu "Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies." SIGNOR-263074 ANK3 protein Q12955 UNIPROT CDH1 protein P12830 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17620337 t miannu "Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton." SIGNOR-266710 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 MAPK1 protein P28482 UNIPROT DAZAP1 protein Q96EP5 UNIPROT "down-regulates activity" phosphorylation Thr269 FTSYIVStPPGGFPP 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-262970 ANKRD11 protein Q6UB99 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" binding 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-266734 CSF2RA protein P15509 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 9606 7716810 f gcesareni "A major pathway which mediates the effects of gm-csf on macrophages involves activation of the latent transcription factor stat5a via a janus kinase 2 (jak2)-dependent pathway." SIGNOR-32220 TBK1 protein Q9UHD2 UNIPROT REL/RELA complex SIGNOR-C68 SIGNOR up-regulates phosphorylation 9606 16888014 t lperfetto "The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel." SIGNOR-217667 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 Ub:E2 complex SIGNOR-C497 SIGNOR RNF144B protein Q7Z419 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-271181 ATR protein Q13535 UNIPROT BRCA1 protein P38398 UNIPROT "up-regulates activity" phosphorylation Ser1457 SEKAVLTsQKSSEYP 9606 BTO:0000773 11278964 t lperfetto "Brca1 is phosphorylated at ser-1423 and ser-1524 after ir and uv;however, ser-1387 is specifically phosphorylated after ir, and ser-1457 is predominantly phosphorylated after uv.atr controls brca1 phosphorylation in vivo. Taken together, our results support a model in which atm and atr act in parallel but somewhat overlapping pathways of dna damage signaling but respond primarily to different types of dna lesion." SIGNOR-106440 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 calcium(2+) smallmolecule CHEBI:29108 ChEBI SLC25A12 protein O75746 UNIPROT "up-regulates activity" "chemical activation" 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-265152 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 SOD3 protein P08294 UNIPROT dioxygen smallmolecule CHEBI:15379 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-272272 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 HRAS protein P01112 UNIPROT BRAF protein P15056 UNIPROT up-regulates binding 10090 BTO:0000944 7706312 t lperfetto "Association of B-Raf with immobilized Ras occurred independently of prior stimulation of cells with serum, suggesting that primarily the production of GTP-Ras by mitogen stimulation is critical for the formation of B-Raf_GTP-Ras complexes." SIGNOR-235478 IKK-complex complex SIGNOR-C14 SIGNOR NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser36 RHDSGLDsMKDEEYE 9606 BTO:0000567 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-209773 GSK2126458 chemical CID:25167777 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192892 MAPKAPK5 protein Q8IW41 UNIPROT DNAJB1 protein P25685 UNIPROT up-regulates phosphorylation Ser151 VNFGRSRsAQEPARK 9606 24309468 t lperfetto "Phosphorylation of heat shock protein 40 (hsp40/dnajb1) by mitogen-activated protein kinase-activated protein kinase 5 (mk5/prak). Mk5 phosphorylates hsp40/dnajb1 in vivo at ser-149 or/and ser-151 and ser-171 in the c-terminal domain of hsp40/dnajb1. Mk5 modestly stimulates the atp hydrolyse activity of hsp40/hsp70 complex and enhances the repression of heat shock factor 1 driven transcription by hsp40/dnajb1." SIGNOR-203460 "A6/b1 integrin" complex SIGNOR-C164 SIGNOR NANOG protein Q9H9S0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001086 18757303 t 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-253282 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 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 NME2 protein P22392 UNIPROT NME2 protein P22392 UNIPROT "up-regulates activity" phosphorylation Ser44 AMKFLRAsEEHLKQH 9606 BTO:0000093 8245015 t miannu "An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells." SIGNOR-250201 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 GTP smallmolecule CHEBI:15996 ChEBI GNAS protein P63092 UNIPROT up-regulates "chemical activation" 9606 17095603 t gcesareni "Galfa subunits cycle between inactive (gdp-bound) and active (gtp-bound) states, and the lifetime of the active state is limited by gtp hydrolysis." SIGNOR-150552 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256453 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 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 SKP2 protein Q13309 UNIPROT CDT1 protein Q9H211 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 10790373 t miannu " Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3." SIGNOR-272565 SKP2 protein Q13309 UNIPROT CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 10790373 t miannu " Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3." SIGNOR-272566 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CDT1 protein Q9H211 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 10790373 t miannu " Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3." SIGNOR-272568 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 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 ESR1 protein P03372 UNIPROT SCN5A protein Q14524 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 BTO:0001264 24493753 f miannu "The effects of β-oestradiol (E2), the biologically active form of oestrogen, are classically mediated by two types of oestrogen receptor (ER): ERα and ERβ. E2 has both non-genomic and genomic effects upon VGSC expression/activity; and (ii) transcriptionally, E2 (via ERα) downregulates functional VGSC (nNav1.5) expression in BCa cells." SIGNOR-253467 COL4A2 protein P08572 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-272348 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 10790373 t miannu " Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3." SIGNOR-272569 ANXA13 protein P27216 UNIPROT NEDD4 protein P46934 UNIPROT "up-regulates quantity" relocalization -1 10871286 t miannu "Annexin XIII has two known isoforms, a and b, that are apically localized, although XIIIa is also found in the basolateral compartment. In vitro binding and coprecipitation experiments showed that the Nedd4-C2 domain interacts with both annexin XIIIa and b in the presence of Ca2+, and the interaction is direct and optimal at 1 μM Ca2+.These results suggest that the apical membrane localization of Nedd4 is mediated by an association of its C2 domain with the apically targeted annexin XIIIb." SIGNOR-272571 STK24 protein Q9Y6E0 UNIPROT STK38 protein Q15208 UNIPROT up-regulates phosphorylation Thr444 DWVFINYtYKRFEGL 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-142467 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 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 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 COA3 protein Q9Y2R0 UNIPROT "MITRAC complex" complex SIGNOR-C538 SIGNOR "form complex" binding 9606 BTO:0000007 23260140 t "By analyzing MITRAC12 interaction partners, we show that recently identified assembly factors, such as c12orf62, CMC1, and the novel assembly factor MITRAC15, are constituents of MITRAC complexes" SIGNOR-272484 UTS2R protein Q9UKP6 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-257252 IL6 protein P05231 UNIPROT AMPK complex SIGNOR-C15 SIGNOR up-regulates 10090 23531613 f "AMPK phosphorylation was increased nearly fourfold (Fig. 2C) with the high dose of IL-6" SIGNOR-255338 GNG3 protein P63215 UNIPROT PI3K complex SIGNOR-C156 SIGNOR up-regulates binding 9606 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-252684 mir-133a1 mirna URS00005EB596_9606 RNAcentral IGF1R protein P08069 UNIPROT "down-regulates quantity" "post transcriptional regulation" 9606 17996649 f miannu "Here, we show that miR-223 is a direct transcriptional target of AML1/ETO. By recruiting chromatin remodeling enzymes at an AML1-binding site on the pre-miR-223 gene, AML1/ETO induces heterochromatic silencing of miR-223. Ectopic miR-223 expression, RNAi against AML1/ETO, or demethylating treatment enhances miR-223 levels and restores cell differentiation." SIGNOR-261973 MECP2 protein P51608 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000093 15870696 f miannu "Valproate (VPA) induces silencing of the ERalpha, cyclin D1 and pS2 promoters. Chromatin immunoprecipitation (ChIP) analysis demonstrates that VPA induces recruitment of the 5-MeCpG binding protein MeCP2 to the ERalpha A promoter and also to the pS2 and cyclin D1 promoters" SIGNOR-254571 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 ANKS1B protein Q7Z6G8 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-264228 DNAJC3 protein Q13217 UNIPROT EIF2AK2 protein P19525 UNIPROT "down-regulates activity" binding 9606 BTO:0000567 25329545 t gcesareni "The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK" SIGNOR-246207 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 EFNA5 protein P52803 UNIPROT EPHA5 protein P54756 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-52476 "ginkgolide B" chemical CHEBI:5356 ChEBI PTAFR protein P25105 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192684 "Complement C1 complex" complex SIGNOR-C309 SIGNOR C2 protein P06681 UNIPROT "up-regulates activity" cleavage Arg243 KTKESLGrKIQIQRS 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-263418 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 PNPLA6 protein Q8IY17 UNIPROT Lysophosphatidylcholine smallmolecule CID:5311264 PUBCHEM "down-regulates quantity" "chemical modification" 9606 25033069 t "PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus" SIGNOR-253610 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PTPRR protein Q15256 UNIPROT "up-regulates activity" phosphorylation 11493009 t "inferred from 70% family members" lperfetto "Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL." SIGNOR-270147 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 PRKCA protein P17252 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-249048 PPP2CB protein P62714 UNIPROT IKBKB protein O14920 UNIPROT "down-regulates activity" dephosphorylation Ser181 DQGSLCTsFVGTLQY 9606 19607706 t "Permanent activation of the upstream kinase IKK beta results from UVB-induced inhibition of the catalytic subunit of Ser-Thr phosphatase PP2A (PP2Ac), leading to immediate phosphorylation and degradation of newly synthesized I kappaB alpha|Chronic Ser 177/181 phosphorylation of IKKβ was due to UVB-induced inhibition of the catalytic subunit of the Ser-Thr phosphatase PP2A (PP2Ac)" SIGNOR-248580 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 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 FYN protein P06241 UNIPROT SCN5A protein Q14524 UNIPROT down-regulates phosphorylation Tyr1495 TEEQKKYyNAMKKLG 9606 15831816 t llicata "This study addresses the effects of the src family tyrosine kinase fyn on na(v)1.5 cardiac sodium channels. Sodium currents were acquired by whole cell recording on hek-293 cells transiently expressing na(v)1.5. Acute treatment of cells with insulin caused a depolarizing shift in steady-state inactivation, an effect eliminated by the src-specific tyrosine kinase inhibitor pp2 we provide evidence that this linker is a substrate for fyn in vitro, and that y1495 is a preferred phosphorylation site." SIGNOR-135600 "Vicriviroc Malate" chemical CID:10218922 PUBCHEM CCR5 protein P51681 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207657 MAPK10 protein P53779 UNIPROT HNRNPK protein P61978 UNIPROT "up-regulates activity" phosphorylation Ser216 ILDLISEsPIKGRAQ 9606 11259409 t miannu "JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein." SIGNOR-250081 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Thr41 GIHSGATtTAPSLSG 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "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-141807 CCKBR protein P32239 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-256908 STMN1 protein P16949 UNIPROT TTL protein Q8NG68 UNIPROT down-regulates binding 9606 23624152 t miannu "Stathmin depresses ttl tubulin tyrosination activityin vitro." SIGNOR-193465 IRX1 protein P78414 UNIPROT EGR1 protein P18146 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-261661 S3I-201 chemical CHEBI:91224 ChEBI STAT3 protein P40763 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194847 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 SLC9A4 protein Q6AI14 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-265603 CSK protein P41240 UNIPROT PTPRC protein P08575 UNIPROT up-regulates phosphorylation Tyr1218 MVSTFEQyQFLYDVI 9606 BTO:0000782 7507203 t llicata "Tyrosine phosphorylation of cd45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase." SIGNOR-26785 CSNK1E protein P49674 UNIPROT LRP6 protein O75581 UNIPROT up-regulates phosphorylation Ser1430 LGYVPHPsSLSGSLP 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-145053 ARNT protein P27540 UNIPROT FOS protein P01100 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 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-253696 PTPN6 protein P29350 UNIPROT ACTG1 protein P63261 UNIPROT down-regulates dephosphorylation Tyr218 DIKEKLCyVALDFEQ 9606 BTO:0000776 12646642 t gcesareni "Our data suggest that shp-1 plays a pivotal role in reorganization of cytoskeletal architecture inducing actin dephosphorylation. These results clearly demonstrate the direct interaction of shp-1 with actin" SIGNOR-99565 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 HCK protein P08631 UNIPROT ELMO1 protein Q92556 UNIPROT up-regulates phosphorylation Tyr18 AIEWPGAyPKLMEID 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-138142 BDNF protein P23560 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates 9606 BTO:0000142 32603820 f miannu "BDNF is a central driver of synaptic plasticity and memory formation and its decreased levels may contribute to the degeneration of specific neuronal populations and progressive atrophy of neurons in the AD-affected brain" SIGNOR-265063 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 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Tyr86 VADIDGQyAMTRAQR 9606 BTO:0001271 17318191 t lperfetto "Bcr_abl_mediated phosphorylation of y86 could induce a conformational change of __catenin impairing its binding to axin" SIGNOR-153435 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 MBD1 protein Q9UIS9 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254036 "DPM complex" complex SIGNOR-C289 SIGNOR "dolichyl beta-D-mannosyl phosphate" smallmolecule CHEBI:17624 ChEBI "up-regulates quantity" "chemical modification" 9606 10835346 t lperfetto "Dolichol-phosphate-mannose (DPM) synthase generates mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation." SIGNOR-262566 OXGR1 protein Q96P68 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-257155 PDPK1 protein O15530 UNIPROT SGK3 protein Q96BR1 UNIPROT "up-regulates activity" phosphorylation Thr320 AISDTTTtFCGTPEY 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-250279 LCK protein P06239 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" phosphorylation Tyr42 DSMKDEEyEQMVKEL 14534291 t lperfetto "Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors" SIGNOR-249374 SYK protein P43405 UNIPROT SH3BP2 protein P78314 UNIPROT "up-regulates activity" phosphorylation Tyr174 YPTDNEDyEHDDEDD 9534 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-246587 PNPLA6 protein Q8IY17 UNIPROT 2-(((R)-2,3-Dihydroxypropyl)phosphoryloxy)-N,N,N-trimethylethanaminium smallmolecule CID:439285 PUBCHEM "up-regulates quantity" "chemical modification" 9606 25033069 t "PNPLA6 encodes NTE, a lysophospholipase that converts lysophosphatidylcholine (LPC) to glycerophosphocholine. PNPLA6 is expressed in neurons throughout the brain, particularly in the cortex, Purkinje cells of the cerebellum, and hippocampus" SIGNOR-253611 MTHFD2L protein Q9H903 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI "up-regulates quantity" "chemical modification" 10116 21163947 t lperfetto "Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown. A new mitochondrial CH(2)-THF dehydrogenase isozyme, encoded by the MTHFD2L gene, has now been identified. " SIGNOR-268252 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 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 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR CEP97 protein Q8IW35 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0004790 30404837 t miannu "Cullin-3-KCTD10-mediated CEP97 degradation promotes primary cilium formation. we identified the cullin-3-RBX1-KCTD10 complex as the E3 ligase that mediates CEP97 degradation and removal from the mother centriole." SIGNOR-272925 ADORA2B protein P29275 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-257240 4,4'-sulfonyldiphenol chemical CHEBI:34372 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-268730 LPAR6 protein P43657 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-256725 Laminin-1 complex SIGNOR-C183 SIGNOR "A1/b1 integrin" complex SIGNOR-C159 SIGNOR "up-regulates activity" binding 9361014 t lperfetto "Using integrin-specific antibodies, recognition sites for the alpha1beta1 and alpha2beta1 integrins were identified in the short arms of both laminin alpha1- and alpha2-chain isoforms. Comparisons with a beta-alpha chimeric short arm protein possessing beta1-chain domain VI further localized these activities to alpha-chain domain VI." SIGNOR-253254 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Thr360 SGISSVPtPSPLGPL 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-244525 MET protein P08581 UNIPROT MET protein P08581 UNIPROT up-regulates phosphorylation Tyr1235 DMYDKEYySVHNKTG 9606 8302603 t lperfetto "Previous work has shown that autophosphorylation of p190met enhances its enzymatic activity and that the major phosphorylation site is tyr1235, located in the catalytic domainonly the replacement of both tyr1234 and tyr1235 yielded a mutant which completely lost the ability to be activated by autophosphorylation" SIGNOR-37727 BMP2 protein P12643 UNIPROT SMAD9 protein O15198 UNIPROT up-regulates 9606 22298955 f gcesareni "Neogenin, a transmembranous protein, was re-ported to regulate bmp receptor association with lipid raft, where bmp induces canonical smad1/5/8 phosphorylation." SIGNOR-195567 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 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 CDK2 protein P24941 UNIPROT PELP1 protein Q8IZL8 UNIPROT up-regulates phosphorylation Ser991 PALPPPEsPPKVQPE 9606 20807815 t llicata "We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function." SIGNOR-167766 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 PRKACA protein P17612 UNIPROT DUOX1 protein Q9NRD9 UNIPROT up-regulates phosphorylation Ser955 KDLCRRAsYISQDMI 9606 19144650 t llicata "We analyzed the duox1 phosphorylation state with an anti-rxx(ps/pt) antibody that could potentially recognize phosphorylation on ser955 and ser1217 but not on thr1007. duox1 but not duox2 activity is stimulated by forskolin (ec50 = 0.1 _m) via protein kinase a-mediated duox1 phosphorylation on serine 955. duox1 is positively regulated by the camp-dependent protein kinase a (pka)6 cascade" SIGNOR-183449 SRC protein P12931 UNIPROT ARHGAP35 protein Q9NRY4 UNIPROT up-regulates phosphorylation Tyr1105 RNEEENIySVPHDST 9606 9819392 t lperfetto "Phosphorylation of y1105, but not the minor site, was modulated in vivo to a greater extent by overexpression of c-src than by the egf receptor and was efficiently catalyzed by c-src in vitro. Mutation of y1105 from tyr to phe resulted in complete loss of p-tyr-dependent complex formation, indicating that p-y1105 was the sole p-tyr residue mediating binding to p120" SIGNOR-61670 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 "8-Hydroxy-7-(6-sulfo-naphthalen-2-ylazo)-quinoline-5-sulfonic acid" chemical CID:92577 PUBCHEM DUSP26 protein Q9BV47 UNIPROT "down-regulates activity" "chemical inhibition" -1 19233143 t lperfetto "Phosphatase activity of dual-specificity protein phosphatase 26 (DUSP26) was decreased by the inhibitor in a dose-dependent manner. Kinetic studies with NSC-87877 and DUSP26 revealed a competitive inhibition." SIGNOR-261979 BMS-265246 chemical CID:5329775 PUBCHEM CDK1 protein P06493 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190431 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 "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 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 CDC20 protein Q12834 UNIPROT SP100 protein P23497 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 22086178 t miannu "Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process." SIGNOR-272724 "SAE1/SAE2 complex" complex SIGNOR-C294 SIGNOR 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-263014 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 TBCK protein Q8TEA7 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 23977024 f miannu "Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule." SIGNOR-266700 SCF-betaTRCP complex SIGNOR-C5 SIGNOR SMAD3 protein P84022 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9534 BTO:0000298 11359933 t miannu "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-272944 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 SCF(TBL1) complex SIGNOR-C533 SIGNOR CTNNB1 protein P35222 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys666 LFRMSEDkPQDYKKR 9606 BTO:0000007 20181957 t miannu "Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). " SIGNOR-271946 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-249646 SIN3B protein O75182 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-266967 CSNK2A1 protein P68400 UNIPROT DDX58 protein O95786 UNIPROT down-regulates phosphorylation Ser854 HPKPKQFsSFEKRAK 9606 21068236 t lperfetto "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)" SIGNOR-169400 "L-glutamine zwitterion" smallmolecule CHEBI:58359 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-268096 GRM3 protein Q14832 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-264353 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 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 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 RNF8 protein O76064 UNIPROT L3MBTL2 protein Q969R5 UNIPROT "up-regulates activity" ubiquitination 9606 31225475 t 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-266787 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 DUSP26 protein Q9BV47 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser20 PLSQETFsDLWKLLP 9606 20562916 t "Dual-specificity phosphatase 26 is a novel p53 phosphatase and inhibits p53 tumor suppressor functions in human neuroblastoma|Inhibiting DUSP26 expression in the IMR-32 neuroblastoma cell line enhanced doxorubicin-induced p53 phosphorylation at Ser20 and Ser37, p21, Puma, Bax expression as well as apoptosis" SIGNOR-248765 entinostat chemical CHEBI:132082 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-257903 PRKDC protein P78527 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-188776 AKT proteinfamily SIGNOR-PF24 SIGNOR ACAP1 protein Q15027 UNIPROT unknown phosphorylation Ser554 SIRPRPGsLRSKPEP 9606 16256741 t llicata "Akt phosphorylates s554 in acap1" SIGNOR-141343 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 SLC36A1 protein Q7Z2H8 UNIPROT glycine smallmolecule CHEBI:15428 ChEBI "up-regulates quantity" relocalization 9606 12748860 t lperfetto "Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut." SIGNOR-264737 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 "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 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 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 APC-c complex SIGNOR-C150 SIGNOR APC-c complex SIGNOR-C150 SIGNOR "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 22086178 t miannu "Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process." SIGNOR-272725 PINK1 protein Q9BXM7 UNIPROT RHOT2 protein Q8IXI1 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0000007 22078885 t miannu "PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C)." SIGNOR-272727 "Fanconi anemia core complex" complex SIGNOR-C300 SIGNOR FANCI protein Q9NVI1 UNIPROT "up-regulates activity" ubiquitination 18985065 t lperfetto "Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding" SIGNOR-263267 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 dutasteride chemical CHEBI:521033 ChEBI ESR2 protein Q92731 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-191445 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 TLK2 protein Q86UE8 UNIPROT ASF1B protein Q9NVP2 UNIPROT unknown phosphorylation Ser198 PGLLPENsMDCI 9606 20016786 t Manara "We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | hASF1b stability does not appear to depend on phosphorylation by TLKs, but recently it has been shown that hASF1b transcription is controlled by the cell-cycle regulated E2F transcription factors" SIGNOR-260788 neratinib chemical CHEBI:61397 ChEBI EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194628 "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 INTS8 protein Q75QN2 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-261472 ITPRIPL1 protein Q6GPH6 UNIPROT ITPR1 protein Q14643 UNIPROT up-regulates binding 9606 BTO:0000938 21368195 t "Induces Ca2+ release that increases the binding affinity of Shh for Boc." 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-172497 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser447 GSPRTPVsPVKFSPG 9606 21035469 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-169154 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 PINK1 protein Q9BXM7 UNIPROT RHOT1 protein Q8IXI2 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0000007 22078885 t miannu "PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C)." SIGNOR-272728 TRAF2 protein Q12933 UNIPROT BIRC3 protein Q13489 UNIPROT up-regulates binding 9606 8548810 t amattioni "The c-iaps associate with traf1 and traf2" SIGNOR-39596 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 RCHY1 protein Q96PM5 UNIPROT COPE protein O14579 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 17721809 t miannu "PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP. " SIGNOR-272630 phosphatidylcholine chemical CHEBI:64482 ChEBI Outer_mitochondrial_membrane complex SIGNOR-C410 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The OMM is comprised of a phospholipid bilayer that houses vital components such as metabolic enzymes and transport proteins|he OMM contains a variety of lipids. The major components of this bilayer include phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) |It has been reported that in the mammalian OMM, the most prominent of these lipids are PC (~54 % of total), PE (~29 %) and PI (~14 %) (Daum and Vance 1997). The remaining lipids comprise approximately 3 % of the total OMM composition." SIGNOR-267000 MRPL12 protein P52815 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-262381 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 DAMPS stimulus SIGNOR-ST18 SIGNOR AIM2 protein O14862 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-256419 CCP110 protein O43303 UNIPROT CETN3 protein O15182 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-265968 PRKACA protein P17612 UNIPROT KCNH2 protein Q12809 UNIPROT up-regulates phosphorylation Ser1137 EGPTRRLsLPGQLGA 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-70718 NDUFB2 protein O95178 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-262165 PSTPIP1 protein O43586 UNIPROT PTPN18 protein Q99952 UNIPROT "up-regulates activity" binding 9534 BTO:0004055 9422760 t lperfetto "These data confirm the importance of these residues to the binding interaction, and they suggest that much of the COOH-terminal region of PTP HSCF may be required for highest affinity binding to PST PIP.|Because this protein-protein interaction appears to be required for the dephosphorylation of PST PIP phosphotyrosines (20), it may be a potentially important new mechanism for the regulation of the cytoskeleton." SIGNOR-262594 SIRT1 protein Q96EB6 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" deacetylation 9606 BTO:0000007 14976264 t lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-122408 AGTR1 protein P30556 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-256881 hsa-mir-223 mirna URS000037EC34_9606 RNAcentral CARM1 protein Q86X55 UNIPROT "down-regulates quantity by repression" "post transcriptional regulation" 9606 24332853 t miannu "PRMT4 is downregulated by miR-223 during normal myeloid differentiation" SIGNOR-261970 GATA6 protein Q92908 UNIPROT CYP11A1 protein P05108 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002850 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-254197 GOT2 protein P00505 UNIPROT L-aspartate(1-) smallmolecule CHEBI:29991 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-268060 FGFR1 protein P11362 UNIPROT PDK1 protein Q15118 UNIPROT up-regulates phosphorylation Tyr136 AEDAKAIyDFTDTVI 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-191719 SMARCC1 protein Q92922 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-269786 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 GATA2 protein P23769 UNIPROT GATA1 protein P15976 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21853041 f miannu "GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1." SIGNOR-256062 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR TSPYL2 protein Q9H2G4 UNIPROT "up-regulates activity" phosphorylation Ser20 RRLSSSEsPQRDPPP 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-250752 WNT1 protein P04628 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates 10116 11149923 f gcesareni "Wnt-1 signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced by chemotherapeutic drugs, including both vincristine and vinblastine. Furthermore, we found that wnt-1-mediated cell survival was dependent on the activation of beta-catenin/t cell factor (tcf) transcription" SIGNOR-85760 IL4R protein P24394 UNIPROT IRS1 protein P35568 UNIPROT up-regulates phosphorylation 9606 BTO:0000782;BTO:0000801;BTO:0000876 BTO:0000887;BTO:0000763;BTO:0001260 12704343 t milica "Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2." SIGNOR-100768 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT "down-regulates activity" monoubiquitination Lys686 HQGKRNPkSPLACTN 9606 21791603 t miannu "Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709)." SIGNOR-272731 SEC23A protein Q15436 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-265289 superoxide smallmolecule CHEBI:18421 ChEBI SOD3 protein P08294 UNIPROT "up-regulates activity" "precursor of" 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-272274 STC2/HMOX1 complex SIGNOR-C244 SIGNOR heme smallmolecule CHEBI:30413 ChEBI "down-regulates quantity by destabilization" 22503972 t lperfetto "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-260405 PPP2CA protein P67775 UNIPROT MAP3K3 protein Q99759 UNIPROT down-regulates dephosphorylation Ser526 MSGTGMRsVTGTPYW 9606 20448038 t lperfetto "Pp2ac binds to the phosphorylated mekk3 and subsequently dephosphorylate mekk3 at thr-516, ser-520, and ser-526 residues to terminate mekk3-mediated ikkbeta/Nf-kappaB Activation" SIGNOR-165233 PRKCD protein Q05655 UNIPROT IL6ST protein P40189 UNIPROT up-regulates phosphorylation Thr890 GQVERFEtVGMEAAT 9606 12361954 t fspada "This interaction, which does not seem to involve a classical phosphotyrosine sh2-mediated binding, however, significantly enhances the interaction of stat3 and the il-6 receptor subunit glycoprotein (gp) 130, which is the initial step for stat3 activation by il-6. Expression of a dominant negative pkcdelta or depletion of the endogenous pkcdelta by phorbol 12-myristate 3-acetate treatment abrogates the association of stat3 with gp130. At the same time, pkcdelta is recruited to gp130 via association with stat3, which may facilitate its phosphorylation on the gp130 receptor. Finally, we identified thr-890, a putative pkc phosphorylation site on gp130, to be critical for the effect of pkcdelta. Our data indicate that pkcdelta plays important regulatory roles in il-6 signaling." SIGNOR-94012 CHAF1A protein Q13111 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f miannu "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254569 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 19762596 t miannu " We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus. " SIGNOR-271883 GCM2 protein O75603 UNIPROT CASR protein P41180 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004712 BTO:0000975 18712808 f miannu "we show that both promoters (P1 and P2) of the calcium-sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild-type GCM2." SIGNOR-254199 RCHY1 protein Q96PM5 UNIPROT POLH protein Q9Y253 UNIPROT "down-regulates activity" monoubiquitination Lys694 SPLACTNkRPRPEGM 9606 21791603 t miannu "Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues.we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions.These results suggest that Pirh2 monoubiquitinates PolH at one of the four lysine residues (K682, K686, K694, and K709)." SIGNOR-272732 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 FBLN5 protein Q9UBX5 UNIPROT ELN protein P15502 UNIPROT "up-regulates activity" binding 9606 18267938 t miannu "The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin." SIGNOR-252137 BTK protein Q06187 UNIPROT PLCG2 protein P16885 UNIPROT "up-regulates activity" phosphorylation Tyr1217 LNNQLFLyDTHQNLR 9606 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-109750 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 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 NFE2L2 protein Q16236 UNIPROT Metastasis phenotype SIGNOR-PH107 SIGNOR up-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-259285 KCNJ10 protein P78508 UNIPROT potassium(1+) smallmolecule CHEBI:29103 ChEBI "up-regulates quantity" relocalization 9606 24561201 t miannu "KCNJ10 encodes Kir4.1, a member of the K+ channel family known as inwardly rectifying K+ (Kir) channels. Kir4.1 channels may comprise either Kir4.1 homomers or Kir4.1/Kir5.1 heteromers" SIGNOR-269446 RBCK1 protein Q9BYM8 UNIPROT LUBAC complex SIGNOR-C527 SIGNOR "form complex" binding 9606 BTO:0000567 17006537 t miannu "Here, we report that a protein complex consisting of two RING finger proteins, HOIL-1L and HOIP, exhibits ubiquitin polymerization activity by recognizing ubiquitin moieties of proteins. The polyubiquitin chain generated by the complex is not formed by Lys linkages, but by linkages between the C- and N-termini of ubiquitin, indicating that the ligase complex possesses a unique feature to assemble a novel head-to-tail linear polyubiquitin chain." SIGNOR-271615 Gbeta proteinfamily SIGNOR-PF4 SIGNOR TWIST1 protein Q15672 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 21502402 t "inferred from 70% family members" 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-270122 UBE3A protein Q05086 UNIPROT SIPA1L1 protein O43166 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 12036950 t miannu " the purified E6AP enhanced the ubiquitination and degradation of E6TP1 in the presence of E6 in vitro. Additionally, the expression of a dominant-negative E6AP mutant (C833A) in cells inhibited the E6-induced degradation of E6TP1. These findings demonstrate that the E6-induced decrease in the levels of E6TP1 protein involves the E6AP-mediated ubiquitination followed by proteasome-dependent degradation." SIGNOR-272608 MRPL2 protein Q5T653 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-262374 MAP3K7 protein O43318 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" phosphorylation 9606 21133840 t miannu "RIP-1 recruitment of MEKK-3 and transforming growth factor-beta (TGFbeta)-activated kinase (TAK1) subsequently activates the IKK (inhibitor of Œ∫B kinase) complex" SIGNOR-256024 DGC complex SIGNOR-C217 SIGNOR "GABA-A (a6-b2-d) receptor" complex SIGNOR-C328 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-265440 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 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 PKG proteinfamily SIGNOR-PF77 SIGNOR "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-266504 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 MTOR protein P42345 UNIPROT TFEB protein P19484 UNIPROT "down-regulates activity" phosphorylation Ser211 LVGVTSSsCPADLTQ 9606 BTO:0000567 SIGNOR-C3 22692423 t gcesareni "Our data points to the lysosome as the site where mTORC1-dependent phosphorylation of TFEB occurs. [...]Our study has revealed a specific role for phosphorylation of TFEB S211 in the negative regulation of the nuclear abundance of TFEB. This occurs through the promotion of 14-3-3 binding and the masking of the nearby NLS on TFEB." SIGNOR-248270 HABP4 protein Q5JVS0 UNIPROT MEF2C protein Q06413 UNIPROT "down-regulates activity" binding 10116 15862299 t llicata "MEF2C DNA-binding activity is inhibited through its interaction with the regulatory protein Ki-1/57." SIGNOR-238283 MTHFD1L protein Q6UB35 UNIPROT formate smallmolecule CHEBI:15740 ChEBI "up-regulates quantity" "chemical modification" 9606 16171773 t lperfetto "A human mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase was previously identified by its similarity to the human cytoplasmic C1-THF synthase. All C1-THF synthases characterized to date, from yeast to human, are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Here we report on the enzymatic characterization of the recombinant human mitochondrial isozyme. Enzyme assays of purified human mitochondrial C1-THF synthase protein revealed only the presence of 10-formyl-THF synthetase activity." SIGNOR-268254 SPI1 protein P17947 UNIPROT CD68 protein P34810 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000801 12676954 f "However, our data show that PU.1/IRF-4 and IRF-8 heterocomplexes down-regulate CD68 promoter activity in macrophages and repression is dependent on the integrity of both the IRF and PU.1 half-sites of this composite element." SIGNOR-254286 "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 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr259 ASVDSSLyNLPRSYS 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-236310 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 PPP2CA protein P67775 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" dephosphorylation Ser474 RTHFPQFsYSASIRE 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-248632 CDC7 protein O00311 UNIPROT MCM2 protein P49736 UNIPROT up-regulates phosphorylation Ser5 sESFTMAS 9606 19647517 t lperfetto "Phosphorylation of mcm2 by cdc7 promotes pre-replication complex assembly during cell-cycle re-entry" SIGNOR-187396 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 oxandrolone chemical CHEBI:7820 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-259265 glutamine smallmolecule CHEBI:28300 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR "up-regulates activity" 9606 BTO:0000567 22749528 f Luana "Leucine and Glutamine Activate Glutaminolysis and mTORC1" SIGNOR-268009 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 USP36 protein Q9P275 UNIPROT SOD2 protein P04179 UNIPROT "up-regulates quantity by stabilization" deubiquitination 21268071 t lperfetto "Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life." SIGNOR-272280 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 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 STUB1 protein Q9UNE7 UNIPROT SMG5 protein Q9UPR3 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 16809764 t miannu "Here, we report that the human ortholog of the yeast ever-shorter telomeres 1B (EST1B) binds HDAC8. This interaction is regulated by protein kinase A-mediated HDAC8 phosphorylation and protects human EST1B (hEST1B) from ubiquitin-mediated degradation. Phosphorylated HDAC8 preferentially recruits Hsp70 to a complex that inhibits the CHIP (C-terminal heat shock protein interacting protein) E3 ligase-mediated degradation of hEST1B. " SIGNOR-272649 PRKCB protein P05771 UNIPROT KCNC4 protein Q03721 UNIPROT down-regulates phosphorylation Ser21 KSGNKPPsKTCLKEE 9606 7993631 t gcesareni "We found that pkc specifically eliminates rapid inactivation of a cloned human a-type k+ channel (hkv3.4), converting this channel from a rapidly inactivating a type to a noninactivating delayed rectifier type." SIGNOR-35626 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 lenalidomide chemical CHEBI:63791 ChEBI IKZF1 protein Q13422 UNIPROT "down-regulates quantity by destabilization" "chemical inhibition" 9606 24328678 t gcesareni "Members of the Ikaros family of transcription factors, specifically Ikaros and Aiolos (encoded by the genes IKZF1 and IKZF3 respectively), are recruited as protein substrates for CRL4CRBN in T cells in response to lenalidomide or pomalidomide treatment." SIGNOR-236910 FARSB protein Q9NSD9 UNIPROT "Phenylalanyl-tRNA synthetase" complex SIGNOR-C473 SIGNOR "form complex" binding 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-270435 CUDC-101 chemical CID:24756910 PUBCHEM ERBB2 protein P04626 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-262255 CSNK2A1 protein P68400 UNIPROT C1R protein P00736 UNIPROT "down-regulates activity" phosphorylation Ser206 TEASGYIsSLEYPRS -1 8635594 t llicata "We provide evidence that this kinase phosphorylates Clr at the level of Ser189. | Accessibility of Ser189 was low in intact C1r, due in part to the presence of one of the oligosaccharides borne by the alpha region, further reduced in the presence of calcium, and abolished when C1r was incorporated into the C1s-C1r-C1r-C1s tetramer or the C1 complex." SIGNOR-250833 GABRG2 protein P18507 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-263761 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 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 CDK1 protein P06493 UNIPROT RANBP2 protein P49792 UNIPROT "up-regulates activity" phosphorylation Ser2251 ASPLASSerPVRKNL -1 26051540 t irozzo "Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment." SIGNOR-259119 APC-c complex SIGNOR-C150 SIGNOR ANLN protein Q9NQW6 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 16040610 t miannu " Ubiquitination of anillin required a destruction-box and was mediated by Cdh1, an activator of APC/C. Overexpression of Cdh1 reduced the levels of anillin, whereas inactivation of APC/C(Cdh1) increased the half-life of anillin." SIGNOR-272655 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser536 SGDEDFSsIADMDFS 9606 SIGNOR-C13 15489227 t gcesareni "Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro." SIGNOR-129943 "A10/b1 integrin" complex SIGNOR-C167 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-269016 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 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 SLC34A3 protein Q8N130 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000671 11880379 t lperfetto "Growth is critically dependent on the retention of a variety of nutrients. The kidney contributes to this positive external balance. In the present study, we isolated a cDNA from the human and rat kidney that encodes a growth-related Na(+)-dependent inorganic phosphate (P(i)) cotransporter (type IIc)." SIGNOR-270577 AKT proteinfamily SIGNOR-PF24 SIGNOR FOXO1 protein Q12778 UNIPROT "down-regulates activity" phosphorylation 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-252350 GCSH protein P23434 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-268241 MFN1 protein Q8IWA4 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-272984 superoxide smallmolecule CHEBI:18421 ChEBI SOD2 protein P04179 UNIPROT "up-regulates activity" "precursor of" 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-272284 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 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 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 NR3C1 protein P04150 UNIPROT AR protein P10275 UNIPROT "down-regulates activity" binding 9606 9162033 t gcesareni "Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity." SIGNOR-48516 RUNX3 protein Q13761 UNIPROT FADD protein Q13158 UNIPROT "up-regulates quantity by expression" "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-255095 ATM protein Q13315 UNIPROT EXO1 protein Q9UQ84 UNIPROT up-regulates phosphorylation 9606 20019063 t gcesareni "The phosphorylation of exo1 by atm appears to regulate the activity of exo1 following resection, allowing optimal rad51 loading and the completion of hr repair." SIGNOR-162304 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 BHLHE40 protein O14503 UNIPROT PER2 protein O15055 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000944 14672706 f lperfetto "Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression" SIGNOR-253717 PTPN13 protein Q12923 UNIPROT STK25 protein O00506 UNIPROT "down-regulates activity" dephosphorylation 9606 17657516 t "To investigate dephosphorylation of CCM3 by FAP-1, phosphorylated GST-CCM3 was incubated with cdFAP-1, and reactions were analyzed by autoradiography. Again, GST-STK25 phosphorylated GST-CCM3 and possessed autophosphorylation activity. cdFAP-1 of 0.005 U were sufficient to dephosphorylate GST-CCM3 as well as the kinase GST-STK25.|More recently, the Golgi matrix protein GM130 was shown to function as a scaffold protein for STK25 and to activate STK25 through stimulation of autophosphorylation." SIGNOR-248711 CDC20 protein Q12834 UNIPROT UBE2S protein Q16763 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 19822757 t lperfetto "Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity" SIGNOR-265082 SOD2 protein P04179 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-272281 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 COL2A1 protein P02458 UNIPROT "A10/b1 integrin" complex SIGNOR-C167 SIGNOR "up-regulates activity" binding 9606 BTO:0000249 25169886 t lperfetto "Isolation, cloning, and sequence analysis of the integrin subunit alpha10, a beta1-associated collagen binding integrin expressed on chondrocytes." SIGNOR-253347 SMARCB1 protein Q12824 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-270747 MTNR1B protein P49286 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-256986 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 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 NR3C1 protein P04150 UNIPROT STAT5A protein P42229 UNIPROT up-regulates 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-44376 CDK1 protein P06493 UNIPROT CUX1 protein P39880 UNIPROT down-regulates phosphorylation Ser1237 TEYSQGAsPQPQHQL 9606 11584018 t lperfetto "Phosphorylation of serines 1237 and 1270 caused inhibition of dna binding in vitro. In cotransfection studies, cyclin a-cdk1 inhibited cdp/cux stable dna binding and prevented repression of the p21(waf1) reporter." SIGNOR-110908 PRKG1 protein Q13976 UNIPROT 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 "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-186788 MSX1 protein P28360 UNIPROT TBP protein P20226 UNIPROT "down-regulates activity" binding -1 8700832 t 2 miannu "Msx-1 is a potent transcriptional repressor and that this activity is independent of its DNA binding function. Here we show that Msx-1 interacts directly with the TATA binding protein (TBP) but not with several other general transcription factors. This interaction is mediated by the Msx-1 homeodomain, specifically through residues in the N-terminal arm. These same N-terminal arm residues are required for repression by Msx-1, suggesting a functional relationship between TBP association and transcriptional repression." SIGNOR-240401 "Mitochondrial respiratory chain complex IV" complex SIGNOR-C280 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-262140 SOD2 protein P04179 UNIPROT dioxygen smallmolecule CHEBI:15379 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-272282 YAP1 protein P46937 UNIPROT TEAD1 protein P28347 UNIPROT up-regulates binding 9606 23431053 t "Crystallographic data revealed that the N-terminal TEAD-binding domain of YAP wraps around a globular structure formed by the C-terminal domains of TEAD1, 2 and 4" gcesareni "When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14." SIGNOR-201465 SOD2 protein P04179 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-272283 SLN protein O00631 UNIPROT ATP2A1 protein O14983 UNIPROT "down-regulates activity" binding 9606 28487373 t lperfetto "These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity." SIGNOR-265929 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 CSNK1E protein P49674 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto "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-227976 Y-27632 chemical CHEBI:75393 ChEBI ROCK2 protein O75116 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207893 PRKACA protein P17612 UNIPROT VASP protein P50552 UNIPROT unknown phosphorylation Thr278 LARRRKAtQVGEKTP -1 8182057 t miannu "The vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cAMP-dependent- (cAK) and cGMP-dependent protein kinase (cGK) in human platelets and other cardiovascular cells.‚  three VASP phosphorylation sites are phosphorylated by cAK and cGK. Thr, Ser I, and Ser 2 correspond to Thr278, Ser157, Ser239 of the VASP protein, respectively" SIGNOR-250065 DRD3 protein P35462 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-256845 PLK3 protein Q9H4B4 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Thr80 RMGSSEStDSGFCLD 9606 18167338 t lperfetto "Here, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cdc25a to promote its proteolysis in early cell-cycle phases. Phosphorylation by gsk-3beta requires priming of cdc25a, and this can be catalyzed by polo-like kinase 3 (plk-3)" SIGNOR-160228 GRM4 protein Q14833 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-264352 UBE2L3 protein P68036 UNIPROT NEDD4 protein P46934 UNIPROT "up-regulates activity" ubiquitination -1 19240029 t miannu "Only UbcH5 and Related Class I E2s Support Ubiquitination of S5a—UbcH5 belongs to the Class I family of E2s which contains a catalytic core (UBC domain) without a distinct Ub binding domain (38). To test whether other Class I E2s can also support ubiquitination of S5a, we assayed the ubiquitination of S5a with UbcH7 and the E3s, Nedd4, or Parkin. With either of these E3s, UbcH7 supported ubiquitination of S5a (Fig. 8, A and B). In addition, another Class I E2, Ubc4, a close homolog of UbcH5, supported ubiquitination of S5a by the APC, a multimeric Ring finger E3 responsible for cell cycle progression through mitosis (39) (Fig. 8C). Thus, multiple Class I E2s can support ubiquitination of S5a by various types of E3s (Table 1)." SIGNOR-272735 TRIM63 protein Q969Q1 UNIPROT TNNI1 protein P19237 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 19240029 t miannu "We used MuRF1 as the E3 as it functions with all these E2s to ubiquitinate one of its typical substrates, troponin I Although UbcH1 and UbcH13/Uev1a support ubiquitination of troponin I by MuRF1, these E2s do not support ubiquitination of S5a, unlike Class I E2s." SIGNOR-272736 ETF complex SIGNOR-C463 SIGNOR FADH2 smallmolecule CHEBI:17877 ChEBI "up-regulates quantity" "chemical modification" 9606 33450351 t miannu "ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a)." SIGNOR-269455 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 STAT3 protein P40763 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-235664 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 IRF5 protein Q13568 UNIPROT IL1B protein P01584 UNIPROT up-regulates "transcriptional regulation" 10090 26315890 f svumbaca "IL-1b was present in the sera of wild-type mice but was not detected in the sera of IRF5-/- mice" SIGNOR-255340 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 rauwolscine chemical CHEBI:48562 ChEBI HTR2B protein P41595 UNIPROT "down-regulates activity" "chemical inhibition" 10036 9459568 t miannu "These studies display the usefulness of [3H]rauwolscine as an antagonist radioligand for the cloned human 5-HT2B receptor. The data in Table 2 show the affinity of a number of compounds for the [3H]rauwolscine labeled human 5-HT2B receptor" SIGNOR-258690 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 MAPK3 protein P27361 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser112 AIKVEPAsPPYYSEK 9606 11733495 t gcesareni "Moreover, the inhibition of erks 1 and 2 with a mek inhibitor, u1026, lead to an inhibition in the decay of ppargamma proteins, indicating that serine phosphorylation influences the degradation of ppargamma in fat cells." SIGNOR-179404 FYN protein P06241 UNIPROT CTLA4 protein P16410 UNIPROT unknown phosphorylation Tyr218 CEKQFQPyFIPIN 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-251160 TG101209 chemical CHEBI:90304 ChEBI FLT3 protein P36888 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207260 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 TEK protein Q02763 UNIPROT TEK protein Q02763 UNIPROT "up-regulates activity" phosphorylation Tyr1102 MLEERKTyVNTTLYE 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-259834 "okadaic acid" chemical CHEBI:44658 ChEBI STK4 protein Q13043 UNIPROT up-regulates 9606 23493077 f gcesareni "Okadaic acid has been frequently used to enhance the phosphorylation of mst1 and mst2 and to trigger the activation of the hippo pathway." SIGNOR-201554 MAPK1 protein P28482 UNIPROT ELK1 protein P19419 UNIPROT "up-regulates activity" phosphorylation Ser389 LSPIAPRsPAKLSFQ 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-235471 MYC protein P01106 UNIPROT HNRNPA1 protein P09651 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20010808 t "We also demonstrate that the oncogenic transcription factor c-Myc upregulates transcription of PTB, hnRNPA1 and hnRNPA2," SIGNOR-268690 FFAR2 protein O15552 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-256946 TWIST1 protein Q15672 UNIPROT CD44 protein P16070 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002590 17487558 f miannu "Immunoblot analysis showed that HEY/si-TWIST cells exhibited decreased expression levels of CD29, CD44 and CD54 compared to those of HEY/si-scrambled cells" SIGNOR-255512 DNA_damage stimulus SIGNOR-ST1 SIGNOR TAOK1 protein Q7L7X3 UNIPROT up-regulates 9606 17396146 f lperfetto "These findings indicate that TAO kinases are regulators of p38-mediated responses to DNA damage and are intermediates in the activation of p38 by ATM." SIGNOR-226599 F3 protein P13726 UNIPROT "Factor FVIIa:TF" complex SIGNOR-C319 SIGNOR "form complex" binding 9606 BTO:0000131 32665005 t lperfetto "During vascular injury, TF is exposed to the blood, where it functions as a cofactor for the circulating zymogen factor VII (FVII). This TF:FVIIa complex can then bind and activate either factor IX (FIX) or factor X (FX), triggering a cascade that generates fibrin and activates platelets, resulting in a hemostatic plug at the site of injury." SIGNOR-263556 STAG2 protein Q8N3U4 UNIPROT TNF protein P01375 UNIPROT up-regulates 9606 14660624 f miannu "Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner." SIGNOR-119988 "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 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 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 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA9 protein Q9Y5G4 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-265678 nalbuphine chemical CHEBI:7454 ChEBI OPRK1 protein P41145 UNIPROT "up-regulates activity" "chemical activation" 10029 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-258658 PRKCA protein P17252 UNIPROT HABP4 protein Q5JVS0 UNIPROT "down-regulates activity" phosphorylation Thr375 GRGARGGtRGGRGRI 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-249252 ROMO1 protein P60602 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-267690 SPOP protein O43791 UNIPROT BMI1 protein P35226 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 15897469 t miannu "Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. To investigate whether BMI1 can form a complex with SPOP and CULLIN3 in vivo, we reconstituted the complex in 293HEK cells. We find that BMI1 readily immunoprecipitates both hemagglutinin (HA)-SPOP and CULLIN3, and, conversely, CULLIN3 immunoprecipitates BMI1 (Fig. 2a). Complex formation depends on the presence of SPOP, in accordance with BMI1 binding to the MATH domain of SPOP (Fig. 1b) and previously published data showing SPOP–CULLIN interaction by means of the BTB/POZ domain of SPOP (30)." SIGNOR-272658 STAT1 protein P42224 UNIPROT IL12A protein P29459 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-249499 Amyloid_fibril_formation phenotype SIGNOR-PH59 SIGNOR Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000590 11578751 f lperfetto "Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death" SIGNOR-251640 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 UMPS protein P11172 UNIPROT "orotidine 5'-phosphate(3-)" smallmolecule CHEBI:57538 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-253581 MAPK3 protein P27361 UNIPROT XPO5 protein Q9HAV4 UNIPROT "down-regulates activity" phosphorylation Ser497 GSLCSVFsPSFVQWE 9606 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-262982 P-TEFb complex SIGNOR-C238 SIGNOR MLLT3 protein P42568 UNIPROT "down-regulates quantity by destabilization" phosphorylation 9606 BTO:0000007 17135274 t miannu "Phosphorylation of Af9 and Enl by P-TEFb promotes their proteolysis" SIGNOR-266800 GCG protein P01275 UNIPROT LATS1 protein O95835 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-199202 ROS stimulus SIGNOR-ST2 SIGNOR GSTA4 protein O15217 UNIPROT up-regulates 9534 BTO:0004055 12646569 f lperfetto "We have also provided evidence that the mitochondrial GSTA4-4 level markedly increases in COS cells under oxidative stress conditions, suggesting its critical role in maintaining the GSH homeostasis under conditions of chemical and oxidative stress" SIGNOR-264797 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 6-bromo-3-(1-methyl-4-pyrazolyl)-5-(3-piperidinyl)-7-pyrazolo[1,5-a]pyrimidinamine chemical CHEBI:131165 ChEBI CHEK1 protein O14757 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206838 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT "up-regulates activity" phosphorylation Ser481 ILAKSPQsTRAVAPQ 9606 BTO:0000599 21189263 t lperfetto "ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking." SIGNOR-272293 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 NXPH1 protein P58417 UNIPROT NRXN1 protein P58400 UNIPROT up-regulates binding 9606 BTO:0000938 9856994 t gcesareni "Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1" SIGNOR-62699 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIA4 protein P48058 UNIPROT "up-regulates activity" "chemical activation" 9606 30825796 t miannu "In the mammalian brain the majority of fast excitatory neurotransmission is carried out by Œ±-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive ionotropic glutamate receptors located within the post-synaptic density of glutamatergic synapses" SIGNOR-264611 PRKCA protein P17252 UNIPROT ACO1 protein P21399 UNIPROT down-regulates phosphorylation Ser711 REFNSYGsRRGNDAV 9606 BTO:0000671 15636585 t gcesareni "Irp1 ser-711 is a phosphorylation site, critical for regulation of rna-binding and aconitase activities." SIGNOR-133188 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 CDK1 protein P06493 UNIPROT CDC25C protein P30307 UNIPROT up-regulates phosphorylation Thr48 VCPDVPRtPVGKFLG 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-78428 GSK3B protein P49841 UNIPROT EIF2B5 protein Q13144 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-175621 3-[2,4-diamino-7-(3-hydroxyphenyl)-6-pteridinyl]phenol chemical CHEBI:94691 ChEBI PIK3CG protein P48736 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-258300 SEPTIN2 protein Q15019 UNIPROT SEPT6/SEPT2 complex SIGNOR-C71 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-148889 FCN2 protein Q15485 UNIPROT MASP2 protein O00187 UNIPROT "up-regulates activity" binding 17204478 t lperfetto "In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2)" SIGNOR-263413 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR MACROH2A1 protein O75367 UNIPROT "up-regulates activity" monoubiquitination 9606 BTO:0000007 15897469 t miannu "BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. t present, we cannot discriminate the main role in vivo of the polyubiquitinated or monoubiquitinated MACROH2A1, because both modifications can be detected (Fig. 2 d and e and ref. 34).Importantly, RNAi-mediated knock-down of CULLIN3 or SPOP results in loss of MACROH2A1 from the inactivated X chromosome (Xi), leading to reactivation of the Xi in the presence of inhibitors of DNA methylation and histone deacetylation. No significant changes in protein stability were observed, suggesting that ubiquitination serves regulatory functions other than protein degradation of BMI1 and MACROH2A1" SIGNOR-272660 "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR BMI1 protein P35226 UNIPROT "up-regulates activity" ubiquitination 9606 BTO:0000007 15897469 t miannu "BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex. Polyubiquitination of endogenous BMI1 could not be detected, suggesting that only a small amount of the protein undergoes this modification. No significant changes in protein stability were observed, suggesting that ubiquitination serves regulatory functions other than protein degradation of BMI1 and MACROH2A1" SIGNOR-272661 SLC34A2 protein O95436 UNIPROT phosphate(3-) smallmolecule CHEBI:18367 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000671 11009570 t lperfetto "Three families of NPCs have been reported to date. The type I family consists of a single species (NaPi-1), which has thus far been found only in rabbit kidney.28 The type II family consists of six species homologues, NaPi 2 to 7, that are expressed predominantly in renal epithelial tissues.The type III family is the most recently identified and consists of two members, Pit-1 (also called Glvr-1) and Pit-2 (also called Ram-1).34" SIGNOR-270578 KTN1 protein Q86UP2 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 30683916 f miannu "Collectively, our findings revealed a novel mechanism wherein MALAT1 interacts with c-MYC to transactivate KTN1 for enhancing EGFR protein expression, which finally contributes to the development of cSCC." SIGNOR-259906 TP53 protein P04637 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR down-regulates 9606 BTO:0000452 7667317 f "P53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts" SIGNOR-255669 PFKP protein Q01813 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "down-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-266469 TNKS2 protein Q9H2K2 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-263384 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000801 17337443 t lperfetto "Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation." SIGNOR-153458 ASIP protein P42127 UNIPROT ATRN protein O75882 UNIPROT up-regulates binding 9606 BTO:0001253 11137996 t gcesareni "Attractin is a low-affinity receptor for agouti protein, but not agrp, in vitro and in vivo." SIGNOR-85496 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 SLC2A3 protein P11169 UNIPROT glucose chemical CHEBI:17234 ChEBI "up-regulates quantity" relocalization 9606 23506862 t miannu "GLUThe SLC2A3 gene encoding GLUT3 was first cloned from a human fetal skeletal muscle cell line (Kayano et al., 1988). It shares ~64% sequence identity with SLC2A1. GLUT3 has a higher apparent affinity (lower Km) and a higher maximum turnover number for glucose than the other Class 1 GLUT proteins, and its principal physiological substrate is clearly D-glucose T1 plays a critical role in cerebral glucose uptake as the major GLUT isoform expressed in brain endothelial cells." SIGNOR-267461 CDK4 protein P11802 UNIPROT MYOG protein P15173 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-176530 BMS-754807 chemical CHEBI:88339 ChEBI INSR protein P06213 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0001802 19996272 t lperfetto "BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR" SIGNOR-262026 PLG protein P00747 UNIPROT APOH protein P02749 UNIPROT "down-regulates activity" cleavage Lys336 HSSLAFWKTDASDVK 9606 BTO:0000131 9596664 t lperfetto "Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI." SIGNOR-266996 ITCH protein Q96J02 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR down-regulates ubiquitination 9606 BTO:0001253 10940313 t gcesareni "Itch binds to the n-terminal portion of the notch intracellular domain via its ww domains and promotes ubiquitination of notch through its hect ubiquitin ligase domain." SIGNOR-254331 RARB protein P10826 UNIPROT THRA protein P10827 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-133234 TRIM63 protein Q969Q1 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)." SIGNOR-272740 JUN protein P05412 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 18641051 f lperfetto "Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death." SIGNOR-253148 "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 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu86 ENTERTTeFWKQYVD 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-263696 PML-RARalpha "fusion protein" SIGNOR-FP2 SIGNOR SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 BTO:0001412 18025157 t "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-255749 GSK3B protein P49841 UNIPROT GYS1 protein P13807 UNIPROT "down-regulates activity" phosphorylation Ser645 RPASVPPsPSLSRHS 11427888 t "Glycogen synthase has multiple serines (residues 640, 644, 648 and 652) separated by three residues, and those Ser residues are phosphorylated sequentially by GSK3 from the C-terminal end after Ser 656 has been phosphorylated by casein kinase II." SIGNOR-251238 MAP2K2 protein P36507 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR up-regulates phosphorylation 9606 BTO:0000142 1411546 t "inferred from 70% of family members" gcesareni "The primary structure of mek, a protein kinase that phosphorylates the erk gene product" SIGNOR-269895 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 CSNK2A1 protein P68400 UNIPROT CALM1 protein P0DP23 UNIPROT "down-regulates activity" phosphorylation Ser82 RKMKDTDsEEEIREA -1 26675311 t miannu "Phosphorylation of CaM at four sites by CK2 was found to follow a sequential order, with Ser81 as the first, Thr79 as the second, and Ser101 or Thr117 as the third. We found that in the complex between CaM and CaMKII, residue E115 of CaM is strongly interacting with K299 of the kinase through forming a salt-bridge (PDB entry 1WEL), it is quite likely that the phosphorylation induced structural change can disrupt this interaction and negatively affect the binding between the two proteins" SIGNOR-266353 ATR protein Q13535 UNIPROT FANCA protein O15360 UNIPROT up-regulates phosphorylation Ser1449 AAPDADLsQEPHLF 9606 19109555 t lperfetto "The s1449a mutant failed to completely correct a variety of fa-associated phenotypes. The dna damage response is coordinated by phosphorylation events initiated by apical kinases atm (ataxia telangectasia mutated) and atr (atm and rad3-related), and atr is essential for proper fa pathway function. Serine 1449 is in a consensus atm/atr site" SIGNOR-182953 EP300 protein Q09472 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" acetylation Lys310 KRTYETFkSIMKKSP 9606 BTO:0002207 15152190 t gcesareni "Using acetylation assays, p300 was found to effectively acetylate RelA/p65 across the amino-acid region containing 1€“317" SIGNOR-238778 MDM2 protein Q00987 UNIPROT NOTCH4 protein Q99466 UNIPROT down-regulates ubiquitination 9606 BTO:0000149 21402876 t gcesareni "We demonstrate that the intracellular domain of notch 4 is targeted for ubiquitylation and hence degradation by the ubiquitin ligase mdm2." SIGNOR-172826 GALR3 protein O60755 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-256719 GATA1 protein P15976 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-254192 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 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 "perfluorooctane-1-sulfonic acid" chemical CHEBI:39421 ChEBI PPARA protein Q07869 UNIPROT "up-regulates activity" "chemical activation" 10090 BTO:0000011 16731579 t miannu "Human, mouse, and rat PPARα were activated by PFOA isomers and PFOS." SIGNOR-268789 CDK1 protein P06493 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser432 SAYGGLTsPGLSYSL 9606 9524113 t lperfetto "With regard to k8 phosphorylation at ser-431, it increases dramatically upon stimulation of cells with epidermal growth factor (egf) or after mitotic arrest and is the major k8 phosphorylated residue after incubating k8 immunoprecipitates with mitogen-activated protein or cdc2 kinases." SIGNOR-56054 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM64B protein A6NI03 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-271271 ADCY2 protein Q08462 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-265004 NTF4 protein P34130 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-85117 MLF1 protein P58340 UNIPROT TP53 protein P04637 UNIPROT up-regulates 9606 15861129 f miannu "Mlf1 induces p53-dependent cell cycle arrest" SIGNOR-135943 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 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 ITGB2 protein P05107 UNIPROT "Av/b2 integrin" complex SIGNOR-C176 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-253204 TWIST2 protein Q8WVJ9 UNIPROT MYB protein P10242 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-255495 F2 protein P00734 UNIPROT Fibrinogen complex SIGNOR-C311 SIGNOR "up-regulates activity" cleavage 9606 BTO:0000131 29880919 t lperfetto "Thrombin is a key enzyme in the pathway and cleaves fibrinogen to fibrin, which spontaneously forms the insoluble polymer that is the basis for the haemostatic plug." SIGNOR-263525 prednisolone chemical CHEBI:8378 ChEBI NR3C1 protein P04150 UNIPROT up-regulates "chemical activation" 9606 8335191 t "Crohn's Disease" gcesareni SIGNOR-251701 SIRT6 protein Q8N6T7 UNIPROT CLOCK/BMAL1 complex SIGNOR-C195 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 25083875 t miannu "SIRT6 is involved in circadian control of gene expression and metabolism. SIRT6 Interacts with CLOCK:BMAL1 and Controls Their Chromatin Recruitment. SIRT6 physically interacts with CLOCK and BMAL1, individually or together, as shown by coimmunoprecipitation (co-IP) (Figures 4A and 4B). SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1." SIGNOR-268157 PRKCA protein P17252 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-248913 DAGLA protein Q9Y4D2 UNIPROT 2-arachidonoylglycerol smallmolecule CHEBI:52392 ChEBI "up-regulates quantity" "chemical modification" 9606 26787883 t miannu "Diacylglycerol lipases (DAGLŒ± and DAGLŒ≤) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol." SIGNOR-264264 "1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-)" smallmolecule CHEBI:57923 ChEBI "1-phosphatidyl-1D-myo-inositol 5-phosphate(3-)" smallmolecule CHEBI:57795 ChEBI "up-regulates quantity" "precursor of" 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-269806 CC2D1A protein Q6P1N0 UNIPROT RAD21 protein O60216 UNIPROT "up-regulates activity" binding 20171170 t centrosome 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 centrosome, it regulates spindle pole localization of the cohesin subunit Scc1, thereby mediating centriole cohesion during mitosis." SIGNOR-268294 PRKACA protein P17612 UNIPROT AURKA protein O14965 UNIPROT "up-regulates activity" phosphorylation Thr288 APSSRRTtLCGTLDY -1 11039908 t miannu "Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro." SIGNOR-250337 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 CXCL12 protein P48061 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 BTO:0000093 15882617 f lperfetto "Stromal fibroblast-derived SDF-1 enhances tumor growth both by stimulating angiogenesis through recruiting circulating EPCs into the tumor mass (endocrine effect) and by direct paracrine stimulation of tumor cells through CXCR4 expressed on carcinoma cells" SIGNOR-252267 POLD1 protein P28340 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-265518 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 Kindlin proteinfamily SIGNOR-PF48 SIGNOR "AX/b2 integrin" complex SIGNOR-C171 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-259026 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 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 "1-phosphatidyl-1D-myo-inositol 4-phosphate" smallmolecule CHEBI:17526 ChEBI "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-260675 SH2B1 protein Q9NRF2 UNIPROT CD79B protein P40259 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000776 "SIGNOR-C433; SIGNOR-C434; SIGNOR-C435; SIGNOR-C436" 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268458 IL13 protein P35225 UNIPROT IL4R protein P24394 UNIPROT "up-regulates activity" binding 9606 19880493 t lperfetto "IL-4 and IL-13 have overlapping but distinct effects on MFs, dependent on a common IL-4R, with profound changes in the expression of a range of cellular proteins and functions broadly implicated in the regulation of inflammation and repair." SIGNOR-249528 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 NUP210 protein Q8TEM1 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-262072 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 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 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 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1951 SPGYSPTsPTYSLTS 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-269341 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 E2F1 protein Q01094 UNIPROT TYMS protein P04818 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-253863 MAPK1 protein P28482 UNIPROT RUNX1 protein Q01196 UNIPROT "up-regulates activity" phosphorylation Thr273 SPSVHPAtPISPGRA 9606 16046550 t "The effect has been demonstrated using Q01196-8" 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-138981 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 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM21 protein P19474 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-271063 bevacizumab antibody DB00112 DRUGBANK VEGFA protein P15692 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 15961063 t miannu "Clinical trials with VEGF inhibitors in a variety of malignancies are ongoing. Recently, a humanized anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the FDA as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy." SIGNOR-259884 SENP1 protein Q9P0U3 UNIPROT HIF1A protein Q16665 UNIPROT up-regulates desumoylation 9606 17981124 t miannu "Sumo-specific protease 1 is essential for stabilization of hif1alpha during hypoxia / our results support a model in which sumoylated hif1_ is unstable but can be stabilized when sumo is removed by senp1" SIGNOR-158891 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser396 DDKKAKTsTRSSAKT 9606 BTO:0000590 20679343 t lperfetto "Alzheimer disease neurons are characterized by extraneuronal plaques formed by aggregated amyloid-? Peptide and by intraneuronal tangles composed of fibrillar aggregates of the microtubule-associated tau protein. Tau is mostly found in a hyperphosphorylated form in these tangleswe find that three residues can be phosphorylated (ser-396, ser-400, and ser-404) by gsk3?" SIGNOR-167286 "Class I MHC:Antigen" complex SIGNOR-C426 SIGNOR CD8A protein P01732 UNIPROT "up-regulates activity" binding 9606 21954283 t scontino "Molecular recognition of pMHCI complexes is mediated primarily by clonally distributed TCRs expressed on the surface of CTLs. The coreceptor CD8 contributes to this antigen-recognition process by binding to a largely invariant region of the MHCI molecule and by promoting intracellular signaling, the effects of which serve to enhance TCR stimuli triggered by cognate ligands." SIGNOR-267991 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 AMPK complex SIGNOR-C15 SIGNOR RPTOR protein Q8N122 UNIPROT down-regulates phosphorylation Ser792 LTQSAPAsPTNKGVH 10090 SIGNOR-C15 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-263044 CSNK2A1 protein P68400 UNIPROT CTNNA1 protein P35221 UNIPROT down-regulates phosphorylation Ser641 TPEELDDsDFETEDF 9606 BTO:0000527 19941816 t gcesareni "We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641." SIGNOR-161847 "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 EGFL7 protein Q9UHF1 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates activity" binding 10090 BTO:0002881 19503073 t miannu "Here we have identified transmembrane receptors of the Notch family as EGFL7-binding molecules. Secreted EGFL7 binds to a region in Notch involved in ligand-mediated receptor activation, thus acting as an antagonist of Notch signalling. Expression of EGFL7 in neural stem cells (NSCs) in vitro decreased Notch-specific signalling and consequently, reduced proliferation and self-renewal of NSCs." SIGNOR-266860 CNTN6 protein Q9UQ52 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR up-regulates relocalization 9606 BTO:0000938 15082708 t gcesareni "Here, we establish that nb-3, a member of the f3/contactin family, acts as a novel notch ligand to participate in oligodendrocyte generation. Nb-3 triggers nuclear translocation of the notch intracellular domain and promotes oligodendrogliogenesis from progenitor cells and differentiation of oligodendrocyte precursor cells via deltex1." SIGNOR-254318 GNE protein Q9Y223 UNIPROT UDP-N-acetyl-alpha-D-glucosamine smallmolecule CHEBI:16264 ChEBI "down-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-266073 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 MAPK1 protein P28482 UNIPROT AHNAK protein Q09666 UNIPROT unknown phosphorylation Thr5794 REFSGPStPTGTLEF 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-262767 STK38L protein Q9Y2H1 UNIPROT ULK1 protein O75385 UNIPROT "down-regulates quantity" phosphorylation Ser495 GVLARKMsLGGGRPY 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-270348 AKT proteinfamily SIGNOR-PF24 SIGNOR RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 BTO:0000222 BTO:0000887;BTO:0001760 10576741 t gcesareni "The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex." SIGNOR-72669 PRKCA protein P17252 UNIPROT SRF protein P11831 UNIPROT down-regulates phosphorylation Ser162 LRRYTTFsKRKTGIM 10090 16537394 t lperfetto "Mimicking phosphorylation of serine-162, a target of protein kinase c-alpha, with an aspartic acid substitution (srf-s162d) completely inhibited srf-dna binding and blocked alpha-actin gene transcription pkc? Highly phosphorylated serine-162." SIGNOR-234461 SRC protein P12931 UNIPROT DAB1 protein O75553 UNIPROT "up-regulates activity" phosphorylation Tyr185 KQCEQAVyQTILEED 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-247072 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 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 DUSP3 protein P51452 UNIPROT MAPK3 protein P27361 UNIPROT "down-regulates activity" dephosphorylation Tyr204 HTGFLTEyVATRWYR 9534 BTO:0004055 10224087 t "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.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-248535 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 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 ATM protein Q13315 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-267661 TAC1 protein P20366 UNIPROT TACR2 protein P21452 UNIPROT up-regulates binding 9606 8925404 t gcesareni "The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag)." SIGNOR-44773 ZBTB16 protein Q05516 UNIPROT RSAD2 protein Q8WXG1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003846 19523849 t lperfetto "Promoter regions from the PLZF-regulated transcripts Rsad2 and Ifit2 were fused to luciferase and activity was measured after IFN treatment. Overexpression of PLZF in RCC1 or ACHN cells produced a dose-dependent induction of the reporter promoters. " SIGNOR-261023 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 ANK3 protein Q12955 UNIPROT SPTBN1 protein Q01082 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 17620337 t miannu "Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos. Ankyrin-G also recruits beta-2-spectrin to E-cadherin-beta-catenin complexes, thus providing a direct connection between E-cadherin and the spectrin/actin skeleton." SIGNOR-266711 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 BMPR1B protein O00238 UNIPROT SMAD1/5/8 proteinfamily SIGNOR-PF35 SIGNOR up-regulates phosphorylation 9606 9335504 t "inferred from 70% of family members" 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-269846 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 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 HDAC2 protein Q92769 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23836662 f miannu "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-254156 FYN protein P06241 UNIPROT SLAMF1 protein Q13291 UNIPROT "up-regulates activity" phosphorylation Tyr307 QDPCTTIyVAATEPV 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-251182 PRKACA protein P17612 UNIPROT KCNN2 protein Q9H2S1 UNIPROT down-regulates phosphorylation Ser464 QAIHQLRsVKMEQRK 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-145028 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 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr785 SINEMLStQALRLDE 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-154175 UBE2D2 protein P62837 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-272668 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 WNT5A protein P41221 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR down-regulates 9606 21078818 f lperfetto "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-227958 HRAS protein P01112 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. lysine residue 227 is essential for the interaction of ras with pi3k we show here, however, that in vivo there are marked quantitative differences in the ability of ki- and ha-ras to activate raf-1 and phosphoinositide 3 kinase. the mechanism of raf-1 activation is complex, but it is clear that one important role of ras is to recruit raf-1 to the plasma membrane where a series of events is initiated that ultimately leads to full raf-1 activation. These events include tyrosine, serine, and threonine phosphorylation plus interactions with ras, phospholipids, 14-3-3 proteins and their associated proteins, and possibly dimerization." SIGNOR-175195 CIITA protein P33076 UNIPROT HLA-DRB1 protein P01911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-253976 PLK1 protein P53350 UNIPROT YY1 protein P25490 UNIPROT up-regulates phosphorylation Thr39 PVETIETtVVGEEEE 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-200087 RPL23A protein P62750 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-262476 DPP3 protein Q9NY33 UNIPROT Angiotensin-2 protein P01019-PRO_0000032458 UNIPROT "down-regulates quantity by destabilization" cleavage -1 34770898 t miannu "Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. The binding of Ang II to hDPP III may lead to changes in the shape and size of subsite S1, an important catalytic site, so as to promote the decomposition of the substrate." SIGNOR-268463 SP1 protein P08047 UNIPROT SLC5A8 protein Q8N695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20082847 t "Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription." SIGNOR-254059 (R)-adrenaline smallmolecule CHEBI:28918 ChEBI LATS1 protein O95835 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-199196 IGFBP5 protein P24593 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR "up-regulates activity" 10090 BTO:0000165 18762576 f "These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop." SIGNOR-255940 GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates binding 9606 22083140 t lperfetto "The role of apc is less clear, but it clearly binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex." SIGNOR-227881 DCAF7 protein P61962 UNIPROT DYRK1A protein Q13627 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 14593110 t Giorgia "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-260630 MYH9 protein P35579 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0004953 32685004 t miannu "Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo." SIGNOR-269284 CEBPB protein P17676 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000738;BTO:0001370 12493739 f mianu "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 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 GAR1 protein Q9NY12 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-263333 sedoheptulose smallmolecule CHEBI:16802 ChEBI "sedoheptulose 7-phosphate" smallmolecule CHEBI:15721 ChEBI "up-regulates quantity" "precursor of" 9606 22682222 t miannu "The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. CARKL bridges glycolysis and PPP by catalyzing the formation of S7P from sedoheptulose" SIGNOR-268137 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 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 POLR2F protein P61218 UNIPROT "RNA Polymerase III" complex SIGNOR-C389 SIGNOR "form complex" binding 9606 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-266139 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 CTF1 protein Q16619 UNIPROT GCH1 protein P30793 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12859689 f miannu "CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA." SIGNOR-252218 IL20 protein Q9NYY1 UNIPROT IL22RA1 protein Q8N6P7 UNIPROT up-regulates binding 9606 11163236 t gcesareni "An IL-20 receptor was identified as a heterodimer of two orphan class II cytokine receptor subunits. Both receptor subunits are expressed in skin and are dramatically upregulated in psoriatic skin. Taken together, these results demonstrate a role in epidermal function and psoriasis for IL-20, a novel cytokine identified solely by bioinformatics analysis." SIGNOR-151877 BMP10 protein O95393 UNIPROT ACVRL1 protein P37023 UNIPROT up-regulates binding 9606 17068149 t acerquone "Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis" SIGNOR-150201 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation Ser255 ELSPTTLsPVNHSLD 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-244727 ZFP36 protein P26651 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by destabilization" "post transcriptional regulation" 25815583 t "The TTP binding site in the 3′ UTR of MyoD would permit TTP-mediated mRNA decay" SIGNOR-253597 H4C1 protein P62805 UNIPROT BRD4 protein O60885 UNIPROT "up-regulates activity" relocalization 9606 acetylation:Lys21;Lys17 GGAKRHRkVLRDNIQ;GLGKGGAkRHRKVLR 27991587 t lperfetto "BRD4 interacts with acetylated nucleosomes via both its BD1 and BD2 domains. Our results indicate that BRD4-BD1 binds to nucleosomes through the acetylated histone H4 tail and does not additionally interact with DNA." SIGNOR-262065 calcium(2+) smallmolecule CHEBI:29108 ChEBI SYT1 protein P21579 UNIPROT "up-regulates activity" "chemical activation" 9606 16679567 t miannu "Because synaptotagmins bind SNAP-25 and Ca2+, SNAP-25 has also been linked to the Ca2+ dependence of exocytosis (42). One model suggests that synaptotagmin blocks full SNARE fusion pore formation by binding to t-SNAREs.This interaction prevents fusion from occurring in the absence of calcium. When Ca2+ is present, synaptotagmin releases the t-SNAREs so they can fully zipper with the v-SNARE, leading to fusion" SIGNOR-263976 MYLIP protein Q8WY64 UNIPROT MYLIP protein Q8WY64 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0001976 14550572 t miannu "MIR contains, beside the ERM domain, a RING zinc finger region.  The present study shows that the ubiquitin ligase activity of the RING can also be directed towards the protein itself indicating that the degradation of MIR can be regulated by autoubiquitination." SIGNOR-271480 Viral_replication stimulus SIGNOR-ST23 SIGNOR Viral_dsRNA stimulus SIGNOR-ST21 SIGNOR up-regulates 9606 31226023 f miannu "Double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses." SIGNOR-260587 APC protein P25054 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR "form complex" binding 9606 BTO:0000007 20181957 t miannu "Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). " SIGNOR-271949 SRC protein P12931 UNIPROT CELF2 protein O95319 UNIPROT "up-regulates activity" phosphorylation Tyr63 LKELFEPyGAVYQIN -1 17855367 t miannu "Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA." SIGNOR-263195 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 dabrafenib chemical CHEBI:75045 ChEBI CDK16 protein Q00536 UNIPROT "down-regulates activity" "chemical inhibition" 9606 29112787 t Monia "We have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. We confirmed NEK9 to be a potent target of dabrafenib by in vitro kinase assays, with inhibition of NEK9 observed in the single-digit nanomolar range." SIGNOR-261073 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 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 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 PRKCA protein P17252 UNIPROT 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-260886 ARAF protein P10398 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation 9606 21779497 t gcesareni "Active raf phosphorylates mek." SIGNOR-175142 NEDD4L protein Q96PU5 UNIPROT SCN1A protein P35498 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-253457 AKT proteinfamily SIGNOR-PF24 SIGNOR KHSRP protein Q92945 UNIPROT "down-regulates activity" phosphorylation Ser193 GLPERSVsLTGAPES 9606 17177604 t lperfetto "Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome." SIGNOR-151216 CDK1 protein P06493 UNIPROT DLG1 protein Q12959 UNIPROT unknown 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." SIGNOR-182757 MAPK8 protein P45983 UNIPROT LAT protein O43561 UNIPROT down-regulates phosphorylation Thr184 PSAPALStPGIRDSA 9606 15192708 t "The effect has been demonstrated using Q43561-2" 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.Mutational analysis revealed that t155 but not t94 or t140 is the site of jnk-mediated phosphorylation (figure 2b). Erk also phosphorylated lat at t155 (figure 2c), whereas p38, which was able to phosphorylate atf2, failed to induce threonine phosphorylation of lat (figure 2d). These results indicate that lat is directly phosphorylated by erk and jnk at the same site, t155." SIGNOR-125774 Diprenorphine chemical CHEBI:4650 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-258790 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 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR CEBPA protein P49715 UNIPROT "down-regulates activity" binding 9606 BTO:0001271 11283671 t apalma "Here we show that AML1–ETO blocks C/EBPα –dependent activation of its own promoter and thereby inhibits autoregulation." SIGNOR-255672 "9,11-Methanoepoxy PGH2" chemical CID:5311493 PUBCHEM TBXA2R protein P21731 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-257589 BAZ2B protein Q9UIF8 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" binding 9606 acetylation:Lys15 ARKSTGGkAPRKQLA 31999386 t 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-266622 FOXS1 protein O43638 UNIPROT FOXO4 protein P98177 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9913 BTO:0004577 18288644 t Luana "Fkhl18 suppressed the transcriptional activity of FoxO3a and FoxO4." SIGNOR-261611 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 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu73 EEKCSFEeAREVFEN 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-263693 "Rigosertib sodium" chemical CID:23696523 PUBCHEM PLK1 protein P53350 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195028 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 SOD1 protein P00441 UNIPROT VDAC1 protein P21796 UNIPROT "down-regulates activity" binding 10090 BTO:0001279 20797535 t "P00441:p.Gly38Arg (mutation causing interaction)" "Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane." SIGNOR-262798 PRKN protein O60260 UNIPROT SEPTIN5 protein Q99719 UNIPROT "down-regulates quantity by destabilization" polyubiquitination -1 14559152 t miannu "SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains.Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins." SIGNOR-272673 PIK3R3 protein Q92569 UNIPROT TP53 protein P04637 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 32606738 t miannu "N this study, we aimed to explore the interaction of p55PIK with p53 and the role of p55PIK in regulating p53-dependent apoptosis in cancer cells. We found that p55PIK directly binds to the DBD domain of p53 via N24 domain. Moreover, the upregulation of p55PIK expression increases transcriptional levels of p53-dependent apoptosis-related genes including GADD45α, S100A9, MDM2 and AIP1. Furthermore, synthetic N24 translocated to nucleus can significantly inhibit cancer cell growth." SIGNOR-261492 CHAF1B protein Q13112 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 15657354 f miannu "Chromatin immunoprecipitation analysis of methyl-CpG binding domain containing proteins detected a greater amount of MeCP2, MBD1, and CAF-1 bound to the MGMT promoter in MGMT-silenced cells. Our findings implicate specific MBD proteins in methylation-mediated transcriptional silencing of MGMT." SIGNOR-254570 IDH1 protein O75874 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "down-regulates quantity" 9606 26178471 t lperfetto "Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)" SIGNOR-253137 EDNRA protein P25101 UNIPROT GNAS protein Q5JWF2 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-256780 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 SP7 protein Q8TDD2 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23530031 f miannu "Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation." SIGNOR-254219 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 PIK3R3 protein Q92569 UNIPROT PIK3CA protein P42336 UNIPROT up-regulates binding 9606 9415396 t gcesareni "The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha" SIGNOR-53597 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 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 PRKCA protein P17252 UNIPROT CD5 protein P06127 UNIPROT up-regulates phosphorylation Thr434 MSFHRNHtATVRSHA 9606 11123317 t amattioni "Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation." SIGNOR-85175 MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR MEK1/2 proteinfamily SIGNOR-PF25 SIGNOR down-regulates 9606 18481201 f lperfetto "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-244877 ULK1 protein O75385 UNIPROT SEC23B protein Q15437 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser186 SCEGISKsYVFRGTK 9606 BTO:0000007 30596474 t lperfetto "Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation." SIGNOR-265285 BCL2 protein P10415 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 1286168 f lperfetto "Bcl-2 functions to inhibit apoptosis in a variety of in vitro and in vivo experiments, suggesting interference with a central mechanism of apoptosis" SIGNOR-249611 HSD3B1 protein P14060 UNIPROT 17alpha-hydroxyprogesterone smallmolecule CHEBI:17252 ChEBI "up-regulates quantity" "chemical modification" 9606 BTO:0000050 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-268636 MAPK9 protein P45984 UNIPROT ATF2 protein P15336 UNIPROT up-regulates phosphorylation Thr71 IVADQTPtPTRFLKN 9606 20068231 t gcesareni "Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity." SIGNOR-163266 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 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT "down-regulates activity" phosphorylation Ser97 TIAESEDsQESVDSV 9606 15073328 t lperfetto "Individual ala substitutions at thr-100, ser-111, or ser-121 inhibited atm-catalyzed phosphate incorporationatm phosphorylated creb in vitro and in vivophosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp)" SIGNOR-124043 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation Ser325 LTSVSRGsSLKILSK 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-260899 ATM protein Q13315 UNIPROT CREB1 protein P16220 UNIPROT down-regulates phosphorylation Ser107 SVDSVTDsQKRREIL 9606 15073328 t lperfetto "Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potential," SIGNOR-124047 PRKCA protein P17252 UNIPROT MARCKS protein P29966 UNIPROT "down-regulates activity" phosphorylation Ser163 KRFSFKKsFKLSGFS -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-249650 HSD3B2 protein P26439 UNIPROT progesterone smallmolecule CHEBI:17026 ChEBI "up-regulates quantity" "chemical modification" 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-268634 TXK protein P42681 UNIPROT CTLA4 protein P16410 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr201 SPLTTGVyVKMPPTE 9606 9813138 t lperfetto "We demonstrate that rlk (resting lymphocyte kinase) is capable of phosphorylating ctla-4 at the yvkm motif. Consistent with this finding, rlk is capable of providing conditions for the binding of the sh2 domains of pi 3-kinase to the receptor. Ctla-4 is therefore the first known substrate for rlk suggesting the possibility that this kinase may participate in ctla-4 function" SIGNOR-61624 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 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 N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide chemical CHEBI:94525 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-257932 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 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 EIF2AK2 protein P19525 UNIPROT EIF2AK2 protein P19525 UNIPROT up-regulates phosphorylation Ser83 NKEKKAVsPLLLTTT 9606 11152499 t tpavlidou "Taken together, these results show that pkr is autophosphorylated on serine 83 and threonines 88, 89, and 90, that this autophosphorylation may enhance kinase activation, and that the inhibition of pkr by hcv e2 is not solely due to duplication of and competition with these autophosphorylation sites." SIGNOR-85769 POU3F4 protein P49335 UNIPROT POU3F2 protein P20265 UNIPROT "up-regulates activity" binding -1 9105675 t miannu "POU proteins (Brain-1, Brain-2, Brain-4 and SCIP) serve as transcriptional transactivators. if they were to form homomeric and heteromeric complexes with each other, depending on the particular combination, they might have different DNA-binding specificities and, thus, activate different genes." SIGNOR-220080 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 WNK3 protein Q9BYP7 UNIPROT SLC12A5 protein Q9H2X9 UNIPROT "down-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-264628 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 SIRT1 protein Q96EB6 UNIPROT SMAD7 protein O15105 UNIPROT down-regulates deacetylation Lys64 RAGCCLGkAVRGAKG 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-150595 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 GDC-0879 chemical CHEBI:83405 ChEBI BRAF protein P15056 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192592 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 ITK protein Q08881 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation 9606 BTO:0000782 20519342 t gcesareni "In t cells, the predominant tec kinase is itk, which functions downstream of the t-cell receptor to regulate phospholipase c-gamma." SIGNOR-165803 PP121 chemical CHEBI:50915 ChEBI PIK3CB protein P42338 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206295 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 PRKACA protein P17612 UNIPROT IGF2R protein P11717 UNIPROT unknown phosphorylation Ser2347 TTCCRRSsNVSYKYS 9606 8318012 t lperfetto "Pka phosphorylates the cytoplasmic mpr 300 domain at ser20 and at a non-identified site," SIGNOR-37839 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 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 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 PPY protein P01298 UNIPROT NPY4R protein P50391 UNIPROT up-regulates binding 9606 BTO:0000142 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-24230 FOXA1 protein P55317 UNIPROT KRT7 protein P08729 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002861 20043065 f miannu "These results suggest that FOXA1 induces not only KRT7 but also LOXL2 in a subset of poor prognostic ESCCs with metastatic lymph nodes. FOXA1 siRNA treatment of esophageal cancer cells reduced the mRNA level of both KRT7 and a stabilizer of epithelial-mesenchymal transition (EMT) regulator LOXL2, and that both FOXA1 and LOXL2 siRNAs reduced invasion and migration of ESCC cells." SIGNOR-254167 MAPK13 protein O15264 UNIPROT EEF2K protein O00418 UNIPROT "down-regulates activity" phosphorylation Ser396 TFDSLPSsPSSATPH -1 11500363 t miannu "eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. eEF2K[S359A] was phosphorylated (presumably at Ser396) by the high concentrations of SAPK4/p38 used in this experiment. However, the inhibition of eEF2K under these conditions was reduced from 82% in the wild-type enzyme to 19% in eEF2K[S359A]" SIGNOR-250089 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 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 TEC protein P42680 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-262235 UVRAG protein Q9P2Y5 UNIPROT BECN1 protein Q14457 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 17106237 t lperfetto "UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis." SIGNOR-150825 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates phosphorylation Ser1766 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-120032 TLR7 protein Q9NYK1 UNIPROT IFNA1 protein P01562 UNIPROT "up-regulates quantity" 9606 BTO:0004625 15661881 f miannu "TLR7 in pDC is functionally associated with the production of IFN-α- and IFN-regulated cytokines, similar to the role of TLR9." SIGNOR-259248 Ub:E2 complex SIGNOR-C497 SIGNOR ZNF511 protein Q8NB15 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-271278 SLC30A9 protein Q6PML9 UNIPROT NUMB protein P49757 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 11782429 t lperfetto "Lnx functions as a ring type e3 ubiquitin ligase that targets the cell fate determinant numb for ubiquitin-dependent degradation." SIGNOR-113704 AV412 chemical CID:11700696 PUBCHEM EGFR protein P00533 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190050 zotepine chemical CHEBI:32316 ChEBI DRD4 protein P21917 UNIPROT "down-regulates activity" "chemical inhibition" 10029 BTO:0000246 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-258555 FKBP5 protein Q13451 UNIPROT NR3C1 protein P04150 UNIPROT down-regulates binding 9606 25790864 t gcesareni "When not associated with glucocorticoids, glucocorticoid receptors are predominantly found in the cytoplasm as part of a multimeric molecular chaperone complex that includes several heat shock proteins (HSPs), such as HSP70 and HSP90, the HSP90_binding protein p23 (also known as PTGES3) and proteins that help to bind HSP90 such as FK506_binding protein 5 (FKBP5)." SIGNOR-251666 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 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 CAD protein P27708 UNIPROT "carbamoyl phosphate(2-)" smallmolecule CHEBI:58228 ChEBI "up-regulates quantity" "chemical modification" 9606 24332717 t "In animals, the first three reactions of the pathway are catalyzed by CAD, an 240 kDa multifunctional protein that combines glutamine-dependent carbamyl phosphate synthetase (GLNCPSase), aspartate transcarbamylase (ATCase), and dihydroorotase (DHOase) activities" SIGNOR-267194 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 CAMK2B protein Q13554 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 t gcesareni "Stimulation via cd2 activated multiple signal transduction pathways, resulting in phosphorylation of distinct sites of stathmin. Ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells." SIGNOR-59358 CDX2 protein Q99626 UNIPROT LCT protein P09848 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9148757 t "By electrophoretic mobility-shift assay it was shown that the factor Cdx-2 (a homoeodomain-protein related to caudal) binds to a TTTAC sequence in the CE-LPH1. Furthermore it was demonstrated that Cdx-2 is able to activate reporter gene transcription by binding to CE-LPH1." SIGNOR-253964 PIM1 protein P11309 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates phosphorylation Ser186 RQRKRHKsDSISLSF 9606 BTO:0000785 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-178619 PPP3CC protein P48454 UNIPROT DNM2 protein P50570 UNIPROT unknown dephosphorylation Ser764 LQSASSHsPTPQRRP 10116 20496096 t "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-248508 PPP3CB protein P16298 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-84044 CDK2 protein P24941 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-180763 PRKACA protein P17612 UNIPROT LIPE protein Q05469 UNIPROT "up-regulates activity" phosphorylation Ser853 IAEPMRRsVSEAALA 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-249202 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 RAD21 protein O60216 UNIPROT ERG protein P11308 UNIPROT "down-regulates activity" relocalization 9606 BTO:0001545 26607380 t miannu "Large-scale AML genome re-sequencing efforts have identified novel recurrently mutated genes, including the members of the cohesin complex (RAD21, SMC3, SMC1A, and STAG2), implicated in the pathogenesis of this disease.Using ATAC-seq, we determined that mutant cohesin lead to a state of elevated chromatin accessibility and higher predicted binding at transcription factor binding sites for ERG, GATA2, and RUNX1. Moreover, using ChIP-Seq, we formally demonstrated increased binding of GATA2 and RUNX1 to these sites. Finally, we demonstrated that knockdown of these three TFs in human HSPC can revert the differentiation block induced by mutant cohesin. These results support a model in which mutant cohesin impairs hematopoietic differentiation and enforces stem cell programs through the modulation of ERG, GATA2, and RUNX1 chromatin accessibility, expression, and activity." SIGNOR-261515 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 (S)-adrenaline smallmolecule CHEBI:40751 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-258454 SGF29 protein Q96ES7 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-269572 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 CDK12 protein Q9NYV4 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1861 TPTSPKYsPTSPKYS 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-176793 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 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD1 protein Q15797 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-270214 UBE3A protein Q05086 UNIPROT PSMD4 protein P55036 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys135 AKRLKKEkVNVDIIN -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-272747 SOD1 protein P00441 UNIPROT dioxygen smallmolecule CHEBI:15379 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-272286 CSNK1E protein P49674 UNIPROT CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser45 GATTTAPsLSGKGNP 9606 12000790 t gcesareni "However, ck1epsilon 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 beta-catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated ck1epsilon as a candidate s45-kinase in several assays, both in vitro and in vivo." SIGNOR-87448 NMB protein P08949 UNIPROT NMBR protein P28336 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." SIGNOR-107022 N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-(2,6-dimethoxyphenoxy)ethanamine chemical CHEBI:64098 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-258472 MAPK13 protein O15264 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser33 LPENNVLsPLPSQAM 9606 BTO:0000093 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-72687 PRKCH protein P24723 UNIPROT PRKD2 protein Q9BZL6 UNIPROT up-regulates phosphorylation Ser876 QGLAERIsVL 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-89431 FOXN4 protein Q96NZ1 UNIPROT PTF1A protein Q7RTS3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0001175 17075007 f Luana " We conclude that Foxn4 functions upstream of Ptf1a to activate its expression, thereby regulating the generation of amacrine and horizontal cells during retinogenesis." SIGNOR-261608 GSK3B protein P49841 UNIPROT 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-260016 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 GABRG2 protein P18507 UNIPROT "GABA-A (a3-b1-g2) receptor" complex SIGNOR-C332 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-263758 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser713 GAEIVYKsPVVSGDT 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-249345 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 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 MYOF protein Q9NZM1 UNIPROT Myoblast_fusion phenotype SIGNOR-PH98 SIGNOR up-regulates 10090 16280346 f "These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes" SIGNOR-255973 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 AKT2 protein P31751 UNIPROT NFKB1 protein P19838 UNIPROT up-regulates 9606 17604717 f gcesareni "Several studies have demonstrated that akt signaling can activate the nf-kb transcription factor downstream of a variety of stimuli, such as tumor necrosis factor (tnfalfa)" SIGNOR-156530 EGFR protein P00533 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation 9606 BTO:0000150 11887937 t gcesareni "Activation of estrogen receptor-alpha (eralpha) by growth factors in the absence of estrogen is a well-documented phenomenon.Egfr tyrosine kinase in vitro stimulated the phosphorylation of recombinant er" SIGNOR-115734 BMPR1B protein O00238 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-255265 "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 COL4A6 protein Q14031 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-272352 CTNNB1 protein P35222 UNIPROT CCND1 protein P24385 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 15735151 f gcesareni "Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), 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-134216 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 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 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 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 AR protein P10275 UNIPROT BTG2 protein P78543 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-253674 SMAD6 protein O43541 UNIPROT BMPR1A protein P36894 UNIPROT down-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-236861 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 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 LCK protein P06239 UNIPROT SH2D2A protein Q9NP31 UNIPROT "up-regulates activity" phosphorylation Tyr305 GEAPSNIyVEVEDEG 9606 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-262890 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 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 SMURF1 protein Q9HCE7 UNIPROT KRT36 protein O76013 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-272695 PPP1CB protein P62140 UNIPROT NOS3 protein P29474 UNIPROT "up-regulates activity" dephosphorylation Thr495 TGITRKKtFKEVANA 9606 BTO:0001176 19036824 t "The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation" SIGNOR-248574 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 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 CSNK2B protein P67870 UNIPROT BRCA1 protein P38398 UNIPROT unknown phosphorylation Ser1572 ESGISLFsDDPESDP -1 10403822 t llicata "Subsequent studies showed that BRCA1 was phosphorylated in vitro by CK2. An analysis by site directed mutagenesis of BRCA1 showed that in vitro phosphorylation by CK2 required a serine at aa1572. These data implicate CK2 as a potential mediator of BRCA1 activity." SIGNOR-251055 STAT5A protein P42229 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001096 14530308 f apalma "Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells" SIGNOR-256583 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 PPP1R8 protein Q12972 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" binding -1 1322907 t "We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity." SIGNOR-255657 CBLB protein Q13191 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" ubiquitination 9606 BTO:0000007 11375397 t lperfetto "Cbl proteins function as ubiquitin protein ligases for the activated epidermal growth factor receptor and, thus, negatively regulate its activity." SIGNOR-236519 CENPA protein P49450 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-263702 PKA proteinfamily SIGNOR-PF17 SIGNOR CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser100 HLSGRKLsLQERSQG 9606 22778263 t lperfetto "Pka phosphorylates ser-100, ser-495, and ser-511the camp/pka pathway can inhibit camkk2 activity" SIGNOR-198146 PMCH protein P20382 UNIPROT MCHR2 protein Q969V1 UNIPROT up-regulates binding 9606 BTO:0000142 10471841 t gcesareni "Upon several purification steps, followed by mass spectrometric analysis and peptide sequencing, the ligand was identified as melanin concentrating hormone (mch), revealing that the orphan slc-1 is the mch receptor." SIGNOR-70520 MDM2 protein Q00987 UNIPROT MDM4 protein O15151 UNIPROT down-regulates ubiquitination 9606 16511560 t lperfetto "The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2." SIGNOR-144970 AVPR1A protein P37288 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-256948 GSK3B protein P49841 UNIPROT EIF2B3 protein Q9NR50 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-175520 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 SEC23B protein Q15437 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-265288 "PAS complex" complex SIGNOR-C190 SIGNOR Multivesicular_body_assembly phenotype SIGNOR-PH83 SIGNOR up-regulates 9606 17556371 f miannu "Sac3 assembles with PIKfyve and ArPIKfyve in a stable ternary complex and controls PtdIns(3,5)P2 levels. We further demonstrate a key function for each of the three proteins in the biogenesis of ECV/MVB transport intermediates from early endosomes." SIGNOR-253532 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 mTORC1 complex SIGNOR-C3 SIGNOR EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Thr37 PPGDYSTtPGGTLFS 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-236694 FCER1 complex SIGNOR-C200 SIGNOR SRC_kinase_family proteinfamily SIGNOR-PF32 SIGNOR up-regulates 9606 BTO:0000830 16470226 f "Alessandro Palma" "It is clear that these initial signalling events involve coalescence of the aggregated receptors with specialized microdomains of the plasma membrane known as lipid rafts9, activation of SRC-family kinases and, subsequently, tyrosine phosphorylation of the receptor subunits" SIGNOR-254963 "Multiaminoacyl-tRNA synthetase" complex SIGNOR-C472 SIGNOR arginine smallmolecule CHEBI:29016 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-270365 PAK1 protein Q13153 UNIPROT ILK protein Q13418 UNIPROT up-regulates phosphorylation Thr173 DTFWKGTtRTRPRNG 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-154307 PRKCZ protein Q05513 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-249251 KPNA6 protein O60684 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. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling." SIGNOR-165343 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 TSPO2 protein Q5TGU0 UNIPROT VDAC1 protein P21796 UNIPROT "up-regulates activity" binding 9606 BTO:0000424 30061676 t miannu "Our results demonstrate the existence of a VDAC-TSPO2-ANT complex that mediates ATP release from RBCs. We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). . The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT." SIGNOR-261826 belinostat chemical CHEBI:61076 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-257742 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER3 protein P43115 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-257571 CDK8 protein P49336 UNIPROT E2F1 protein Q01094 UNIPROT down-regulates phosphorylation Ser375 PVDEDRLsPLVAADS 9606 18794899 t lperfetto "E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1." SIGNOR-181078 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 RHEB protein Q15382 UNIPROT FKBP8 protein Q14318 UNIPROT "down-regulates activity" "gtpase-activating protein" 9606 19222999 t lperfetto "Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1." SIGNOR-233568 HYDIN protein Q4G0P3 UNIPROT GATA4 protein P43694 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001086 32376282 t miannu "HYDIN promotes expression of Gata4 in cardiomyocyte differentiation. HYDIN functions as a positive regulator of human cardiomyocyte differentiation and promotes expression of cardiac contractile genes in hESC cells. This is mediated through GATA4, a critical transcription factor in heart development. Cardiac-specific Hydin knockdown in vivo leads to Gata4 downregulation and enhanced atrial septal defect (ASD) risk in mice. GATA4 is a fundamental TF in embryonic heart development and cardiac differentiation, and reduction in GATA4 function results in a diverse range of CHDs" SIGNOR-265479 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 (+)-pilocarpine chemical CHEBI:8207 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-258629 WWTR1 protein Q9GZV5 UNIPROT NKX2-1 protein P43699 UNIPROT up-regulates binding 9606 BTO:0000887 16397409 t gcesareni "Taz also binds to the transcription factor ttf-1 that is involved in formation and differentiation of the lungs and respiratory epithelia, and stimulates the production of pulmonary surfactant." SIGNOR-143472 axitinib chemical CHEBI:66910 ChEBI FLT4 protein P35916 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-171860 superoxide smallmolecule CHEBI:18421 ChEBI SOD1 protein P00441 UNIPROT "up-regulates activity" "precursor of" 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-272288 "tamoxifen citrate" chemical CHEBI:9397 ChEBI ESR2 protein Q92731 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-259300 HIPK2 protein Q9H2X6 UNIPROT HMGA1 protein P17096 UNIPROT down-regulates phosphorylation Ser36 PRKQPPVsPGTALVG 9606 17960875 t gcesareni "Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation." SIGNOR-158616 IL3 protein P08700 UNIPROT IL3RA protein P26951 UNIPROT up-regulates binding 9606 11700046 t gcesareni "The results demonstrate that both the association and dissociation rates for the binding of il-3 to the il-3ralpha are altered by truncation and by amino acid substitution at individual sites. Intracellular signaling studies using k116w and e43n demonstrate that differences in the il-3alpha binding characteristics are reflected in magnitude and kinetics of stat5 phosphorylation." SIGNOR-111404 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 "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 DCAF12 protein Q5T6F0 UNIPROT MAGEA3 protein P43357 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0002806 31267705 t miannu " The CRL4‐DCAF12 E3 ubiquitin ligase degrades MAGE‐A3/6" SIGNOR-272254 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 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 axitinib chemical CHEBI:66910 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-258076 IRS1 protein P35568 UNIPROT PIK3CA protein P42336 UNIPROT "up-regulates activity" binding 9606 20966354 t lperfetto "Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin." SIGNOR-168985 LTBR protein P36941 UNIPROT B_cell_maturation phenotype SIGNOR-PH15 SIGNOR up-regulates 9606 17633025 f lperfetto "The lymphotoxin-beta receptor (ltbetar, tnfrsf3) signaling pathway activates gene transcription programs and cell death important in immune development and host defense." SIGNOR-156899 FGF1 protein P05230 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 10618369 t lperfetto "We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2." SIGNOR-73811 U2AF1 protein Q01081 UNIPROT U2AF1/U2AF2 complex SIGNOR-C78 SIGNOR "form complex" binding 9606 8647433 t miannu "The splicing factor u2af (u2 snrnp auxiliary factor) is a heterodimer with subunits of 65 and 35 kd (u2af65 and u2af35)." SIGNOR-41945 "NuA4 complex" complex SIGNOR-C459 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation 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-269286 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 PRKCA protein P17252 UNIPROT RAF1 protein P04049 UNIPROT unknown phosphorylation Ser497 ATVKSRWsGSQQVEQ 9606 12551925 t gcesareni "For example, PKCα phosphorylates Raf-1 at serine 499 (13), but mutation of this residue did not impede activation of Raf-1 by the physiological stimulators Ras and Lck. Similarly, both v-Src and phorbol esters were able to activate Raf-1 even though the PKC phosphorylation sites at serine 497 and serine 499 were mutated to alanine (14). Thus, although some PKC phosphorylation sites on Raf-1 have been identified, these sites do not appear to be required for activation of Raf-1." SIGNOR-37844 IFNG protein P01579 UNIPROT Demyelination phenotype SIGNOR-PH155 SIGNOR up-regulates 10090 BTO:0000227 24507514 f miannu "Beside its wellknown antiviral and proinflammatory action, overexpression of IFN-g in the CNS could participate in demyelination. Transgenic overexpression of IFN-g in the mouse by CNS oligodendrocytes led to chronic demyelination that may be severe" SIGNOR-263833 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 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 MARCHF5 protein Q9NX47 UNIPROT DNM1L protein O00429 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 16874301 t miannu "We found that MITOL associated with and ubiquitinated mitochondrial fission protein hFis1 and Drp1.Pulse–chase experiment also indicated that MITOL overexpression promoted Drp1 turnover." SIGNOR-271894 ATM protein Q13315 UNIPROT TAOK1 protein Q7L7X3 UNIPROT up-regulates phosphorylation Thr643 EELNKRQtQKDLEHA 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-154171 LRIG1 protein Q96JA1 UNIPROT "ErbB receptor family" proteinfamily SIGNOR-PF36 SIGNOR down-regulates ubiquitination 9606 16123311 t "inferred from 70% of family members" 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-269872 ESR1 protein P03372 UNIPROT PSEN2 protein P49810 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 14764652 f lperfetto "Estrogen-induced transcriptional activities of both ERalpha and ERbeta and mRNA expression of estrogen-responsive genes, including pS2, c-myc, and cyclin D1, were suppressed by PP5 but enhanced by PP5 antisense oligonucleotide." SIGNOR-271691 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 Bafetinib chemical CID:24853523 PUBCHEM LYN protein P07948 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190227 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 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 CDK2 protein P24941 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-180759 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 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 PIAS1 protein O75925 UNIPROT FHL1 protein Q13642 UNIPROT down-regulates sumoylation Lys300 PRGPGLVkAPVWWPM 9606 17509614 t gcesareni "Pias1 (the protein inhibitor of activated stat1) interacts with kyot2 directly and attenuates kyot2-mediated transcriptional repression. We demonstrate that kyot2 is modified by sumoylation at two lysine residues, k144 and k171. Sumoylation of the transfected kyot2 is enhanced by pias1" SIGNOR-154805 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 CEBPB protein P17676 UNIPROT GFER protein P55789 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000599 20690902 f miannu "In the present study, we investigated transcription of hHSS triggered by EGF (epidermal growth factor) and the role of C/EBPβ (CCAAT/enhancer-binding protein β) as a potential core factor responsible for hHSS transcription in HepG2 cells. The results show that EGF suppresses hHSS mRNA expression at early time points. Using a promoter deletion assay, we identified a proximal region (-358/-212) that is required for EGF suppression. Overexpression of C/EBPβ enhances EGF suppression of hHSS, and mutation of the C/EBPβ-binding site at -292/-279 or siRNA (short interfering RNA) interference abolishes EGF suppression." SIGNOR-253772 RABGEF1 protein Q9UJ41 UNIPROT RAB5A protein P20339 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 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-260707 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 BTO:0000562 9211863 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-49367 (-)-anisomycin chemical CHEBI:338412 ChEBI MAPK11 protein Q15759 UNIPROT up-regulates "chemical activation" 9606 Other t "CellSignaling;phospho-p38 MAPK (Thr180/Tyr182) (D3F9) XP?? Rabbit mAb" gcesareni SIGNOR-189675 FST protein P19883 UNIPROT INHBA protein P08476 UNIPROT "down-regulates activity" binding 10090 BTO:0005787 24627466 t lperfetto "Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. |FST315-ΔHBS-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-251715 PRKD1 protein Q15139 UNIPROT ATP7B protein P35670 UNIPROT "up-regulates activity" phosphorylation Ser1453 DDDGDKWsLLLNGRD 9606 BTO:0000599 21189263 t lperfetto "ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking." SIGNOR-272294 GDF5 protein P43026 UNIPROT TRPS1 protein Q9UHF7 UNIPROT "up-regulates activity" relocalization 10090 BTO:0005092 18363966 t "Regulation of localization" 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-251867 PRKCD protein Q05655 UNIPROT CXCR4 protein P61073 UNIPROT "down-regulates activity" phosphorylation Ser339 GKRGGHSsVSTESES 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-260901 YARS1 protein P54577 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-regulates quantity" "chemical modification" 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-270519 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser111 PHLSPSLsPLGGQAA 9606 22196886 t lperfetto "Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression" SIGNOR-195316 GSK3B protein P49841 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-159442 "bisindolylmaleimide i" chemical CID:2396 PUBCHEM PRKCB protein P05771 UNIPROT down-regulates "chemical inhibition" 9606 Other t CellSignaling gcesareni SIGNOR-190347 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 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 SMO protein Q99835 UNIPROT GNG12 protein Q9UBI6 UNIPROT up-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-152817 NFE2L2 protein Q16236 UNIPROT GCLC protein P48506 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22459801 f miannu "Different expression pattern of Nrf2 regulated genes in end-stage liver disease samples were observed: glutamate-cysteine ligase (GCLC) and glutathione-S-transferase A1 (GSTA1) were significantly down-regulated in most liver disease groups, whereas heme oxidase 1 (HMOX1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) were not significantly suppressed." SIGNOR-254643 ARVCF protein O00192 UNIPROT ERBIN protein Q96RT1 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 11821434 t miannu "We characterized the interactions between the Erbin PDZ domain and both ARVCF and δ-catenin in vitro and in vivo. endogenous δ-catenin and Erbin co-localized in and co-immunoprecipitated from neurons. These results suggest that δ-catenin and ARVCF may function to mediate the association of Erbin with the junctional cadherin-catenin complex." SIGNOR-252119 "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-270396 Ub:E2 complex SIGNOR-C497 SIGNOR RNF10 protein Q8N5U6 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-271064 BAZ1B protein Q9UIG0 UNIPROT H2AX protein P16104 UNIPROT up-regulates phosphorylation Tyr143 ATQASQEy 9606 19092802 t gcesareni "We show that wstf phosphorylates tyr 142 of h2a.x, and that wstf activity has an important role in regulating several events that are critical for the dna damage response" SIGNOR-182831 MAPK8 protein P45983 UNIPROT BCL2L1 protein Q07817 UNIPROT down-regulates phosphorylation Ser62 PSWHLADsPAVNGAT 9606 BTO:0001130 12633850 t gcesareni "By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. 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 to permit prostate cancer cells to die by apoptosis" SIGNOR-99219 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr18 EPPLSQEtFSDLWKL 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-75025 CHEK2 protein O96017 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser378 SKKGQSTsRHKKLMF 9606 BTO:0001321 15659650 t lperfetto "The cell cycle checkpoint kinases CHK1 and CHK2 have been shown to phosphorylate multiple sites in the N-terminal domain of p53, consequently leading to p53 stabilization and activation. Phosphorylation of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage." SIGNOR-74835 CHUK protein O15111 UNIPROT FOXA2 protein Q9Y261 UNIPROT down-regulates phosphorylation Ser107 AGMGPHLsPSLSPLG 9606 22196886 t lperfetto "Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression" SIGNOR-195312 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 8622669 t lperfetto "Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases. MKK3 is therefore a specific activator of p38 MAP kinase that is independent of the JNK and ERK signaling pathways." SIGNOR-40356 MAPK10 protein P53779 UNIPROT PPM1J protein Q5JR12 UNIPROT down-regulates phosphorylation Ser93 HAGRAVQsPPDTGRR 9606 18553930 t gcesareni "Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells." SIGNOR-178926 prazosin chemical CHEBI:8364 ChEBI ADRA1B protein P35368 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-258469 ATIC protein P31939 UNIPROT 10-formyltetrahydrofolate(2-) smallmolecule CHEBI:57454 ChEBI "down-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-267325 PPP2R2A protein P63151 UNIPROT PP2CA_R1A_R2A complex SIGNOR-C132 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-243430 CEBPD protein P49716 UNIPROT CCL20 protein P78556 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-254056 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide chemical CHEBI:94504 ChEBI HDAC3 protein O15379 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191430 baicalein chemical CHEBI:2979 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-258158 exemestane chemical CHEBI:4953 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191520 PRKCA protein P17252 UNIPROT PA2G4 protein Q9UQ80 UNIPROT unknown phosphorylation Ser363 ALLQSSAsRKTQKKK 9606 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-249089 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 SKIL protein P12757 UNIPROT SMAD5 protein Q99717 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 smad8." SIGNOR-95474 GNAS protein P63092 UNIPROT ADCY1 protein Q08828 UNIPROT "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-156958 GATA1 protein P15976 UNIPROT NBEAL2 protein Q6ZNJ1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000132 28082341 f lperfetto "In conclusion, we herein show a long-distance regulatory region with GATA1 binding sites as being a strong enhancer for NBEAL2 expression." SIGNOR-261881 MAP3K1 protein Q13233 UNIPROT MAP2K4 protein P45985 UNIPROT "up-regulates activity" phosphorylation 9606 9712898 t lperfetto "The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, SEK1" SIGNOR-236376 TFCP2 protein Q12800 UNIPROT TF protein P02787 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20796026 f miannu "Ectopic expression of CP2 led to increased transferrin expression at both the mRNA and protein levels, whereas knockdown of CP2 down-regulated transferrin mRNA and protein expression." SIGNOR-255429 GLI2 protein P10070 UNIPROT Myelination phenotype SIGNOR-PH206 SIGNOR up-regulates NBK6142 f "Whilst shh signalling is required for ventral oligodendrogenesis in the entire central nervous system, Gli2 activity only regulates oligodendrocyte development in the ventral spinal cord. Gli3 plays a nonessential role in ventral oligodendrogenesis during normal development. " SimoneGraziosi SIGNOR-269214 GSK3B protein P49841 UNIPROT CCNE1 protein P24864 UNIPROT down-regulates phosphorylation Thr395 PLPSGLLtPPQSGKK 9606 14536078 t gcesareni "Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380" SIGNOR-118559 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 BAD protein Q92934 UNIPROT BCL2L1 protein Q07817 UNIPROT "down-regulates activity" binding 7834748 t lperfetto "Bad binds more strongly to Bcl-x, than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-x,, but not that of Bcl-2. When Bad dimerized with Bcl-x,, Bax was displaced and apoptosis was restored." SIGNOR-249617 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 GPR183 protein P32249 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-256715 TLK1 protein Q9UKI8 UNIPROT RAD9A protein Q99638 UNIPROT up-regulates phosphorylation Ser328 VLPSISLsPGPQPPK 9606 18940270 t llicata "Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna." SIGNOR-181748 SND1 protein Q7KZF4 UNIPROT MGLL protein Q99685 UNIPROT "down-regulates quantity by destabilization" binding 9606 26997225 t irozzo "Interaction of SND1 with MGLL resulted in ubiquitination and proteosomal degradation of MGLL. We demonstrate that interaction of SND1 with MGLL results in increased ubiquitination and subsequent proteosomal degradation of MGLL. This down-regulation of MGLL is required for SND1 to exert its pro-tumorigenic activity because forced overexpression of MGLL markedly abrogates cell proliferation." SIGNOR-259138 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser638 FDFPKTPsSQNLLAL 9606 SIGNOR-C15 21205641 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-170867 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 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 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 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 CD22 protein P20273 UNIPROT SH2B1 protein Q9NRF2 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 32323266 t scontino "SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK." SIGNOR-268444 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 phenytoin chemical CHEBI:8107 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-258160 P2RY4 protein P51582 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-257006 MAPK3 protein P27361 UNIPROT ALOX5 protein P09917 UNIPROT "up-regulates activity" phosphorylation Ser664 QLPYYYLsPDRIPNS 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-264440 TLR9 protein Q9NR96 UNIPROT 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-266742 TRAF7 protein Q6Q0C0 UNIPROT Cell_death phenotype SIGNOR-PH109 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-256666 VRK1 protein Q99986 UNIPROT TP53BP1 protein Q12888 UNIPROT up-regulates phosphorylation 9606 22621922 t miannu "The kinase vrk1 is activated by dna double strand breaks induced by ionizing radiation (ir) and specifically phosphorylates 53bp1 in serum-starved cells./ Vrk1 knockdown resulted in the defective formation of 53bp1 foci in response to ir both in number and size" SIGNOR-197625 CDK7 protein P50613 UNIPROT 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-51288 TUBGCP5 protein Q96RT8 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-262329 SRC protein P12931 UNIPROT MYLK protein Q15746 UNIPROT up-regulates phosphorylation Tyr464 QEGSIEVyEDAGSHY 9606 12408982 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-95238 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 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 SRC protein P12931 UNIPROT CHKA protein P35790 UNIPROT "up-regulates activity" phosphorylation Tyr197 RSLGPKLyGIFPQGR 9606 BTO:0000093 21822308 t miannu "We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333." SIGNOR-266351 STRA6 protein Q9BX79 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "up-regulates quantity" relocalization 9913 17255476 t lperfetto "We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex" SIGNOR-265107 CSF1 protein P09603 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-72455 SGX-523 chemical CHEBI:90624 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-258282 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 ADAM17 protein P78536 UNIPROT TNF protein P01375 UNIPROT "up-regulates quantity" cleavage 9606 BTO:0000782 9034190 t lperfetto "We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified." SIGNOR-46754 BARD1 protein Q99728 UNIPROT "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR "form complex" binding 25400280 t lperfetto "Intriguingly, another BRCA1 complex, the BRCA1–A complex, which itself contains RAP80 along with MERIT40, BRCC36/45 and Abraxas, has been reported to inhibit DNA end resection, suggesting that, in some contexts, BRCA1 may function to limit and/or prevent over resection of DNA breaks." SIGNOR-263223 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 CDK2 protein P24941 UNIPROT MCM3AP protein O60318 UNIPROT "up-regulates activity" phosphorylation Ser508 FWHRKKIsPNKKPFS 10090 BTO:0000776 11526238 t miannu "To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. ​(Fig.1C1C Left; ref. 22)." SIGNOR-262734 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 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 RET protein P07949 UNIPROT MAPK3 protein P27361 UNIPROT up-regulates phosphorylation Tyr204 HTGFLTEyVATRWYR 9606 16153436 t gcesareni "We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1)." SIGNOR-140298 ABCE1 protein P61221 UNIPROT 80S_cytosolic_ribosome complex SIGNOR-C455 SIGNOR "down-regulates quantity by destabilization" binding 9606 28368393 t miannu "The essential ATP-binding cassette protein ABCE1 splits 80S ribosomes into 60S and 40S subunits after canonical termination or quality-control-based mRNA surveillance processes. Compared to the pre-splitting state, we observe repositioning of ABCE1's iron-sulfur cluster domain, which rotates 150° into a binding pocket on the 40S subunit. This repositioning explains a newly observed anti-association activity of ABCE1. Notably, the movement implies a collision with A-site factors, thus explaining the splitting mechanism." SIGNOR-270816 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 10090 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-236988 MAT2B protein Q9NZL9 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR down-regulates 9606 BTO:0001938 30942439 f miannu "MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen" SIGNOR-261243 CPT1A protein P50416 UNIPROT O-palmitoyl-L-carnitine smallmolecule CHEBI:17490 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-267129 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 midostaurin chemical CHEBI:63452 ChEBI PRKCA protein P17252 UNIPROT "down-regulates activity" "chemical inhibition" 16969355 t lperfetto "Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases" SIGNOR-261981 SCN2A protein Q99250 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-253404 CDK1 protein P06493 UNIPROT MAP4 protein P27816 UNIPROT down-regulates phosphorylation Ser787 KAPEKRAsPSKPASA 9606 10791892 t gcesareni "Ser787 in the proline-rich region of human map4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Phosphorylation on ser-787 negatively regulates map4 activity to promote microtubule assembly." SIGNOR-77087 CAMK2A protein Q9UQM7 UNIPROT ETS1 protein P14921 UNIPROT down-regulates phosphorylation Ser285 QRVPSYDsFDSEDYP 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-96342 IRAK4 protein Q9NWZ3 UNIPROT IRAK1 protein P51617 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 11960013 t lperfetto "In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1." SIGNOR-117315 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr447 SEELDENyVPMNPNS 10090 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251313 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 ROCK1 protein Q13464 UNIPROT MYL12B protein O14950 UNIPROT up-regulates phosphorylation Ser20 KRPQRATsNVFAMFD 9606 12185584 t lperfetto "Here we found that rho-kinase has an activity for mrlc diphosphorylation at both threonine 18 and serine 19 in nonmuscle cells using sequential column chromatographies." SIGNOR-91542 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR 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-244681 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 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 "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI CDP-diacylglycerol(2-) smallmolecule CHEBI:58332 ChEBI "up-regulates quantity" "precursor of" 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-267019 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 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 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 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-201286 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 PPP1CA protein P62136 UNIPROT DDX58 protein O95786 UNIPROT "up-regulates activity" dephosphorylation Ser8 MTTEQRRsLQAFQDY 9606 BTO:0000007 23499489 t lperfetto "We identified PP1alpha and PP1gamma as primary phosphatases responsible for MDA5 and RIG-I dephosphorylation, leading to their activation.|endogenous RIG-I and MDA5 that interacted with PP1 exhibited markedly decreased phosphorylation levels at S8 and S88, respectively " SIGNOR-264581 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 CAMK4 protein Q16566 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.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-85110 SP1 protein P08047 UNIPROT CADM1 protein Q9BY67 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 18794147 f lperfetto "Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation." SIGNOR-268958 FBXO5 protein Q9UKT4 UNIPROT FZR1 protein Q9UM11 UNIPROT down-regulates ubiquitination 9606 11751633 t gcesareni "Emi1 binds cdh1 and inhibits apc-cdh1 activity." SIGNOR-113385 GSK3B protein P49841 UNIPROT CTNNB1 protein P35222 UNIPROT "down-regulates activity" phosphorylation Ser33 QQQSYLDsGIHSGAT 9606 BTO:0000586 SIGNOR-C110 16293724 t gcesareni "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-141799 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 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-154783 GSK3B protein P49841 UNIPROT ARNTL protein O00327 UNIPROT down-regulates phosphorylation Thr21 DFMSPGPtDLLSSSL 9606 20049328 t lperfetto "Gsk3beta phosphorylates bmal1 specifically on ser 17 and thr 21 and primes it for ubiquitylation. In the absence of gsk3beta-mediated phosphorylation, bmal1 becomes stabilized and bmal1 dependent circadian gene expression is dampened." SIGNOR-162790 TBXA2R protein P21731 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-256887 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 33627125 t miannu "DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2" SIGNOR-269202 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 POLR2K protein P53803 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-266141 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 STK3 protein Q13188 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation Thr180 DTMAKRNtVIGTPFW 9606 BTO:0000150 20231902 t gcesareni "Consistent with previous studies, sts alone induces mst2 cleavage and autophosphorylation of thr180, an indicator of mst2 activation, as well as apoptosis." SIGNOR-164310 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 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 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 EPHA2 protein P29317 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 9606 12400011 t gcesareni "We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases." SIGNOR-94804 NOTCH2 protein Q04721 UNIPROT TCF3 protein P15923 UNIPROT down-regulates binding 9606 9528794 t gcesareni "In an effort to identify processes that regulate e47, and potentially b-cell development, we found that activated notch1 and notch2 effectively inhibit e47 activity." SIGNOR-56222 AKT proteinfamily SIGNOR-PF24 SIGNOR SH2B2 protein O14492 UNIPROT unknown phosphorylation Ser598 SARSRSNsAERLLEA 10090 16141217 t "Serine 588 of APS is a newly identified target for protein kinase B in intact cells and in vitro. The precise function of this PKB-mediated phosphorylation event is not entirely clear but may be responsible for regulating cellular localization and will be the subject of future investigation." SIGNOR-251487 GATA1 protein P15976 UNIPROT RUNX1T1 protein Q06455 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002731 20487545 f Regulation miannu "GATA-1 transcription factor binds and transactivates the ETO proximal promoter in an erythroid/megakaryocytic-specific manner. Thus, trans-acting factors that are essential in erythroid/megakaryocytic differentiation govern ETO expression." SIGNOR-251929 ATM protein Q13315 UNIPROT NFAT5 protein O94916 UNIPROT up-regulates phosphorylation Ser1197 HIQTPMLsQEQAQPP 9606 15173573 t lperfetto "Tonebp/orebp contains atm consensus phosphorylation sites at ser-1197, ser-1247, and ser-1367. In conclusion, signaling via atm is necessary for full activation of tonebp/orebp" SIGNOR-125073 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 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 FBXO32 protein Q969P5 UNIPROT Protein_degradation phenotype SIGNOR-PH96 SIGNOR up-regulates 10090 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-255342 PAK1 protein Q13153 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser405 KTQTPPVsPAPQPTE 9606 21079800 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-169690 FGF2 protein P09038 UNIPROT TGFB1 protein P01137 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 15780951 f 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-134791 ATF4 protein P18848 UNIPROT SARS2 protein Q9NP81 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-269425 JNK proteinfamily SIGNOR-PF15 SIGNOR CTNNB1 protein P35222 UNIPROT down-regulates phosphorylation Ser37 YLDSGIHsGATTTAP 9606 20419129 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-165026 BCL2 protein P10415 UNIPROT DIABLO protein Q9NR28 UNIPROT down-regulates 9606 14585074 f amattioni "Bcl- confers protection to apoptosis by interference with bax/bak-mediated release of the pro-apoptotic mitochodrial factors smac/diablo and htra2/omi" SIGNOR-88885 PRKCA protein P17252 UNIPROT CDC42EP4 protein Q9H3Q1 UNIPROT "down-regulates activity" phosphorylation Ser80 SSKRSLLsRKFRGSK 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-263161 FOXO6 protein A8MYZ6 UNIPROT FBXO32 protein Q969P5 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-236560 PTPN2 protein P17706 UNIPROT EGFR protein P00533 UNIPROT down-regulates dephosphorylation 9606 BTO:0000527 11514572 t gcesareni "Tc45 dephosphorylated delta egfr in u87mg glioblastoma cells and inhibited mitogen-activated protein kinase erk2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping tc45-d182a mutant, which is capable of forming stable complexes with tc45 substrates, suppressed the activation of erk2 but not phosphatidylinositol 3-kinase. The activation results in reduced egfr phosphorylation after egf stimulation. Introduction of the alpha(1) cytoplasmic domain peptide into cells induces phosphatase activation and inhibits egf-induced cell proliferation and anchorage-independent growth of malignant cells." SIGNOR-109804 Tomivosertib chemical CID:118598754 PUBCHEM MKNK2 protein Q9HBH9 UNIPROT "down-regulates activity" "chemical inhibition" 9606 29526098 t "Simone Vumbaca" "Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation." SIGNOR-261117 VEGFA protein P15692 UNIPROT Angiogenesis phenotype SIGNOR-PH46 SIGNOR up-regulates 9606 16301830 f "VEGF as a key mediator of angiogenesis in cancer." SIGNOR-256597 SRC protein P12931 UNIPROT IGF1R protein P08069 UNIPROT "up-regulates activity" phosphorylation Tyr973 RLGNGVLyASVNPEY -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-247193 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 U2AF1/U2AF2 complex SIGNOR-C78 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-263945 1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane chemical CHEBI:125354 ChEBI CXCR4 protein P61073 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206268 APBA2 protein Q99767 UNIPROT NRXN1 protein Q9ULB1 UNIPROT "up-regulates activity" binding 9534 BTO:0000298 11036064 t miannu "Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa." SIGNOR-264039 SEMA3B protein Q13214 UNIPROT PLXNA2 protein O75051 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-261812 Ub:E2 complex SIGNOR-C497 SIGNOR UHRF2 protein Q96PU4 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-270958 SOCS3 protein O14543 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" binding 9606 24600449 t miannu "The ability of SOCS3 to simultaneously bind to JAK and to the cytokine receptor explains the specificity of the suppression. SOCS3 binds JAK and gp130 receptor simultaneously, using two opposing surfaces: while the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by the gp130 receptor, a subdomain in the SH2 domain of SOCS3 is also required for inhibition of JAK, binding in a phospho-independent manner to a non-canonical surface of JAK2 (58, 59). The KIR of SOCS3 occludes the substrate-binding groove on JAK2." SIGNOR-255329 "SB 203580" chemical CHEBI:90705 ChEBI MAPK14 protein Q16539 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000567 11606413 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-111064 CHUK protein O15111 UNIPROT MAP3K14 protein Q99558 UNIPROT "down-regulates quantity by destabilization" phosphorylation Thr559 TGDYIPGtETHMAPE 9606 BTO:0000776 20501937 t lperfetto "Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis." SIGNOR-165622 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 PAK1 protein Q13153 UNIPROT CTBP1 protein Q13363 UNIPROT "down-regulates activity" phosphorylation Ser158 REGTRVQsVEQIREV 9606 12872159 t lperfetto "Pak1 phosphorylates ctbp selectively on ser158 within a putative regulatory loop, triggering ctbp cellular redistribution and blocking ctbp ak1 superphosphorylates ctbp and inhibits ctbp dehydrogenase activitycorepressor functions." SIGNOR-103943 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 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 NTN4 protein Q9HB63 UNIPROT UNC5 proteinfamily SIGNOR-PF98 SIGNOR "up-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-268184 N(1)-(5-phospho-beta-D-ribosyl)glycinamide(1-) smallmolecule CHEBI:143788 ChEBI (6S)-5,6,7,8-tetrahydrofolate(2-) smallmolecule CHEBI:57453 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-268103 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 "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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR ALYREF protein Q86V81 UNIPROT up-regulates phosphorylation Thr219 GGGTRRGtRGGARGR 9606 18562279 t llicata "Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export." SIGNOR-179054 TIMM29 protein Q9BSF4 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-267707 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 HNRNPA1 protein P09651 UNIPROT TRA2B protein P62995 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000586 31311954 t lperfetto "HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells." SIGNOR-262280 GNAQ protein P50148 UNIPROT RHOA protein P61586 UNIPROT up-regulates binding 9606 17606614 t gcesareni "Recently, the dbl-family guanine nucleotide exchange factor (gef) p63rhogef/geft has been described as a novel mediator of galpha(q/11) signaling to rhoa based on its ability to synergize with galpha(q/11) resulting in enhanced rhoa signaling in cells." SIGNOR-156534 EIF3L protein Q9Y262 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-266389 CSNK2A1 protein P68400 UNIPROT TELO2 protein Q9Y4R8 UNIPROT down-regulates phosphorylation Ser487 AQLAGSDsDLDSDDE 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. ere, we show that tel2 is constitutively phosphorylated on conserved serines 487 and 491 by casein kinase 2 (ck2)" SIGNOR-200202 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 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 VARS1 protein P26640 UNIPROT ATP(4-) smallmolecule CHEBI:30616 ChEBI "down-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-270527 "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 glycine smallmolecule CHEBI:15428 ChEBI GLRA1 protein P23415 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-264980 HIP1 protein O00291 UNIPROT REST protein Q13127 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21832040 f miannu "HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK)." SIGNOR-255076 RCOR1 protein Q9UKL0 UNIPROT REST protein Q13127 UNIPROT "up-regulates activity" binding 9606 BTO:0000007 10449787 t 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-220618 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 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 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 PRKCG protein P05129 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-249085 PYGB protein P11216 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI "up-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-267952 EIF3E protein P60228 UNIPROT MAD2L1 protein Q13257 UNIPROT "down-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-259157 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 PXN protein P49023 UNIPROT ILK protein Q13418 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 11304546 t gcesareni "Co-immunoprecipitation from fibroblasts confirmed that the association between paxillin and ilk occurs in vivo in both adherent cells and cells in suspension. [__] thus, paxillin binding is necessary for efficient focal adhesion targeting of ilk and may therefore impact the role of ilk in integrin-mediated signal transduction events." SIGNOR-106824 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 OGT protein O15294 UNIPROT TET1 protein Q8NFU7 UNIPROT "up-regulates activity" glycosylation 9606 BTO:0002181 23729667 t irozzo "The DNA demethylation enzyme Tet1 interacts with Ogt and is O-GlcNAcylated. Tet1 protein stability is positively regulated by O-GlcNAcylation, and its repression function on targeting genes is dependent on Ogt." SIGNOR-259184 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 "vinorelbine L-tartrate" chemical CHEBI:32296 ChEBI TUBB protein P07437 UNIPROT "down-regulates activity" "chemical inhibition" 9606 7740336 t miannu "Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France) and paclitaxel (Taxol; Bristol-Myers Oncology, Princeton, NJ) as single-agent therapy exhibit good activity in breast and lung cancers. Because these agents bind to distinct sites on tubulin and affect microtubules in opposite ways, a pilot study was conducted of the combination of vinorelbine and paclitaxel in patients with metastatic breast cancer or lung cancer who were refractory to first-line chemotherapy." SIGNOR-259348 GDNF protein P39905 UNIPROT RHOQ protein P17081 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-252185 TAL1 protein P17542 UNIPROT Erythrocyte_differentiation phenotype SIGNOR-PH104 SIGNOR "up-regulates activity" 10090 BTO:0004911 29713515 f "The truncated form TAL1-s is required for erythroid progenitors differentiation, while the full-length protein TAL1-l is required for megakaryocytic differentiation of progenitor cells." SIGNOR-259970 MAPK8IP3 protein Q9UPT6 UNIPROT MAP3K1 protein Q13233 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-71471 AVPR1B protein P47901 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-257063 GNAI1 protein P63096 UNIPROT ADCY1 protein Q08828 UNIPROT "down-regulates activity" binding 9606 15922020 t "Activation of receptors coupled to inhibitory G proteins (Galpha i/o) has opposing consequences for cyclic AMP accumulation and the activity of cyclic AMP-dependent protein kinase, depending on the duration of stimulation. Acute activation inhibits the activity of adenylate cyclase, thereby attenuating cyclic AMP accumulation; in contrast, persistent activation of Galpha i/o-coupled receptors produces a paradoxical enhancement of adenylate cyclase activity, thus increasing cyclic AMP accumulation when the action of the inhibitory receptor is terminated." SIGNOR-256532 GNB1 protein P62873 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-145119 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 FCN3 protein O75636 UNIPROT MASP1 protein P48740 UNIPROT "up-regulates activity" binding 9606 BTO:0000392 11907111 t lperfetto "H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP." SIGNOR-263410 SOCS1 protein O15524 UNIPROT VCB-Cul2 complex SIGNOR-C524 SIGNOR "up-regulates activity" binding 9534 10747851 t miannu "Recent evidence indicates that SOCS1 interacts with elongins B and C, which are components of a ubiquitin ligase complex, VCB (VHL/elonginC/B), based on the VHL (von Hippel Lindau) tumor suppressor protein." SIGNOR-272564 CTF1 protein Q16619 UNIPROT TH protein P07101 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 12859689 f miannu "CT-1 exerted these effects by decreasing tyrosine hydroxylase, GTP cyclohydrolase (GCH) and NE transporter mRNAs, while IL-6 lowered only GCH mRNA." SIGNOR-252219 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 "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 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 RASGEF1C protein Q8N431 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-161505 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Thr373 TVLVKDStNRDSLDM 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-129332 OXTR protein P30559 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-257178 STK3 protein Q13188 UNIPROT MOB1A protein Q9H8S9 UNIPROT up-regulates phosphorylation Thr74 QINMLYGtITEFCTE 9606 BTO:0000007 18362890 t 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-177977 CDK7 protein P50613 UNIPROT POLR2A protein P24928 UNIPROT down-regulates 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-120020 MAPK14 protein Q16539 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation Ser727 NTIDLPMsPRTLDSL 9606 18691976 t gcesareni "Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." SIGNOR-179912 CDK7 protein P50613 UNIPROT TP53 protein P04637 UNIPROT up-regulates phosphorylation Ser392 FKTEGPDsD 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-51292 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 SP3 protein Q02447 UNIPROT CADM1 protein Q9BY67 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 18794147 f lperfetto "Treatment with mithramycin A, an inhibitor of Sp1 or Sp3 binding, resulted in reduction of Cadm1 gene expression, therefore suggesting a potential role of Sp1/Sp3 in Cadm1 regulation." SIGNOR-268959 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 RASA1 protein P20936 UNIPROT HRAS protein P01112 UNIPROT down-regulates binding 9606 10394594 t lperfetto "The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection of GTPase-activating proteins (GAPs) speed up the processthe 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." SIGNOR-68990 ACSS1 protein Q9NUB1 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-271830 EIF3D protein O15371 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-266397 CYCS protein P99999 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-253100 EHF protein Q9NZC4 UNIPROT SPRR1B protein P22528 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 12682075 f "Consistent with this, overexpression of EBS-binding proteins ESE-1 and ESE-3 significantly stimulated SPRR1B promoter activity. Furthermore, preceding SPRR1B transcription, PMA up-regulated mRNA expression of ETS family members such as ESE-1 and ESE-3" SIGNOR-254280 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 DNA_damage stimulus SIGNOR-ST1 SIGNOR PALB2 protein Q86YC2 UNIPROT "up-regulates activity" 9606 BTO:0001938 19369211 f lperfetto "Consistent with the converging functions of the BRCA proteins in DNA repair, cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair. We propose that, via its direct interaction with PALB2, BRCA1 fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Our findings uncover PALB2 as the molecular adaptor between the BRCA proteins, and suggest that impaired HR repair is one of the fundamental causes for genomic instability and tumorigenesis observed in patients carrying BRCA1, BRCA2, or PALB2 mutations." SIGNOR-244490 ADNP protein Q9H2P0 UNIPROT MAP1LC3B protein Q9GZQ8 UNIPROT "up-regulates activity" binding 10116 BTO:0000601 24365867 t miannu "Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes." SIGNOR-266759 CADPS2 protein Q86UW7 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-264339 SOS2 protein Q07890 UNIPROT HRAS protein P01112 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-175262 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 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 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 TP53 protein P04637 UNIPROT AFP protein P02771 UNIPROT "down-regulates quantity by repression" "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-254482 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 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 4-amino-5-fluoro-3-[5-(4-methyl-1-piperazinyl)-1,3-dihydrobenzimidazol-2-ylidene]-2-quinolinone chemical CHEBI:91395 ChEBI FGFR3 protein P22607 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-258105 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser186 PVLRQSIsFSGLPSG -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250152 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 POU2AF1 protein Q16633 UNIPROT POU2F1 protein P14859 UNIPROT up-regulates binding 9606 BTO:0000776 12727885 t miannu "Obf1 enhances transcriptional potential of oct1." SIGNOR-100968 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 "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 FGFR3 protein P22607 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-258081 PLK1 protein P53350 UNIPROT CEP55 protein Q53EZ4 UNIPROT up-regulates phosphorylation Ser436 PTAALNEsLVECPKC 9606 16198290 t lperfetto "Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. s425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436...enabling it to relocate to the midbody to function in mitotic exit and cytokinesis." SIGNOR-140898 CSNK1D protein P48730 UNIPROT MDM2 protein Q00987 UNIPROT down-regulates phosphorylation 9606 20708156 t gcesareni "Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase." SIGNOR-167520 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 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 F2R protein P25116 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-256875 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 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 CCT239065 chemical CID:44131523 PUBCHEM BRAF protein P15056 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190907 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 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 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 ACTB protein P60709 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-270599 RORA protein P35398 UNIPROT NLGN1 protein Q8N2Q7 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-265136 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 ANK1 protein P16157 UNIPROT SLN protein O00631 UNIPROT "down-regulates activity" binding 9606 28487373 t lperfetto "These results suggest that sAnk1 interacts with SLN both directly and in complex with SERCA1 and reduces SLN's inhibitory effect on SERCA1 activity." SIGNOR-265930 PRKCD protein Q05655 UNIPROT RPS3 protein P23396 UNIPROT "up-regulates activity" phosphorylation Ser6 sKKRKFVA 9606 19059439 t Manara "Here we show that PKCδ phosphorylates rpS3 resulting in its mobilization in the nucleus to repair damaged DNA" SIGNOR-260894 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 (S)-(-)-sulpiride chemical CHEBI:64119 ChEBI DRD3 protein P35462 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-258733 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT up-regulates phosphorylation Thr175 HDTSFAKtFVGTPYY 9606 17197699 t gcesareni "Enzymatic activity, induced;" SIGNOR-151763 "GPIb-IX-V complex" complex SIGNOR-C270 SIGNOR FLNA protein P21333 UNIPROT "up-regulates activity" relocalization 9606 16293600 t lperfetto "The cytoplasmic domain of GPIbα of the GPIb-IX-V complex binds to actin filaments through FLNa|This immediately means that clustering of the GPIb-IX-V complex and anchoring of FLNa to actin filaments by activation could also increase avidity, which could withstand high shear stress." SIGNOR-261846 GSK3B protein P49841 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates phosphorylation 9606 BTO:0000782 16407239 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-217430 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 EPS15 protein P42566 UNIPROT EGFR protein P00533 UNIPROT "down-regulates activity" binding 10029 BTO:0002988 15383614 t gcesareni "We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role" SIGNOR-243278 CSNK1E protein P49674 UNIPROT PER1 protein O15534 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-267997 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 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 RPAP2 protein Q8IXW5 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1672 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-248751 sertindole chemical CHEBI:9122 ChEBI DRD3 protein P35462 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-258547 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 RAC3 protein P60763 UNIPROT CIB1 protein Q99828 UNIPROT "up-regulates activity" binding 10029 BTO:0000246 11756406 t Gianni "We here report that CIB, a protein that binds to the alpha(IIb)beta(3) fibrinogen receptor, interacts exclusively with activated (V12) Rac3 but not Rac1 or Rac2. Binding of V12Rac3 to CIB was mediated by the C-terminal end of Rac3 and by Rac3 membrane localization" SIGNOR-269060 IL11 protein P20809 UNIPROT IL6ST protein P40189 UNIPROT up-regulates binding 9606 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-4" SIGNOR-48033 GLS protein O94925 UNIPROT "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI "down-regulates quantity" "chemical modification" 9606 22049910 t miannu "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-260000 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNAI1 protein P63096 UNIPROT "up-regulates activity" binding 9606 31160049 t miannu "Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0." SIGNOR-255006 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation 9606 10480932 t lperfetto "We have found that p38 mitogen-activated protein kinase, and its direct activator MKK6 are rapidly activated in response to TGF-beta." SIGNOR-70607 linifanib chemical CHEBI:91435 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193660 CTDSP2 protein O14595 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-248294 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 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 FOXO1 protein Q12778 UNIPROT SMURF1 protein Q9HCE7 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 BTO:0001103 21798082 t "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 (see below), and their degradation via the proteasome" SIGNOR-256268 CASP12 protein Q6UXS9 UNIPROT CASP9 protein P55211 UNIPROT up-regulates cleavage 9606 BTO:0000222 12097332 t gcesareni "Caspase-12 specifically cleaves and activates procaspase-9 in cytosolic extracts. Results suggest that caspase-12 can activate caspase-9 without involvement of cytochromec." SIGNOR-90318 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 PIM2 protein Q9P1W9 UNIPROT 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-250395 palbociclib chemical CHEBI:85993 ChEBI CCND2 protein P30279 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205701 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 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 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide chemical CHEBI:91353 ChEBI MAP2K2 protein P36507 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191024 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 2-[4-[3-[2-(trifluoromethyl)-9-thioxanthenylidene]propyl]-1-piperazinyl]ethanol chemical CHEBI:93235 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-258728 BIX-02188 chemical CID:66524294 PUBCHEM MAP2K5 protein Q13163 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190365 Isoetharine chemical CHEBI:6005 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." SIGNOR-258432 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 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 DIO proteinfamily SIGNOR-PF83 SIGNOR L-thyroxine smallmolecule CHEBI:18332 ChEBI "down-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-267043 NF90-NF45 complex SIGNOR-C443 SIGNOR DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 9606 21969602 f miannu "The NF90/NF45 complex participates in DNA break repair via nonhomologous end joining" SIGNOR-268490 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 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 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 AKAP12 protein Q02952 UNIPROT PKA proteinfamily SIGNOR-PF17 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-271837 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 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 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-151671 ZNF521 protein Q96K83 UNIPROT EBF1 protein Q9UH73 UNIPROT down-regulates binding 9606 BTO:0000776 14630787 t miannu "Ehzf inhibits the transcriptional activity of early b-cell factor (ebf), a transcription factor essential for specification of the b-cell lineage /ability to interact with the neural and hematopoietic transcription factor olf1/ebf1 and inhibit its binding to dna" SIGNOR-119300 LCK protein P06239 UNIPROT ZAP70 protein P43403 UNIPROT unknown phosphorylation Tyr69 ERQLNGTyAIAGGKA 9606 BTO:0000661 7961936 t "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." SIGNOR-251396 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 PRKACA protein P17612 UNIPROT GYS1 protein P13807 UNIPROT unknown phosphorylation Ser8 MPLNRTLsMSSLPGL -1 2117608 t miannu "Phosphorylation of rabbit muscle glycogen synthase by cyclic AMP-dependent protein kinase has been shown to enhance subsequent phosphorylation by casein kinase I . phosphorylation at Ser7 is required for modification of Ser10 by casein kinase I." SIGNOR-249988 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 zotepine chemical CHEBI:32316 ChEBI ADRA2B protein P18089 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-258559 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 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 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 AML1-ETO "fusion protein" SIGNOR-FP1 SIGNOR PTPRC protein P08575 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-255686 "SAGA complex" complex SIGNOR-C465 SIGNOR H3-2 protein Q5TEC6 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-269633 CDK5 protein Q00535 UNIPROT CLOCK protein O15516 UNIPROT up-regulates phosphorylation Thr461 KIPTDTStPPRQHLP 9606 24235147 t lperfetto "Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock." SIGNOR-203231 TLN1 protein Q9Y490 UNIPROT ITGB8 protein P26012 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-257636 CYC-116 chemical CID:6420138 PUBCHEM AURKA protein O14965 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191221 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 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 SRC protein P12931 UNIPROT RAPGEF1 protein Q13905 UNIPROT up-regulates phosphorylation Tyr504 APIPSVPyAPFAAIL 9606 15320955 t llicata "C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases." SIGNOR-128273 IKBKB protein O14920 UNIPROT CYLD protein Q9NQC7 UNIPROT "down-regulates activity" phosphorylation Ser432 KMPNTNGsIGHSPLS 9606 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-204724 MAPK3 protein P27361 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 t 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-121856 FOXO proteinfamily SIGNOR-PF27 SIGNOR TRIM63 protein Q969Q1 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 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-252927 PAMPs stimulus SIGNOR-ST11 SIGNOR FCN3 protein O75636 UNIPROT "up-regulates activity" binding -1 11907111 t lperfetto "H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates." SIGNOR-263406 PC protein P11498 UNIPROT pyruvate smallmolecule CHEBI:15361 ChEBI "down-regulates quantity" "chemical modification" 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-266554 GATA1 protein P15976 UNIPROT HOXA10 protein P31260 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 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-254470 PPP4C protein P60510 UNIPROT BANF1 protein O75531 UNIPROT up-regulates dephosphorylation Ser4 sQKHRDFV 9606 16495336 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-144779 linifanib chemical CHEBI:91435 ChEBI PDGFRB protein P09619 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193666 CAMK2A protein Q9UQM7 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 BTO:0000661 9686569 t gcesareni "Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. In vitro, ser16 of recombinant human stathmin was phosphorylated also by purified cam kinase ii, and in vivo, cam kinase ii activity was indeed stimulated in cd2-triggered jurkat cells. Altogether, our results favor an association of cam kinase ii activity with costimulatory signals of t lymphocyte activation and phosphorylation of stathmin on ser16." SIGNOR-59354 ELOVL5 protein Q9NYP7 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-267891 IDH2 protein P48735 UNIPROT D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI "down-regulates quantity" 9606 26178471 t lperfetto "Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG)" SIGNOR-253136 DPP10 protein Q8N608 UNIPROT KCND2 protein Q9NZV8 UNIPROT "up-regulates activity" relocalization 9534 BTO:0000298 15454437 t Luisa "Coexpression of DPP10 changes the subcellular localization of Kv4.2 expressed in COS-7 cells by promoting surface trafficking.DPP10 accelerates Kv4.2 inactivation at high and low voltages" SIGNOR-269006 PRKCD protein Q05655 UNIPROT CDH1 protein P12830 UNIPROT "down-regulates activity" phosphorylation Thr790 TRNDVAPtLMSVPRY 10029 27203386 t Manara "Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin." SIGNOR-260893 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 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 "all-trans-retinoic acid" smallmolecule CHEBI:15367 ChEBI HNF4G protein Q14541 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000972 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-254444 NR3C1 protein P04150 UNIPROT PCK1 protein P35558 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 26652733 f "These results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK." SIGNOR-256107 PRKRA protein O75569 UNIPROT DICER1/hAgo2/PRKRA complex SIGNOR-C41 SIGNOR "form complex" binding 9606 23661684 t lperfetto "Immunoprecipitation and reconstitution experiments in various systems have shown that Dicer associates with proteins in the Argonaute (Ago) family of endonucleases and with specific double-stranded RNA-binding proteins (dsRBPs) (3–7). | In humans, these dsRBPs are protein activator of PKR (PACT) (5) and trans-activation response RNA-binding protein (TRBP) (3,4)." SIGNOR-255318 FCN2 protein Q15485 UNIPROT MASP1 protein P48740 UNIPROT "up-regulates activity" binding 9606 BTO:0000392 11907111 t lperfetto "H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP." SIGNOR-263411 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 DAXX protein Q9UER7 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-256596 MAP3K8 protein P41279 UNIPROT MAP2K1 protein Q02750 UNIPROT up-regulates phosphorylation Ser222 LIDSMANsFVGTRSY 9606 8131746 t gcesareni "Activation of mek family kinases requires phosphorylation of two conserved ser/thr residues.Phosphopeptide analysis demonstrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf" SIGNOR-36449 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 "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 ERK1/2 proteinfamily SIGNOR-PF1 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-270172 "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000011 25533466 f miannu "We concluded that FBXL10 recruits the noncanonical PRC1 complex to directly repress Cdk1, Uhrf1, and Pparg that may account for the FBXL10-mediated inhibition of adipogenesis." SIGNOR-252251 EXOC7 protein Q9UPT5 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-270782 PARD6A protein Q9NPB6 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-227559 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR DCX protein O43602 UNIPROT unknown phosphorylation Thr289 AGPKASPtPQKTSAK 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-250656 GOLGA7 protein Q7Z5G4 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-261354 NUP98-HOXA9 "fusion protein" SIGNOR-FP15 SIGNOR PECAM1 protein P16284 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 platelet endothelial cell adhesion molecule PECAM1 is also downregulated by NUP98‐HOXA9." SIGNOR-261500 RAF1 protein P04049 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates binding 9606 15618521 t "inferred from 70% of family members" gcesareni "Raf-1 prevents dimerization and phosphorylation of the activation loop of mst2 independently of its protein kinase activity.Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (mst2)" SIGNOR-269942 AKT2 protein P31751 UNIPROT STK3/4 proteinfamily SIGNOR-PF41 SIGNOR down-regulates phosphorylation 9606 BTO:0000150 20231902 t "inferred from 70% of family members" 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-269937 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 FANCL protein Q9NW38 UNIPROT FANCI protein Q9NVI1 UNIPROT "up-regulates activity" ubiquitination SIGNOR-C300 18985065 t lperfetto "Phosphorylation of FANCD2 and Fanconi anemia core components (broken pink circles) affects the efficiency of, but is not essential for, ID ubiquitination by the FA core complex, together with E1 and UBE2T. Analogously, ubiquitination of FANCD2 (solid orange ovals) is essential for DNA repair, activating the ID complex for chromatin binding" SIGNOR-263266 RAD52 protein P43351 UNIPROT DNA_repair phenotype SIGNOR-PH57 SIGNOR up-regulates 27649245 f lperfetto "Homologous recombination (HR) plays an important role in maintaining genomic integrity. It is responsible for repair of the most harmful DNA lesions, DNA double-strand breaks and inter-strand DNA cross-links. HR function is also essential for proper segregation of homologous chromosomes in meiosis, maintenance of telomeres, and resolving stalled replication forks. Defects in HR often lead to genetic diseases and cancer. Rad52 is one of the key HR proteins, which is evolutionarily conserved from yeast to humans| in mammals, Rad52 knockouts showed no significant DNA repair or recombination phenotype. |These new findings indicate an important backup role for Rad52, which complements the main HR mechanism in mammals." SIGNOR-251507 BTG1 protein P62324 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-221019 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 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 INSR protein P06213 UNIPROT IRS1 protein P35568 UNIPROT "up-regulates activity" phosphorylation Tyr465 GEEELSNyICMGGKG 10116 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-236713 calcitriol smallmolecule CHEBI:17823 ChEBI propan-2-ol smallmolecule CHEBI:17824 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-270573 TTBK1 protein Q5TCY1 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser516 GDRSGYSsPGSPGTP 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-148970 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 PAK proteinfamily SIGNOR-PF13 SIGNOR NF2 protein P35240 UNIPROT down-regulates phosphorylation 9606 18071304 t "inferred from 70% family members" 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-269976 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 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 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 MAP3K4 protein Q9Y6R4 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 9606 21152872 f lperfetto "We found that mekk1/mekk4 as opposed to ask1, are responsible for trail-induced c-jun nh2-terminal kinase (jnk) or p38 activation," SIGNOR-170534 CDKN2A protein P42771 UNIPROT Immortality phenotype SIGNOR-PH47 SIGNOR down-regulates 9606 10648628 f "Human keratinocytes that express hTERT and also bypass a p16(INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics" SIGNOR-259286 TBL1X protein O60907 UNIPROT SCF(TBL1) complex SIGNOR-C533 SIGNOR "form complex" binding 9606 BTO:0000007 20181957 t miannu "Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). " SIGNOR-271948 CTDSPL2 protein Q05D32 UNIPROT HBE1 protein P02100 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 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-251779 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 PTPN6 protein P29350 UNIPROT LYN protein P07948 UNIPROT "down-regulates activity" dephosphorylation Tyr397 RVIEDNEyTAREGAK 10116 15537644 t "SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397" SIGNOR-248471 FOXO proteinfamily SIGNOR-PF27 SIGNOR CDKN1B protein P46527 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 10783894 t gcesareni "AFX transcriptionally activates p27kip1, resulting in increased protein levels." SIGNOR-252928 H4C1 protein P62805 UNIPROT Nucleosome complex SIGNOR-C371 SIGNOR "form complex" binding -1 21812398 t lperfetto "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-265311 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 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 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation 6239 SIGNOR-C15 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-252983 AGRP protein O00253 UNIPROT MC3R protein P41968 UNIPROT down-regulates binding 9606 BTO:0001253 9311920 t gcesareni "Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r, melanocortin receptor subtypes implicated in weight regulation." SIGNOR-51067 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 AT9283 chemical CID:11696609 PUBCHEM JAK2 protein O60674 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190017 PTPRJ protein Q12913 UNIPROT Gbeta proteinfamily SIGNOR-PF4 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-269897 NDUFV1 protein P49821 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-262183 CDK5 protein Q00535 UNIPROT ATM protein Q13315 UNIPROT up-regulates phosphorylation Ser794 LSNCTKKsPNKIASG 9606 BTO:0000938 19151707 t lperfetto "Here we show that cdk5 (cyclin-dependent kinase 5), activated by dna damage, directly phosphorylates atm at ser 794 in post-mitotic neurons. Phosphorylation at ser 794 precedes, and is required for, atm autophosphorylation at ser 1981, and activates atm kinase activity" SIGNOR-183454 PSMD12 protein O00232 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-263352 IFNB1 protein P01574 UNIPROT MGMT protein P16455 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000711 17564708 f miannu "we observed that IFN-beta sensitized TMZ-resistant glioma cells with the unmethylated MGMT promoter and that the mechanism of action was possibly due to attenuation of MGMT expression via induction of TP53. In this context, IFN-beta inactivates MGMT via p53 gene induction and enhances the therapeutic efficacy to TMZ." SIGNOR-255438 "pyridoxal 5'-phosphate(2-)" smallmolecule CHEBI:597326 ChEBI PSAT1 protein Q9Y617 UNIPROT "up-regulates activity" "chemical activation" 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-268561 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 MYF5 protein P13349 UNIPROT Skeletal_muscle_differentiation phenotype SIGNOR-PH1 SIGNOR up-regulates 9606 8288123 f miannu "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 enhancers." SIGNOR-37409 anastrozole chemical CHEBI:2704 ChEBI CYP19A1 protein P11511 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189614 CREB1 protein P16220 UNIPROT SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001379 34751390 t scontino "CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription." SIGNOR-267137 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 KITLG protein P21583 UNIPROT KIT protein P10721 UNIPROT "up-regulates activity" binding 9606 17259966 t mainnu "The most relevant and still unique mast-cell growth factor is SCF, which is the ligand of KIT, a receptor with tyrosine-kinase activity that is expressed on the surface of all human and murine mast cells" SIGNOR-254946 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr179 PQSNIPEtPPPGYLS 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-182822 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 RXRA protein P19793 UNIPROT RARB protein P10826 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-16668 SORBS1 protein Q9BX66 UNIPROT CBL protein P22681 UNIPROT up-regulates binding 9606 BTO:0000887 11001060 t gcesareni "Cbl is recruited to the insulin receptor by interaction with the adapter protein cap, through one of three adjacent sh3 domains in the carboxy terminus of cap" SIGNOR-82283 "prostaglandin E2" smallmolecule CHEBI:15551 ChEBI AKT1 protein P31749 UNIPROT up-regulates "chemical activation" 9606 16293724 t gcesareni "Pge2 also stimulated akt activity in a pi3k-dependent manner." SIGNOR-141817 FOXO6 protein A8MYZ6 UNIPROT 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-236567 F2R protein P25116 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-254852 CEBPA protein P49715 UNIPROT HAMP protein P81172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001950 18671304 f miannu "HCV-induced ROS stabilized the expression of two negative hepcidin regulators, HIF1alpha and HIF2alpha, and its expression was decreased by a HDAC inhibitor or an anti-oxidant. HCV-induced ROS also caused hypoacetylation of histones and inhibited binding of two positive regulators, C/EBPalpha and STAT3, to the hepcidin promoter, whereas anti-oxidant treatment of cells recovered C/EBPalpha and STAT3 binding to the hepcidin promoter." SIGNOR-253770 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 TLR2 protein O60603 UNIPROT TICAM1 protein Q8IUC6 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-266746 AURKB protein Q96GD4 UNIPROT CKAP2 protein Q8WWK9 UNIPROT up-regulates phosphorylation Ser628 FLTPVRRsRRLQEKT 9606 20458174 t lperfetto "Here, we report that tmap is a novel substrate of the aurora b kinase. Ser627 of tmap was specifically phosphorylated by aurora b both in vitro and in vivo. Nearly all mutations at the phosphorylation motif had dramatic effects on the subcellular localization of tmap." SIGNOR-165410 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 ILK protein Q13418 UNIPROT PPP1R14A protein Q96A00 UNIPROT "up-regulates activity" phosphorylation Thr38 QKRHARVtVKYDRRE 9606 12144526 t miannu "Phosphopeptide mapping, phospho amino acid analysis and immunoblotting using phospho-specific antibodies indicated that ilk predominantly phosphorylated the site critical for potent inhibition, i.e. Thr(38) of cpi-17" SIGNOR-90828 TNFRSF17 protein Q02223 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 10903733 f miannu "Overexpression of bcma activates jnk" SIGNOR-79489 DDX21 protein Q9NR30 UNIPROT TICAM1 protein Q8IUC6 UNIPROT "up-regulates activity" binding 10090 21703541 t miannu "We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-κB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA." SIGNOR-260192 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 ethanol chemical CHEBI:16236 ChEBI GLRA2 protein P23416 UNIPROT "up-regulates activity" "chemical activation" 8355 BTO:0000964 8700149 t 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-258496 IL17A protein Q16552 UNIPROT KLF2 protein Q9Y5W3 UNIPROT up-regulates "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-210111 HTR1D protein P28221 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-256864 LPAR1 protein Q92633 UNIPROT GNA12 protein Q03113 UNIPROT up-regulates binding 9606 22863277 t 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." SIGNOR-198507 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 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 SLC36A1 protein Q7Z2H8 UNIPROT proline smallmolecule CHEBI:26271 ChEBI "up-regulates quantity" relocalization 9606 12748860 t lperfetto "Both PAT1 and PAT2 mediate 1:1 symport of protons and small neutral amino acids such as glycine, alanine, and proline.|The first member of the SLC36 family, present in both intracellular and plasma membranes, was identified independently as a lysosomal amino acid transporter (LYAAT1) responsible for the export of lysosomal proteolysis products into the cytosol and as a proton/amino acid transporter (PAT1) responsible for the absorption of amino acids in the gut." SIGNOR-264741 RPS6KA4 protein O75676 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR unknown phosphorylation 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" SIGNOR-265355 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 superoxide smallmolecule CHEBI:18421 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto "The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment." SIGNOR-272277 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 "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 "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194518 NBR1 protein Q14596 UNIPROT GABARAPL2 protein P60520 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-184267 PP2 chemical CHEBI:78331 ChEBI SRC protein P12931 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0001760 12351660 t gcesareni "Treatment of l6 cells with pp2 or su6656, specific inhibitors of src family kinases, and transient transfection of dominant-inhibitory src inhibited the formation of myotubes and expression of myogenin." SIGNOR-93549 NLGN2 protein Q8NFZ4 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-264161 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 KCNJ8 protein Q15842 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-262054 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 EFNA5 protein P52803 UNIPROT EPHA8 protein P29322 UNIPROT up-regulates binding 9606 9330863 t gcesareni "Efna5 are able to activate epha8" SIGNOR-52479 AKT3 protein Q9Y243 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-249644 "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 PLK1 protein P53350 UNIPROT WEE1 protein P30291 UNIPROT down-regulates phosphorylation Ser53 GHSTGEDsAFQEPDS 9606 BTO:0000567 15070733 t gcesareni "Phosphorylation of serines 53 and 123 (s53 and s123) of wee1a by polo-like kinase 1 (plk1) and cdk, respectively, are required for binding to beta-trcp." SIGNOR-123832 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 "ado-trastuzumab emtansine" antibody DB05773 DRUGBANK ERBB2 protein P04626 UNIPROT "down-regulates activity" binding 9606 19010901 t miannu "The anatomy of an antibody–cytotoxic drug conjugate can be divided into three general components: the antibody, the linker, and the cytotoxic drug. The efficacy of any such conjugate is dictated in part by the differential expression of the target antigen in tumor versus normal tissue. HER2 is a clinically validated target for the treatment of breast cancer. Trastuzumab and, more recently, lapatinib are approved for clinical use in women whose breast cancer overexpresses HER2. a trastuzumab conjugate, which simply uses HER2 as an address for the delivery of a potent cytotoxic agent, may offer promise as an effective therapeutic modality." SIGNOR-259882 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 MYC protein P01106 UNIPROT ITGA7 protein Q13683 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 14525975 f lperfetto "This report provides evidence that alpha7 gene expression during muscle differentiation is regulated by the c-Myc transcription factor. In myoblasts, alpha7 is expressed at basal levels, but following conversion to myotubes the expression of the integrin is strongly elevated. The increased alpha7 mRNA and protein levels following myogenic differentiation are inversely correlated with c-Myc expression. Transfection of myoblasts with the c-Myc transcription factor down-regulated alpha7 expression" SIGNOR-241769 DDX5 protein P17844 UNIPROT DDX5/DDX17 complex SIGNOR-C40 SIGNOR "form complex" binding 9606 12595555 t miannu "The highly related dead box rna helicases p68 and p72 exist as heterodimers in cells" SIGNOR-98406 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 CREB5 protein Q02930 UNIPROT RASGRP3 protein Q8IV61 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002815 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-253808 RORA protein P35398 UNIPROT PCP2 protein Q8IVA1 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-266849 CSNK2A1 protein P68400 UNIPROT NFKBIA protein P25963 UNIPROT down-regulates phosphorylation Ser288 PESEDEEsYDTESEF 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-40506 SCNN1A protein P37088 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-269272 NFE2L2 protein Q16236 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-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-256262 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 TGFB1 protein P01137 UNIPROT DNAH10 protein Q8IVF4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 31836722 f miannu "The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation." SIGNOR-265552 TNF protein P01375 UNIPROT DNAH10 protein Q8IVF4 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000667 31836722 f miannu "The protein expression of DNAH10 was assessed by Western blot analysis after stimulation of primary keratinocytes (P4) with inflammatory cytokine TNFα or growth factor TGF-β1 and their combination (Fig. 5C). Treatment with TNFα, TGF-β1, and their combination down regulated the expression of DNAH10 in keratinocytes after a 24-h-stimulation." SIGNOR-265551 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 CSNK1A1 protein P48729 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-264877 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 MAT2B protein Q9NZL9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0001938 30942439 f miannu "MAT2B Promotes Proliferation and Inhibits Apoptosis in Osteosarcoma by Targeting Epidermal Growth Factor Receptor and Proliferating Cell Nuclear Antigen" SIGNOR-261242 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 ZMYND8 protein Q9ULU4 UNIPROT NAV2 protein Q8IVL1 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-266209 DCTPP1 protein Q9H773 UNIPROT ABCB1 protein P08183 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003878 27612427 f Monia "DCTPP1 attenuates the sensitivity of human gastric cancer cells to 5-fluorouracil by up-regulating MDR1 expression epigenetically; Moreover, low expression of DCTPP1 led to the increase in intracellular 5-methyl-dCTP, which was strongly associated with the promoter hyper-methylation, leading to the subsequent low-expression of MDR1 and the increased intracellular accumulation of 5-FU in DCTPP1-knockdown BGC-823 cells. These results provide new insights into the roles of DCTPP1 as a chemosensitizer in clinical application." SIGNOR-261178 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 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 ICAM1 protein P05362 UNIPROT Chemotaxis phenotype SIGNOR-PH93 SIGNOR up-regulates 9606 23994464 f apalma "Before leaving the vessel lumen, neutrophils crawl on the endothelium, primarily using cell surface Mac-1 integrins binding to endothelial ICAM-1. After finding the place for transmigration, neutrophils migrate to the interstitium through transcellular or paracellular routes and begin chemotaxing towards the site of infection/inflammation within the perivascular and interstitial space." SIGNOR-255042 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 KLHL3 protein Q9UH77 UNIPROT WNK1 protein Q9H4A3 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000567 23387299 t miannu "CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms." SIGNOR-272099 KLHL2 protein O95198 UNIPROT WNK4 protein Q96J92 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 23838290 t miannu "We found that KLHL2, as well as KLHL3, was co-immunoprecipitated with all four WNK isoforms. The direct interaction of KLHL2 with WNKs was confirmed on fluorescence correlation spectroscopy. Co-expression of KLHL2 and Cullin3 decreased the abundance of WNK1, WNK3 and WNK4 within HEK293T cells, and a significant increase of WNK4 ubiquitination by KLHL2 and Cullin3 was observed both in HEK293T cells and in an in vitro ubiquitination assay. These results suggest that KLHL2-Cullin3 also functions as an E3-ligase for WNK isoforms within the body." SIGNOR-272118 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 MCM10 protein Q7L590 UNIPROT RECQL4 protein O94761 UNIPROT down-regulates binding 9606 19696745 t miannu "Mcm10 inhibits recq4 helicase activity." SIGNOR-187701 ITGA5 protein P08648 UNIPROT "A5/b1 integrin" complex SIGNOR-C163 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-253177 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 EFNB3 protein Q15768 UNIPROT EPHB3 protein P54753 UNIPROT up-regulates binding 9606 9484836 t gcesareni "Ephrin-b3, a ligand for the receptor ephb3, expressed at the midline of the developing neural tube." SIGNOR-54711 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine chemical CHEBI:91451 ChEBI RAF1 protein P04049 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206385 hydromorphone chemical CHEBI:5790 ChEBI OPRD1 protein P41143 UNIPROT "up-regulates activity" "chemical activation" 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-258143 RPS6KA3 protein P51812 UNIPROT TINF2 protein Q9BSI4 UNIPROT unknown phosphorylation Ser330 ASTGKSKsPCQTLGG 9606 23977114 t lperfetto "Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase rsk2. The consequence of tin2 phosphorylation during mitosis remains to be determined" SIGNOR-202536 PKA proteinfamily SIGNOR-PF17 SIGNOR ARHGEF6 protein Q15052 UNIPROT "down-regulates activity" phosphorylation Ser684 GSSTRKDsIPQVLLP 9606 BTO:0000132 26507661 t lperfetto "Screening for potential mediators of this effect resulted in the identification of the Rac1-specific GTPase-activating protein ARHGAP17 and the guanine nucleotide exchange factor ARHGEF6 as new PKA and PKG substrates in platelets. We mapped the PKA/PKG phosphorylation sites to serine 702 on ARHGAP17 using Phos-tag gels and to serine 684 on ARHGEF6. |we show that ARHGEF6 is constitutively linked to GIT1, a GAP of Arf family small G proteins, and that ARHGEF6 phosphorylation enables binding of the 14-3-3 adaptor protein to the ARHGEF6/GIT1 complex." SIGNOR-272160 C1QBP protein Q07021 UNIPROT KRT1 protein P04264 UNIPROT "up-regulates activity" binding 9606 14691569 t "Regulation of binding" miannu "Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored." SIGNOR-251881 CDK1 protein P06493 UNIPROT EZH2 protein Q15910 UNIPROT down-regulates phosphorylation Thr487 APAEDVDtPPRKKKR 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-174058 CDK5/CDK5R1 complex SIGNOR-C144 SIGNOR 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-251587 SATB1 protein Q01826 UNIPROT AREG protein P15514 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-255133 HIPK1 protein Q86Z02 UNIPROT DAXX protein Q9UER7 UNIPROT "down-regulates activity" phosphorylation Ser668 KKICTLPsPPSPLAS 9606 12529400 t Manara "HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. | Therefore, phosphorylation at Ser 669 by HIPK1 diminishes the ability of Daxx to repress transcription." SIGNOR-260842 simvastatin chemical CHEBI:9150 ChEBI HMGCR protein P04035 UNIPROT "down-regulates activity" "chemical inhibition" -1 1433193 t miannu "Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro." SIGNOR-258348 FBXO45 protein P0C2W1 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 25460509 t miannu "One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively." SIGNOR-272182 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 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 HMGA2 protein P52926 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 25300915 f miannu "This study unraveled a novel function ofhmga2in induction of apoptosis in human primary cell lines" SIGNOR-205465 JAK1 protein P23458 UNIPROT STAT3 protein P40763 UNIPROT "up-regulates activity" phosphorylation 9606 26260587 t "IL10R2 recruits cytoplasmic protein Jak1 followed by phosphorylation of tyrosine at position 705 in the STAT3 (705Y-STAT3) molecule. Phosphorylated STAT3 forms a homodimer, which is then translocated to the nucleus to facilitate transcriptional regulation of target genes." SIGNOR-253590 PRKCB protein P05771 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-249247 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 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 MECP2 protein P51608 UNIPROT GPRIN1 protein Q7Z2K8 UNIPROT "up-regulates quantity by expression" "post transcriptional regulation" 10090 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-264679 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 JAK1 protein P23458 UNIPROT IL2RB protein P14784 UNIPROT "up-regulates activity" phosphorylation Tyr536 LPLNTDAyLSLQELQ 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-251341 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser338 PAPKLVEsPKEGKGS 9534 BTO:0000298 14623875 t llicata "DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase." SIGNOR-251088 CDK2 protein P24941 UNIPROT NPM1 protein P06748 UNIPROT "down-regulates activity" phosphorylation Thr234 SFKKQEKtPKTPKGP 9606 SIGNOR-C16 12058066 t gcesareni "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-89609 AKT1 protein P31749 UNIPROT 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-252521 CYP19A1 protein P11511 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI "down-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-268672 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 CSNK2A1 protein P68400 UNIPROT XRCC1 protein P18887 UNIPROT "up-regulates activity" phosphorylation Ser475 IDIEGVQsEGQDNGA 10029 BTO:0002640 15066279 t llicata "We show that inhibiting XRCC1 phosphorylation by mutation of the CK2 phosphorylation sites or preventing CK2 activity using a highly specific inhibitor ablates the rapid repair of cellular DNA single-strand breaks by XRCC1. |" SIGNOR-250972 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 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 CDK9 protein P50750 UNIPROT SMAD1 protein Q15797 UNIPROT down-regulates phosphorylation Ser214 PTSSDPGsPFQMPAD 9606 19914168 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-161666 "PAR-1 (Protease-Activated Receptor) Selective Activating Peptide" smallmolecule CID:71312048 PUBCHEM F2RL1 protein P55085 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-257485 solifenacin chemical CHEBI:135530 ChEBI CHRM3 protein P20309 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-258313 CALM2 protein P0DP24 UNIPROT CAMKK2 protein Q96RR4 UNIPROT up-regulates binding 9606 BTO:0000782 BTO:0000142 9822657 t miannu "The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk." SIGNOR-266329 "BRCA1-BARD1 complex" complex SIGNOR-C297 SIGNOR "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-263216 EGFR protein P00533 UNIPROT CCDC50 protein Q8IVM0 UNIPROT "down-regulates activity" phosphorylation Tyr279 TDGEDADyTHFTNQQ 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-262851 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 TNF protein P01375 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-252285 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 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 MK-2206 chemical CHEBI:67271 ChEBI AKT2 protein P31751 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-176046 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser213 QNIPAHYsPRTSPIM 9606 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-248516 PTH1R protein Q03431 UNIPROT LRP6 protein O75581 UNIPROT up-regulates binding 9606 23151663 t gcesareni "Parathyroid hormone (pth) binding to its receptor pth1r induces association of the pthpth1r complex with lrp6and phosphorylation of pppsp sites by protein kinase_ a, which in turn triggers wnt." SIGNOR-199533 GRB10 protein Q13322 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 10090 BTO:0001516 23246379 t "Grb10 transduces signal from FLT3 by direct interaction with p85 and Ba/F3-FLT3-ITD cells expressing Grb10 exhibits higher STAT5 activation" SIGNOR-255946 GSK3B protein P49841 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR "form complex" binding 9606 BTO:0000586 9734785 t lperfetto "Axin, an inhibitor of the wnt pathway, interacts with beta-catenin, gsk-3beta and apc and reduces the beta-catenin level." SIGNOR-227299 CTDSP1 protein Q9GZU7 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1644 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-248781 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 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 HSPA1A protein P0DMV8 UNIPROT FLCN protein Q8NFG4 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 27353360 t "These data suggest that inhibition of Hsp70 does not lead to an increase in misfolded FLCN but instead to its degradation." SIGNOR-256506 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 PLCG1 protein P19174 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser146 GRKRRQTsMTDFYHS 9606 31575057 t gcesareni "Phosphorylation at Ser-146 by PKCδ increases p21 stability" SIGNOR-262962 KLKB1 protein P03952 UNIPROT KNG1 protein P01042 UNIPROT "up-regulates activity" cleavage Arg389 PPGFSPFrSSRIGEI 9606 BTO:0000131 cleavage:Arg390 CTTKTSTrIVGGTNS 28966616 t lperfetto "Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1)." SIGNOR-263548 CLASP1 protein Q7Z460 UNIPROT CLIP1 protein P30622 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 15631994 t 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-265091 MSN protein P26038 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-268434 Phagocytosis phenotype SIGNOR-PH97 SIGNOR TGFB1 protein P01137 UNIPROT "up-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-255444 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 furtrethonium chemical CHEBI:134764 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-258642 PTPN1 protein P18031 UNIPROT CAV1 protein Q03135 UNIPROT unknown dephosphorylation Tyr14 VDSEGHLyTVPIREQ -1 16388599 t "The scaffolding protein caveolin-1 is also a participant in these pathways and is specifically phosphorylated on tyrosine 14, when these pathways are activated. Here, we provide evidence that PTP1B can efficiently catalyze the removal of the phosphoryl group from phosphocaveolin-1." SIGNOR-248430 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 SLC2A2 protein P11168 UNIPROT α-D-glucose smallmolecule CHEBI:17925 ChEBI "up-regulates quantity" relocalization 9606 25421524 t "The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion." SIGNOR-267385 AKT proteinfamily SIGNOR-PF24 SIGNOR CFLAR protein O15519 UNIPROT "down-regulates quantity" phosphorylation Ser273 LLRDTFTsLGYEVQK 9606 19339247 t gcesareni "TNFalpha enhanced FLIP(L) serine phosphorylation, which was increased by activated Akt-1. Serine 273, a putative Akt-1 phosphorylation site in FLIP(L), was critical for the activation-induced reduction of FLIP(L). Thus, these observations document a novel mechanism where by TNFalpha facilitates the reduction of FLIP(L) protein, which is dependent on the phosphatidylinositol 3-kinase/Akt signaling." SIGNOR-245304 HIF1A protein Q16665 UNIPROT TM9SF4 protein Q92544 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001545 25961573 t miannu "Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion." SIGNOR-266705 NfKb-p65/p50 complex SIGNOR-C13 SIGNOR GADD45B protein O75293 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 11713530 f gcesareni "Here we report that nf-kappab complexes downregulate the c-jun amino-terminal kinase (jnk) cascade, thus establishing a link between the nf-kappab and the jnk pathways. This link involves the transcriptional upregulation of gadd45beta/myd118, which downregulates jnk induced by the tnf receptor (tnf-r)." SIGNOR-111963 TNF protein P01375 UNIPROT PIK3CD protein O00329 UNIPROT up-regulates 9606 10485710 f gcesareni "Tnf activates phosphatidylinositol-3-oh kinase (pi(3)k)" SIGNOR-70622 ZFX protein P17010 UNIPROT FBP1 protein P09467 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0003081;BTO:0000849 30616754 t lperfetto "For instance, nucleophosmin (NPM1) and zinc-finger protein X-linked (ZFX) bind to the E-box and ZFX binding site on the FBP1 promoter, respectively, and restrain FBP1 expression to facilitate aerobic glycolysis in PDAC and melanoma" SIGNOR-267595 MTHFD2 protein P13995 UNIPROT (6R)-5,10-methenyltetrahydrofolate smallmolecule CHEBI:57455 ChEBI "up-regulates quantity" "chemical modification" 9606 16100107 t lperfetto "Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase|One of the enzymes in this pathway, the NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC),5 catalyzes the interconversion of 5,10-methylenetetrahydrofolate (methylene-THF) and 10-formyltetrahydrofolate (formyl-THF) in mammalian mitochondria." SIGNOR-268255 CAMK2A protein Q9UQM7 UNIPROT SRF protein P11831 UNIPROT "up-regulates activity" phosphorylation Ser103 RGLKRSLsEMEIGMV 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-250638 "phosphatidylinositol bisphosphate" smallmolecule CHEBI:37328 ChEBI CADPS2 protein Q86UW7 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000938 24363652 t miannu "CAPS exhibits low affinity but functionally significant interactions with plasma membrane PIP2 via its central PH (pleckstrin homology) domain (82, 111). PIP2 enhanced CAPS stimulation of SNARE-dependent liposome fusion with wild-type but not with mutant PH domain CAPS proteins" SIGNOR-264335 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 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 APAF1 protein O14727 UNIPROT CASP9 protein P55211 UNIPROT up-regulates binding 9606 9390557 t gcesareni "During apoptosis, apaf-1 binds to cytochrome c and in the presence of atp/datp forms an apoptosome, leading to the recruitment and activation of the initiator caspase, caspase-9 .in particular, caspase-9 is recruited and activated by apaf-1 .casp9 and apaf-1 bind to each other via their respective nh2-terminal ced-3 homologous domains in the presence of cycs and datp, an event that leads to casp9 activation." SIGNOR-53579 CSNK2A1 protein P68400 UNIPROT HMGA1 protein P17096 UNIPROT unknown phosphorylation Ser103 EGISQESsEEEQ -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-250893 WNT16 protein Q9UBV4 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-131677 PRKCA protein P17252 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser303 RGAPPRRsSIRNAHS 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-89150 HLA-G protein P17693 UNIPROT KIR2DL4 protein Q99706 UNIPROT up-regulates binding 9606 10190900 t gcesareni "Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules." SIGNOR-66132 leucine smallmolecule CHEBI:25017 ChEBI Glutaminolysis phenotype SIGNOR-PH119 SIGNOR "up-regulates activity" 9606 BTO:0000567 22749528 f Luana "Leucine and Glutamine Activate Glutaminolysis and mTORC1" SIGNOR-268011 glutamine smallmolecule CHEBI:28300 ChEBI Gln-tRNA(Gln) smallmolecule CHEBI:29166 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-270394 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr1189 RDIYETDyYRKGGKG -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-254704 ABL1 protein P00519 UNIPROT MUC1 protein P15941 UNIPROT "up-regulates quantity by stabilization" phosphorylation Tyr1243 NGGSSLSyTNPAVAA 9606 16888623 t Manara "The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site. " SIGNOR-260830 BTF3 protein P20290 UNIPROT ATM protein Q13315 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-253948 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 chlorphenamine chemical CHEBI:52010 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-257786 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 HECTD4 protein Q9Y4D8 UNIPROT AR protein P10275 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-267148 EIF3F protein O00303 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates deubiquitination Lys1759 CGVLLSRkRRRQHGQ 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-170158 HIF1A protein Q16665 UNIPROT NT5E protein P21589 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000414 12370277 f miannu "Examination of the CD73 gene promoter identified at least one binding site for hypoxia-inducible factor-1 (HIF-1) and inhibition of HIF-1alpha expression by antisense oligonucleotides resulted in significant inhibition of hypoxia-inducible CD73 expression" SIGNOR-254423 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 SEMA3C protein Q99985 UNIPROT NRP2 protein O60462 UNIPROT up-regulates binding 9606 BTO:0000938 16816121 t gcesareni "Our experiments establish that small peptides containing the consensus decd sequence of sperm fertilinbeta bind specifically to an alpha6beta1 integrin receptor on the egg membrane. We conclude that fertilinbeta binds directly to the alpha6beta1 integrin on the egg surface and this partnership mediates sperm-egg fusion." SIGNOR-147564 MAP2K3 protein P46734 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" phosphorylation Thr180 RHTDDEMtGYVATRW 9606 8622669 t lperfetto "Mkk3 is a protein kinase that phosphorylates and activates p38 map kinase but does not phosphorylate the related jnk or erk map kinases." SIGNOR-40349 CAMK1 protein Q14012 UNIPROT DNM1L protein O00429 UNIPROT "up-regulates activity" phosphorylation Ser637 VPVARKLsAREQRDC 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-262552 PKI-587 chemical CID:44516953 PUBCHEM PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-205989 MAX protein P61244 UNIPROT MGA protein Q8IWI9 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-240261 MAPK3 protein P27361 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Ser551 ELQAPVRsPITRSFA 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-249461 GRK2 protein P25098 UNIPROT OPRD1 protein P41143 UNIPROT "down-regulates activity" phosphorylation Thr358 ATARERVtACTPSDG 9606 BTO:0000007 11040053 t "GRK2 strongly enhanced agonist-stimulated phosphorylation of the wild-type DOR (WT), but Delta15 or mutant DOR (T358A/T361A/S363G) failed to show any detectable phosphorylation under these conditions. agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus. GRKs are important mediators in agonist-induced opioid receptor phosphorylation and desensitization." SIGNOR-251457 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 GLS2 protein Q9UI32 UNIPROT glutamine smallmolecule CHEBI:28300 ChEBI "down-regulates quantity" "chemical modification" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266909 RPS6KA1 protein Q15418 UNIPROT NR4A3 protein Q92570 UNIPROT unknown phosphorylation Ser376 GRRGRLPsKPKSPLQ 9606 BTO:0000007 16223362 t lperfetto "We have established that two related proteins, Nurr1 and Nor1, are also phosphorylated on the equivalent site by RSK in cells in response to mitogenic stimulation. | Similar to Nur77, when FLAG€“Nor1 was expressed in HEK-293 cells, its phosphorylation on Ser377 was stimulated by both PMA and EGF" SIGNOR-249297 MTOR protein P42345 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Thr412 NQVFLGFtYVAPSVL 9606 BTO:0000007 SIGNOR-C3 10579915 t lperfetto "S6 kinases are under the control of the PI3K relative, mammalian Target Of Rapamycin (mTOR), which may serve an additional function as a checkpoint for amino acid availability." SIGNOR-72682 FYN protein P06241 UNIPROT FYB1 protein O15117 UNIPROT "up-regulates activity" phosphorylation Tyr651 LDMGDEVyDDVDTSD 9606 10570256 t " two tyrosines, Tyr595 and Tyr651, of FYB are major sites of phosphorylation by FYN-T and mediate binding to SLP-76 in Jurkat T cells. We further demonstrate that the loss of SLP-76 binding by mutation of these sites markedly reduced the ability of FYN-T-FYB-SLP-76 to up-regulate IL-2 transcription." SIGNOR-251164 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 NME1 protein P15531 UNIPROT NME1 protein P15531 UNIPROT "up-regulates activity" phosphorylation Ser44 GLKFMQAsEDLLKEH 9606 BTO:0000093 8245015 t miannu "An acid-stable (nonhistidine) phosphorylation was identified on autophosphorylated purified recombinant Nm23 proteins and [32P]orthophosphate-labeled human breast carcinoma and murine melanoma Nm23. Phosphoamino acid analysis identified serine as the acid-stable phosphorylation and serine 44 as the major site of phosphorylation. The biological relevance of the novel phosphorylation identified herein is suggested by the direct correlation of in vivo Nm23 acid-stable phosphorylation levels, but not Nm23 NDPK activity, with suppression of tumor metastatic potential among control and nm23-1 transfected murine melanoma cells." SIGNOR-250303 LRAT protein O95237 UNIPROT retinol smallmolecule CHEBI:50211 ChEBI "down-regulates quantity" "chemical modification" 10090 18093970 t lperfetto "We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis" SIGNOR-265110 "lysophosphatidic acids" smallmolecule CHEBI:32957 ChEBI LPAR1 protein Q92633 UNIPROT up-regulates "chemical activation" 10116 BTO:0003293 8276865 t milica "LPA activates its own G protein-coupled receptor(s) leading to stimulation of phospholipase C and inhibition of adenylate cyclase." SIGNOR-37365 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 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1132 TLPHGPRsASVSSIS 9606 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 hSos1.Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1" SIGNOR-43939 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 FBXW7 protein Q969H0 UNIPROT MYC protein P01106 UNIPROT "down-regulates quantity" ubiquitination 9606 SIGNOR-C135 20852628 t gcesareni "We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it." SIGNOR-243545 ABL1 protein P00519 UNIPROT RACK1 protein P63244 UNIPROT up-regulates phosphorylation Tyr52 LTRDETNyGIPQRAL 9606 19423701 t lperfetto "Phosphorylation of rack1 on tyrosine 52 by c-abl is required for insulin-like growth factor i-mediated regulation of focal adhesion kinase.Tyrosine 52 is further shown to be phosphorylated by c-abl kinase, and the c-abl inhibitor sti571 disrupts fak interaction with rack1" SIGNOR-185649 PTEN protein P60484 UNIPROT "SL1 complex" complex SIGNOR-C464 SIGNOR "down-regulates quantity by destabilization" 16055704 f lperfetto "PTEN represses RNA Polymerase I transcription by disrupting the SL1 complex" SIGNOR-269645 (8R)-7-propyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-13,14-diol chemical CHEBI:92234 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-258731 XIAP protein P98170 UNIPROT CASP3 protein P42574 UNIPROT "down-regulates activity" binding 9606 10548111 t amattioni "The linker region located adjacent to the bir2 domain also participates in the binding of xiap to the effector caspases (-3 and -7)." SIGNOR-71954 TGFB2 protein P61812 UNIPROT TGFBR3 protein Q03167 UNIPROT up-regulates binding 9606 10746731 t gcesareni "Betaglycan binds tgf-b isoforms with high affinity and increases the functional interaction between tgf-b and its type ii and type i signalling receptors." SIGNOR-76473 CDH19 protein Q9H159 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-265858 AKT proteinfamily SIGNOR-PF24 SIGNOR CLK2 protein P49760 UNIPROT up-regulates phosphorylation Thr127 RRRRRSRtFSRSSSQ 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-244218 TP53INP1 protein Q96A56 UNIPROT GABARAP protein O95166 UNIPROT up-regulates binding 9606 22421968 t gcesareni "Tp53inp1 is also able to interact with atg8-family proteins" SIGNOR-196664 FGFR1 protein P11362 UNIPROT FGFR1 protein P11362 UNIPROT up-regulates phosphorylation Tyr585 PPGLEYCyNPSHNPE 10116 19224897 t lperfetto "Autophosphorylation of Y653 is followed by the ordered autophosphorylation of several key tyrosine residues within binding sites for the SH2 or PTB domains of signaling proteins that bind to and are phosphorylated by activated FGFR1. This second-stage autophosphorylation occurs on Y583, in the kinase insert region (a noncatalytic sequence within the kinase domain), followed by autophosphorylation of Y463 in the juxtamembrane region, Y766 in the C-terminal tail, and Y585 in the kinase insert region" SIGNOR-235682 STOML2 protein Q9UJZ1 UNIPROT ATP smallmolecule CHEBI:15422 ChEBI "up-regulates quantity" 9606 20359165 f Giorgia "In addition, mitochondrial and whole-cell ATP levels in resting SLP-2hi T cells were significantly higher than those in SLP-2lo T cells (P < 0.05) (Fig. 7d). Such an increase in ATP levels in SLP-2hi T cells correlated with increased resistance to depletion of mitochondrial ATP with oligomycin" SIGNOR-260384 UCHL5 protein Q9Y5K5 UNIPROT SMAD2 protein Q15796 UNIPROT "up-regulates activity" deubiquitination 9606 16027725 t lperfetto "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases" SIGNOR-217610 MAPK11 protein Q15759 UNIPROT RPS6KA5 protein O75582 UNIPROT up-regulates phosphorylation Thr700 LSSNPLMtPDILGSS 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-59451 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 ATM protein Q13315 UNIPROT XPA protein P23025 UNIPROT unknown phosphorylation Ser196 RSLEVWGsQEALEEA -1 16540648 t llicata "Kinase phosphorylation assays were done with synthesized short peptides (20-mer) with the sequences at Ser173 and Ser196 of XPA, respectively. Both peptides seemed to be good substrates for DNA-PK, ATR ( Fig. 2D), and ATM (data not shown)." SIGNOR-250580 PDK2 protein Q15119 UNIPROT PDHA1 protein P08559 UNIPROT down-regulates phosphorylation Ser232 NRYGMGTsVERAAAS -1 7782287 t gcesareni "Sites 1, 2, and 3 in the E1 mutants were phosphorylated either individually or in the presence of the other sites by the dihydrolipoamide acetyltransferase-protein X-E1 kinase indicating a site-independent mechanism of phosphorylation." SIGNOR-33040 GIT1 protein Q9Y2X7 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 14523024 t gcesareni "Git1 interaction with plcgamma is required for plcgamma activation based on inhibition of tyrosine phosphorylation" SIGNOR-118454 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR PPARG protein P37231 UNIPROT "down-regulates activity" 9606 17139329 f 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-253537 MAPK1 protein P28482 UNIPROT TSC1 protein Q92574 UNIPROT down-regulates phosphorylation 9606 BTO:0000150;BTO:0001573 17671177 t gcesareni "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 signalin." SIGNOR-157162 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 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-258214 CH5132799 chemical CID:49784945 PUBCHEM PIK3CG protein P48736 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190952 SYNE1 protein Q8NF91 UNIPROT MSH2/MSH6 complex SIGNOR-C60 SIGNOR "up-regulates activity" binding 9606 BTO:0001950 24781983 t miannu "Nesprin-1 is involved in the DNA Damage Response network. The Nesprin-1 interaction with MSH2 and MSH6 (MutSα complex) is a constitutive cellular event required for proper DNA repair." SIGNOR-261823 YWHAE protein P62258 UNIPROT NDEL1 protein Q9GZM8 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 17202468 t miannu "14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation" SIGNOR-252160 JMJD1C protein Q15652 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" demethylation 9606 BTO:0000007 32034158 t miannu "We now determine that JMJD1C is recruited by USF-1 to various lipogenic genes for H3K9 demethylation to enhance chromatin accessibility in the fed state." SIGNOR-265331 cabozantinib chemical CHEBI:72317 ChEBI KDR protein P35968 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207842 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 BLM protein P54132 UNIPROT UIMC1 protein Q96RL1 UNIPROT "up-regulates activity" binding 9606 BTO:0001938 23708797 t miannu "Here, we demonstrate that the ubiquitin/SUMO-dependent DNA damage response (UbS-DDR), controlled by the E3 ligases RNF8/RNF168, triggers BLM recruitment to sites of replication fork stalling via ubiquitylation in the N-terminal region of BLM and subsequent BLM binding to the ubiquitin-interacting motifs of . " SIGNOR-272116 SMURF2 protein Q9HAU4 UNIPROT SMAD5 protein Q99717 UNIPROT down-regulates ubiquitination 9606 22298955 t 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-193378 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 KLC1 protein Q07866 UNIPROT TOR1A protein O14656 UNIPROT "up-regulates activity" binding 10116 14970196 t Monia "We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding." SIGNOR-261172 TCF12 protein Q99081 UNIPROT NOTCH3 protein Q9UM47 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 22577461 f miannu "Hebalt positively regulates t-cell genes, such as pt_ and notch3" SIGNOR-197517 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 SRC protein P12931 UNIPROT CTNND1 protein O60716 UNIPROT "up-regulates activity" phosphorylation Tyr302 DYGMMSDyGTARRTG -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-246504 PTPN12 protein Q05209 UNIPROT WAS protein P42768 UNIPROT "down-regulates activity" dephosphorylation Tyr291 AETSKLIyDFIEDQG 10090 14707117 t "Mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities|WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST" SIGNOR-248660 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 PRKACA protein P17612 UNIPROT CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0001103 21902831 t gcesareni "Phosphorylation of CREB by PKA allows it to initiate the transcription of genes that contain a CRE element, two of which are PAX3 and MYF5." SIGNOR-176560 MAPK1 protein P28482 UNIPROT PDE4D protein Q08499 UNIPROT down-regulates phosphorylation 9606 10828059 t "The effect has been demonstrated using Q08499-2" llicata "Long pde4d forms are inhibited by erk2 phosphorylation" SIGNOR-77574 NAE complex SIGNOR-C131 SIGNOR CUL9 protein Q8IWT3 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-243169 "MYOD1/SWI/SNF complex" complex SIGNOR-C93 SIGNOR TNNT3 protein P45378 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-136942 PTPRC protein P08575 UNIPROT LCK protein P06239 UNIPROT "down-regulates activity" dephosphorylation Tyr394 RLIEDNEyTAREGAK 9606 11259588 t "Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity" SIGNOR-248351 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 ezogabine chemical CHEBI:68584 ChEBI KCNQ3 protein O43525 UNIPROT up-regulates "chemical activation" 9606 Other t "Selleck;anticonvulsant for KCNQ2/3 currents" gcesareni SIGNOR-206541 AKT proteinfamily SIGNOR-PF24 SIGNOR Survival phenotype SIGNOR-PH13 SIGNOR up-regulates 9606 16288293 f miannu "Akt promotes both cell growth and cell survival by inactivating its downstream substrates including GSK3, BAD, FOXO and TSC2." SIGNOR-251550 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser312 TESITATsPASMVGG 10116 BTO:0004428 12510059 t lperfetto "Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylationOne of the specific Ser phosphorylation sites in IRS-1 that has been proposed to negatively modulate the insulin signal is Ser312 (numbered according to the human sequence). Prior studies have demonstrated that IRS-1 associates with and is phosphorylated by JNK in vitro on Ser312" SIGNOR-236591 MAPK8 protein P45983 UNIPROT IRS1 protein P35568 UNIPROT down-regulates phosphorylation Ser315 ITATSPAsMVGGKPG 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-118861 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 UBE3A protein Q05086 UNIPROT MCM7 protein P33993 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000567 9852095 t miannu "The characterization of this interaction in turn led to the discovery that Mcm7 is a substrate for both E6-AP-dependent and -independent ubiquitination and is specifically targeted for degradation by the 26 S proteasome." SIGNOR-272543 BAD protein Q92934 UNIPROT Survival phenotype SIGNOR-PH13 SIGNOR down-regulates 9606 BTO:0000830 15526160 f miannu "C-Kit promotes survival via PI3-kinase-dependent activation of Akt and phosphorylation of Bad, a pro-apoptotic molecule, at S136 in vivo." SIGNOR-254953 RANBP2 protein P49792 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-262088 PLK4 protein O00444 UNIPROT TUBGCP6 protein Q96RT7 UNIPROT "up-regulates activity" phosphorylation Ser1114 HGHVSNAsIRVGENV -1 22302995 t miannu "Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication." SIGNOR-262902 Cullin4-RBX1-DDB1 complex SIGNOR-C119 SIGNOR WIPI2 protein Q9Y4P8 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 30898011 t miannu "Here we show that WIPI2/ATG18B (WD repeat domain, phosphoinositide interacting 2), an autophagy-related (ATG) protein that plays a critical role in autophagosome biogenesis, is a direct substrate of CUL4-RING ubiquitin ligases (CRL4s)" SIGNOR-272302 BMAL1/NPAS2 complex SIGNOR-C431 SIGNOR PER2 protein O15055 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-267969 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 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 "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 2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol chemical CHEBI:93773 ChEBI ARAF protein P10398 UNIPROT down-regulates "chemical inhibition" 9606 12970777 t gcesareni "At drug concentrations around the reported ic(50) for the raf inhibitor l-779,450, it suppressed dna synthesis and induced apoptosis in hematopoietic fdc-p1 cells transformed to grow in response to either raf-1 or a-raf (fd/deltaraf-1:er and fd/deltaa-raf:er)" SIGNOR-100355 PRCC protein Q92733 UNIPROT MAD2L2 protein Q9UI95 UNIPROT up-regulates relocalization 9606 15218244 t miannu "We found that the human papillary renal cell carcinoma-associated proteinprccinteracts with the cell cycle control proteinmad2b, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function." SIGNOR-126516 AKT proteinfamily SIGNOR-PF24 SIGNOR TSC2 protein P49815 UNIPROT "down-regulates activity" phosphorylation Thr1462 GLRPRGYtISDSAPS 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-244365 GAST protein P01350 UNIPROT EGR1 protein P18146 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000269 22228178 f "Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation." SIGNOR-254252 SP4 protein Q02446 UNIPROT CRX protein O43186 UNIPROT "up-regulates activity" binding 9606 15781457 t miannu "Sp4 directly binds Crx. Sp4 and Sp1 produce much higher levels of transcriptional activation when co-transfected with Crx, they may additionally act by directly increasing the rate of transcriptional initiation by the general transcriptional apparatus through their activation domains." SIGNOR-225333 PRKCA protein P17252 UNIPROT CBL protein P22681 UNIPROT "down-regulates quantity" phosphorylation Ser642 PRLGSTFsLDTSMSM 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-249057 SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR M2_polarization phenotype SIGNOR-PH55 SIGNOR up-regulates 9606 27418133 f "The SMAD2/3 and PI3K/AKT signaling pathways were crucial for TGF-?-induced SNAIL overexpression in THP-1 cells. These findings suggest that TGF-? skews macrophage polarization towards a M2-like phenotype via SNAIL up-regulation, and blockade of TGF-?/SNAIL signaling restores the production of pro-inflammatory cytokines" SIGNOR-253587 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 ROS stimulus SIGNOR-ST2 SIGNOR ARNT protein P27540 UNIPROT "up-regulates quantity by expression" 22387692 f lperfetto "Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species." SIGNOR-253689 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 Diprenorphine chemical CHEBI:4650 ChEBI OPRK1 protein P41145 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-258791 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 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 ITGB2 protein P05107 UNIPROT "AX/b2 integrin" complex SIGNOR-C171 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-253194 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 dopamine smallmolecule CHEBI:18243 ChEBI noradrenaline smallmolecule CHEBI:33569 ChEBI "up-regulates quantity" "precursor of" 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-264182 GGCX protein P38435 UNIPROT F9 protein P00740 UNIPROT "up-regulates activity" carboxylation Glu54 YNSGKLEeFVQGNLE 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-263687 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 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 18-hydroxycorticosterone smallmolecule CHEBI:16485 ChEBI aldosterone smallmolecule CHEBI:27584 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-268686 GPCR proteinfamily SIGNOR-PF33 SIGNOR GNB/GNG complex SIGNOR-C202 SIGNOR "up-regulates activity" binding 9606 23994464 t miannu "Instead, our current understanding is that the majority of GPCR signal transduction in neutrophils occurs through the G gamma/beta subunit. G-protein-coupled receptors in neutrophils primarily signal through the Gβγ heterodimer, activating two parallel pathways through PLCβ2/3 and PI3Kγ." SIGNOR-255007 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 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 PRKCQ protein Q04759 UNIPROT ITGB1 protein P05556 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000165 26431586 f lperfetto "It is known that the teta isoform of the PKC family promotes the fusion of myoblasts and regulates the expression of caveolin-3 and beta1D integrin [15]. Of note, it has also been demonstrated that PKCepsilon expression increases during insulin-induced myogenic differentiation of the C2C12 cells." SIGNOR-241525 FBXO2 protein Q9UK22 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 10090 BTO:0000938 20854419 t miannu "SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced β-amyloid production." SIGNOR-271902 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 "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 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 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 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 MAPK3 protein P27361 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-249467 RIN1 protein Q13671 UNIPROT HRAS protein P01112 UNIPROT up-regulates binding 9606 11784866 t gcesareni "We demonstrate that the ras effector protein rin1 binds to activated ras with an affinity (k(d), 22 nm) similar to that observed for raf1." SIGNOR-113967 PDPK2P protein Q6A1A2 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Thr256 EHNSTTStFCGTPEY 9606 10191262 t gcesareni "Our results are consistent with a model in which activation of sgk by igf-1 or hydrogen peroxide is initiated by a ptdins(3,4, 5)p3-dependent activation of pdk2, which phosphorylates ser422." SIGNOR-66234 CSNK2A1 protein P68400 UNIPROT HCLS1 protein P14317 UNIPROT unknown phosphorylation Thr23 TQGDDWDtDPDFVND 9606 10806407 t llicata "The in vivo Ser/Thr phosphorylation of HS1 is enhanced by okadaic acid and reduced by specific inhibitors of casein kinase (CK)2. In vitro, HS1 is an excellent substrate for either CK2 alpha subunit alone (Km = 47 nM) or CK2 holoenzyme | It is likely therefore that Thr16 and/or Thr23 account for the phosphate incorporated into HS1 threonyl residue(s) upon incubation with CK2." SIGNOR-250886 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 ponatinib chemical CHEBI:78543 ChEBI ABL1 protein P00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206277 DACT2 protein Q5SW24 UNIPROT TGFBR1 protein P36897 UNIPROT down-regulates binding 9606 17197390 t lpetrilli "Here, we provide evidence that unlike dpr1 that modulates wnt signaling, mdpr2 negatively regulates tgf-? Signaling and promotes tgf-? Receptor degradation in lysosomes. these results suggest that mdpr2 interferes with tgf-? By directly binding to and targeting the receptors for lysosomal inhibitor-sensitive degradation." SIGNOR-151750 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 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 NSD1 protein Q96L73 UNIPROT NfKb-p65/p50 complex SIGNOR-C13 SIGNOR up-regulates methylation 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-217388 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 PTPN2 protein P17706 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-75918 DUSP1 protein P28562 UNIPROT MAPK14 protein Q16539 UNIPROT "down-regulates activity" dephosphorylation 9606 BTO:0000567 12356755 t gcesareni "Here we show that glucocorticoids synergistically enhance nthi-induced tlr2 expression via specific up-regulation of the mapk phosphatase-1 (mkp-1) that, in turn, leads to dephosphorylation and inactivation of p38 mapk, the negative regulator for tlr2 expression." SIGNOR-93873 RNF216 protein Q9NWF9 UNIPROT TLR8 protein Q9NR97 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 31385713 t miannu "E3 ligase RNF216 (ring finger protein 216) targets TLR8 for ubiquitination and degradation. " SIGNOR-272257 UBXN1 protein Q04323 UNIPROT NGLY1 protein Q96IV0 UNIPROT "up-regulates activity" binding 9606 15362974 t miannu "PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome." SIGNOR-261060 USP8 protein P40818 UNIPROT EGFR protein P00533 UNIPROT "up-regulates quantity by stabilization" deubiquitination 9606 BTO:0000567 16120644 t irozzo "Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells." SIGNOR-259103 CRTC2 protein Q53ET0 UNIPROT NR3C1 protein P04150 UNIPROT "up-regulates activity" binding 9606 26652733 t "We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR)." SIGNOR-256101 PPP2CA protein P67775 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.|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-248648 SMARCC1 protein Q92922 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-270709 Crenolanib chemical CID:10366136 PUBCHEM PDGFRA protein P16234 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191121 GSK3B protein P49841 UNIPROT RELA protein Q04206 UNIPROT "up-regulates activity" phosphorylation Thr254 RQVAIVFRtPPYADPS 10090 BTO:0000249 22761446 t "Redundant functions of GSK-3_ and GSK-3_ through phosphorylation of RelA at Thr-254 play a crucial role in early stages of chondrocyte differentiation" SIGNOR-255828 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 "nitric oxide" smallmolecule CHEBI:16480 ChEBI ROS stimulus SIGNOR-ST2 SIGNOR up-regulates 9606 35681445 f lperfetto "The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment." SIGNOR-272279 ARHGEF15 protein O94989 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-260541 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 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 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide chemical CHEBI:91433 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-195675 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 24239470 t miannu "The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis" SIGNOR-251530 SLC6A4 protein P31645 UNIPROT serotonin smallmolecule CHEBI:28790 ChEBI "up-regulates quantity" relocalization 9606 BTO:0000132 17506858 t miannu "Serotonin (5HT) is a platelet-stored vasoconstrictor. Altered concentrations of circulating 5HT are implicated in several pathologic conditions, including hypertension. The actions of 5HT are mediated by different types of receptors and terminated by a single 5HT transporter (SERT). Therefore, SERT is a major mechanism that regulates plasma 5HT levels to prevent vasoconstriction and thereby secure a stable blood flow." SIGNOR-263952 MTOR protein P42345 UNIPROT SGK1 protein O00141 UNIPROT up-regulates phosphorylation Ser422 AEAFLGFsYAPPTDS 9606 SIGNOR-C2 18925875 t gcesareni "Mtorc2 immunoprecipitated from wild-type, but not from mlst8- or rictor-knockout cells, phosphorylated sgk1 at ser(422)" SIGNOR-181531 IDH complex SIGNOR-C396 SIGNOR 2-oxoglutarate(2-) smallmolecule CHEBI:16810 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-266252 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 SRSF11 protein Q05519 UNIPROT APOE protein P02649 UNIPROT "up-regulates quantity by stabilization" "post transcriptional regulation" 10090 31269452 t miannu "We demonstrate that SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of apoE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling." SIGNOR-269671 MAPK8 protein P45983 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-32425 NFYA protein P23511 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 12427542 t 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-254816 TP53 protein P04637 UNIPROT NFKB2 protein Q00653 UNIPROT up-regulates binding 9606 16990795 t gcesareni "P52 cooperates with p53 to regulate other known p53 target genes." SIGNOR-149811 PRKCA protein P17252 UNIPROT IQGAP1 protein P46940 UNIPROT up-regulates phosphorylation Ser1443 DKMKKSKsVKEDSNL 9606 BTO:0000150;BTO:0000938 15695813 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-133861 PTPN11 protein Q06124 UNIPROT IRS1 protein P35568 UNIPROT down-regulates dephosphorylation Tyr1179 GLENGLNyIDLDLVK 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-27024 GOT2 protein P00505 UNIPROT oxaloacetate(2-) smallmolecule CHEBI:16452 ChEBI "up-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-267517 malonyl-CoA smallmolecule CHEBI:15531 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-268090 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 CC2D1B protein Q5T0F9 UNIPROT HTR1A protein P08908 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007;BTO:0000938 19423080 t nucleus lperfetto "Human Freud-2/CC2D1B: a novel repressor of postsynaptic serotonin-1A receptor expression|Human Freud-2 showed strong repressor activity at the human 5-HT1A or heterologous promoter in human HEK-293 5-HT1A-negative cells and neuronal SK-N-SH cells, a model of postsynaptic 5-HT1A receptor-positive cells." SIGNOR-268298 CSNK2A2 protein P19784 UNIPROT SAT1 protein P21673 UNIPROT unknown phosphorylation Ser146 FYKRRGAsDLSSEEG -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-251034 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 PRKCD protein Q05655 UNIPROT H3C1 protein P68431 UNIPROT "up-regulates activity" phosphorylation Thr46 PHRYRPGtVALREIR 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-185144 "vincaleukoblastine sulfate" chemical CHEBI:9984 ChEBI TUBB protein P07437 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-259256 "Brivanib alaninate" chemical CID:11154925 PUBCHEM FGFR3 protein P22607 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190723 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 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 CBX1 protein P83916 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-264493 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 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 LY-2157299 chemical CHEBI:137064 ChEBI TGFBR2 protein P37173 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193778 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 MRTFB protein Q9ULH7 UNIPROT SRF protein P11831 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0001260 21673106 t gcesareni "Similarly, the myocd-related transcription factor (mrtf) family of proteins, mrtf-a and mrtf-b, are also involved in the transcriptional regulation of contractile gene markers as coactivators of srf." SIGNOR-174316 PTH1R protein Q03431 UNIPROT SLC34A1 protein Q06495 UNIPROT "down-regulates quantity" 28363951 f lperfetto "PTH inhibits reabsorption of phosphate from the glomerular filtrate in RPT by decreasing the abundance of sodium-phosphate co-transporters NPT2a and NPT2c on the apical membrane, thus enhancing renal phosphate excretion" SIGNOR-270556 STK4 protein Q13043 UNIPROT TNNI3 protein P19429 UNIPROT unknown phosphorylation Thr143 RGKFKRPtLRRVRIS 9606 BTO:0000671 18986304 t llicata "Ms analysis indicated that mst1 phosphorylates ctni at thr(31), thr(51), thr(129) and thr(143)." SIGNOR-182053 MTA2 protein O94776 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-263853 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 RPS6KA1 protein Q15418 UNIPROT 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-249162 AHSP protein Q9NZD4 UNIPROT HBA1 protein P69905 UNIPROT "up-regulates quantity by stabilization" binding 9606 18179859 t Regulation miannu "α-Hemoglobin stabilizing protein (AHSP) binds α-hemoglobin (Hb), avoiding its precipitation and its pro-oxidant activity." SIGNOR-251770 RLIM protein Q9NVW2 UNIPROT ZFP42 protein Q96MM3 UNIPROT "down-regulates quantity by destabilization" ubiquitination 22596162 t lperfetto "RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1." SIGNOR-269002 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 ESR1 protein P03372 UNIPROT SCN8A protein Q9UQD0 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000938 22169964 f miannu "In this study, quantitative real-time PCR analysis showed that the gene expression levels of TTX-S (Nav1.1 and Nav1.7) and TTX-R (Nav1.8 and Nav1.9) sodium channel subtypes were elevated in DRGs of αERKO and βERKO mice, whereas Nav1.6 mRNA decreased in αERKOs but showed no changes in βERKO mice" SIGNOR-253476 ERG protein P11308 UNIPROT ADAMTS1 protein Q9UHI8 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 19396168 f miannu "ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression." SIGNOR-253910 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 TNKS protein O95271 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-261249 PDK1 protein Q15118 UNIPROT PDHA2 protein P29803 UNIPROT down-regulates phosphorylation Ser291 TYRYHGHsMSDPGVS 9606 16436377 t gcesareni "Human pdh1 and rat pdh2 were expressed previously and were shown to have different specific activities and the ability to be phosphorylated by pdk1 and pdk2" SIGNOR-143966 PATZ1 protein Q9HBE1 UNIPROT RNF4 protein P78317 UNIPROT down-regulates binding 9606 10713105 t miannu "In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression" SIGNOR-75775 UBE3A protein Q05086 UNIPROT TP53 protein P04637 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 9497376 t miannu "E6AP and E6 together provide the E3-ubiquitin protein ligase activity in the transfer of ubiquitin to p53. In vitro studies have shown that E6AP can form a high energy thiolester bond with ubiquitin and, in the presence of E6, transfer ubiquitin to p53. In this study we have addressed the role of E6AP in vivo in the degradation of p53. " SIGNOR-272552 PPP3CB protein P16298 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser99 PFRGRSRsAPPNLWA 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-248384 LUBAC complex SIGNOR-C527 SIGNOR PRKCA protein P17252 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001938 17069764 t miannu "In this report, we demonstrated that LUBAC, a ubiquitin ligase complex, is an E3 of activated cPKCs. LUBAC preferentially bound PMA-activated PKCa and PKCbII and their constitutively active mutants (Fig. 2). degradation of PMA-activated PKCa was delayed in HOIL-1L/-MEF (Fig. 3F). These results indicate that LUBAC is the ubiquitin ligase that induces ubiquitination and degradation of activated cPKCs." SIGNOR-271618 RUNX1 protein Q01196 UNIPROT BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002580 34902205 t lperfetto "RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia." SIGNOR-272145 FBXL2 protein Q9UKC9 UNIPROT AURKB protein Q96GD4 UNIPROT "down-regulates quantity by destabilization" binding 10090 BTO:0002268 23370391 t miannu "The SCF complex contains a catalytic core consisting of Skp1, Cullin1, and the E2 ubiquitin-conjugating (Ubc) enzyme and a F box component that acts as a receptor targeting numerous substrates via phosphodegron elicited interactions. our screening studies suggested that FBXL2 also targets Aurora B protein for ubiquitination and degradation." SIGNOR-272097 L-arginine chemical CHEBI:16467 ChEBI SLC38A9 protein Q8NBW4 UNIPROT "up-regulates activity" "chemical activation" 9606 29053970 t "SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins" SIGNOR-254895 Ub:E2 complex SIGNOR-C497 SIGNOR MYCBP2 protein O75592 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-271134 resveratrol chemical CHEBI:27881 ChEBI SIRT1 protein Q96EB6 UNIPROT "up-regulates activity" "chemical activation" -1 12939617 t gcesareni "We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53" SIGNOR-238786 CSNK1D protein P48730 UNIPROT GSK3B/Axin/APC complex SIGNOR-C110 SIGNOR up-regulates phosphorylation 9606 12000790 t lperfetto "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/mscomplex of axin and casein kinase i (cki) induces betBeta-catenin phosphorylation at a single site: serine 45 (s45)" SIGNOR-227970 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 MAPK3 protein P27361 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Ser345 QARPGPQsPGSPLEE 9606 8626435 t esanto "Upon activation, several serine residues on the cytosolic oxidase subunit p47phox become phosphorylated. Mitogen-activated protein kinase phophorylated only the peptide containing ser345/348." SIGNOR-40821 SLBP protein Q14493 UNIPROT H2BC21 protein Q16778 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-265386 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 M2_polarization phenotype SIGNOR-PH55 SIGNOR TGFb proteinfamily SIGNOR-PF5 SIGNOR 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-263824 NR2C2 protein P49116 UNIPROT LHCGR protein P22888 UNIPROT "up-regulates quantity by expression" "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-266217 BMS-554417 chemical CID:54754526 PUBCHEM INSR protein P06213 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190458 STAT3 protein P40763 UNIPROT POMC protein P01189 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000007 19049975 t miannu "We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter." SIGNOR-263497 ATM protein Q13315 UNIPROT L3MBTL2 protein Q969R5 UNIPROT "up-regulates activity" phosphorylation 9606 31225475 t 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-266785 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM55 protein Q9BYV6 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-270968 AKT1 protein P31749 UNIPROT CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 t lperfetto "Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination" SIGNOR-252536 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 "Host translation inhibitor nsp1" protein P0C6X7-PRO_0000037309 UNIPROT IRF3 protein Q14653 UNIPROT "down-regulates activity" 9606 17715225 f miannu "SARS-CoV nsp1 inhibits virus-dependent activation of IRF3 and IRF7." SIGNOR-262503 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 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 CASP3 protein P42574 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" cleavage -1 10579725 t lperfetto "P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro" SIGNOR-72677 MRPL53 protein Q96EL3 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-262345 PRKACA protein P17612 UNIPROT FLNA protein P21333 UNIPROT up-regulates phosphorylation Ser2152 TRRRRAPsVANVGSH 9606 15228085 t gcesareni "Site-directed mutagenesis analysis indicated that serine 2152 is the unique substrate in the c-terminal region of abp for endogenously activated pka." SIGNOR-126659 PRKACA protein P17612 UNIPROT RAP1B protein P61224 UNIPROT up-regulates phosphorylation Ser179 PGKARKKsSCQLL 9606 19651783 t llicata "These results provide a mechanistic explanation for the differential effects of rap1 phosphorylation by pka on effector protein interaction. camp is one among several pathways leading to rap1 activation" SIGNOR-187410 PKA proteinfamily SIGNOR-PF17 SIGNOR PHF2 protein O75151 UNIPROT "up-regulates activity" phosphorylation Ser954 QKSKKKKsAKRKLTP 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-264512 PRKG1 protein Q13976 UNIPROT SLC6A4 protein P31645 UNIPROT up-regulates phosphorylation Thr276 SIWKGVKtSGKVVWV 9606 BTO:0000567 17913921 t gcesareni "These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5." SIGNOR-158186 ATM protein Q13315 UNIPROT TP53BP1 protein Q12888 UNIPROT unknown phosphorylation Ser25 PCLIIEDsQPESQVL 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-100641 CBP/p300 complex SIGNOR-C6 SIGNOR SMAD3 protein P84022 UNIPROT "up-regulates activity" acetylation Lys19 VKRLLGWkKGEQNGQ 9606 BTO:0000567;BTO:0002181;BTO:0000552 17074756 t lperfetto "We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfb-dependent manner. the p300-dependent acetylation of smad3 was attenuated when lys19 was mutated, whereas mutation of lys20 had no effect, suggesting that lys19 is acetylated also in smad3." SIGNOR-236126 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 PTK2 protein Q05397 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" phosphorylation Tyr118 VGEEEHVySFPNKQK 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-28243 DOK1 protein Q99704 UNIPROT "AE/b7 integrin" complex SIGNOR-C186 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-257696 NCKAP1 protein Q9Y2A7 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-253569 "pazopanib hydrochloride" chemical CHEBI:71217 ChEBI KIT protein P10721 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-201250 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR Epigenetic_regulation phenotype SIGNOR-PH203 SIGNOR up-regulates 9606 33941852 f "Multi-subunit ATPase-dependent chromatin remodelling complexes SWI/SNF (switch/sucrose non-fermentable) are fundamental epigenetic regulators of gene transcription. " SIGNOR-268623 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 HECW2 protein Q9P2P5 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" binding 9606 BTO:0000093 27119228 t miannu "NEDL2 acts as a scaffold protein to promote GDNF-stimulated Akt activation. biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. NEDL2 binds p85, p110 and Akt with different domains" SIGNOR-269459 CREBBP protein Q92793 UNIPROT MEF2C protein Q06413 UNIPROT up-regulates binding 9606 SIGNOR-C6 11062529 t gcesareni "The cofactors grip-1, cbp/p300 and pcaf have hat activity and function as co-activators for mef-2c during myogenesis." SIGNOR-83843 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 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR UBTF protein P17480 UNIPROT "up-regulates activity" phosphorylation Ser484 ERGKLPEsPKRAEEI 10090 BTO:0000944 10202152 t llicata "We have identified Ser484 as a direct target for cyclin-dependent kinase 4 (cdk4)-cyclin D1- and cdk2-cyclin E-directed phosphorylation. Mutation of Ser484 impairs rDNA transcription in vivo and in vitro. " SIGNOR-250754 NUMA1 protein Q14980 UNIPROT TUBB2A protein Q13885 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-116936 MSL2 protein Q9HCI7 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-271976 SIAH2 protein O43255 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-140651 PRKCA protein P17252 UNIPROT DGKD protein Q16760 UNIPROT "down-regulates activity" phosphorylation Ser70 QNNSFQRsKRRYFKL 9534 15228384 t lperfetto "The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain." SIGNOR-249266 L3MBTL2 protein Q969R5 UNIPROT RNF168 protein Q8IYW5 UNIPROT "down-regulates quantity" binding 9606 31225475 t 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-266788 "NLRC4 inflammasome" complex SIGNOR-C223 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-256384 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 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 BORA protein Q6PGQ7 UNIPROT AURKA protein O14965 UNIPROT up-regulates binding 9606 16890155 t gcesareni "Both drosophila and human bora can bind to aurora-a and activate the kinase in vitro." SIGNOR-148661 MC1R protein Q01726 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-257085 COX5A protein P20674 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-267751 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 PPP2CB protein P62714 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-248591 3-phosphonatooxypyruvate(3-) smallmolecule CHEBI:18110 ChEBI 3-phosphonato-D-glycerate(3-) smallmolecule CHEBI:58272 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-268566 Scribble_complex_DLG3-LLGL1_variant complex SIGNOR-C507 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-270898 KAT2B protein Q92831 UNIPROT SMAD2 protein Q15796 UNIPROT up-regulates acetylation Lys19 VKRLLGWkKSAGGSG 9606 SIGNOR-C7 17074756 t gcesareni "We demonstrate that both smad2 and smad3 are acetylated by the coactivators p300 and cbp in a tgfbeta-dependent manner. Smad2 is also acetylated by p/caf. The acetylation of smad2 was significantly higher than that of smad3. Lys(19) in the mh1 domain was identified as the major acetylated residue in both the long and short isoform of smad2.....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" SIGNOR-150273 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 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 INSR protein P06213 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190446 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 PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192617 CHEK2 protein O96017 UNIPROT CDC25A protein P30304 UNIPROT "down-regulates quantity" phosphorylation Ser178 LFTQRQNsAPARMLS 9606 12676583 t Manara "Chk2 phosphorylates a subset of the Chk1-targeted sites of Cdc25A | Phosphorylation of serines 123, 178, 278, and 292 regulates both basal and IR-induced accelerated proteolysis of Cdc25A" SIGNOR-260833 FUS protein P35637 UNIPROT SMN1 protein Q16637 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-262107 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 "SB 431542" chemical CHEBI:91108 ChEBI TGFBR1 protein P36897 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206706 PP121 chemical CHEBI:50915 ChEBI MTOR protein P42345 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206289 THRA protein P10827 UNIPROT RARG protein P13631 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-133246 IKBKE protein Q14164 UNIPROT RELA protein Q04206 UNIPROT up-regulates phosphorylation Ser468 AVFTDLAsVDNSEFQ 9606 SIGNOR-C13 15489227 t gcesareni "Overexpressed ikkepsilon and tbk1 phosphorylate ser-536 in vivo and in vitro." SIGNOR-129939 CTTN protein Q14247 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10116 23015759 f miannu "Through alternative splicing, a single CTTNBP2 gene encodes three different transcripts, namely short (S), long (L), and intron forms. The interaction with cortactin is required for the function of CTTNBP2-S in dendritic spine formation because the CTTNBP2-S mutant, which no longer interacts with cortactin, is unable to rescue the spine defects resulting from CTTNBP2 knockdown. Thus CTTNBP2-S may control cortactin–F-actin cytoskeletons and regulate the formation and maintenance of dendritic spines in neurons." SIGNOR-261696 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 GPR183 protein P32249 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-257110 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide chemical CHEBI:92401 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-257998 PCSK7 protein Q16549 UNIPROT RELA protein Q04206 UNIPROT up-regulates 10090 BTO:0000165;BTO:0000222 BTO:0000887;BTO:0001103 14767066 f lperfetto "Treatment with sb203580 significantly reduced this cooperation, consistent with the idea that p38 indirectly stimulates the transactivating activity of p65 through a mechanism involving cbp." SIGNOR-235734 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 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 PRKACA protein P17612 UNIPROT RAF1 protein P04049 UNIPROT down-regulates phosphorylation Ser259 SQRQRSTsTPNVHMV 9606 11971957 t gcesareni "Serines 43, 259, and 621 are phosphorylated by PKA in vitro and induced by cAMP in vivo.cAMP increased Raf-1 serine 259 phosphorylation in a PKA-dependent manner with kinetics that correlated with ERK deactivation." SIGNOR-86141 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 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 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 SRC protein P12931 UNIPROT ITGB2 protein P05107 UNIPROT "down-regulates activity" phosphorylation 9606 BTO:0000876 25624455 t miannu "PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role." SIGNOR-254740 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 GAP43 protein P17677 UNIPROT Neurite_outgrowth phenotype SIGNOR-PH134 SIGNOR up-regulates 10090 21938722 f miannu "Growth associated protein 43 (Gap43) is a neuron-specific phosphoprotein, which plays critical role in axon growth and synapses functions during neurogenesis. " SIGNOR-266769 PIM1 protein P11309 UNIPROT BAD protein Q92934 UNIPROT "down-regulates activity" phosphorylation Ser118 GRELRRMsDEFVDSF 9606 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-250390 RNF8 protein O76064 UNIPROT H2AX protein P16104 UNIPROT up-regulates ubiquitination 9606 18001824 t gcesareni "Rnf8 can ubiquitylate histone h2a and h2ax," SIGNOR-159309 BRAP protein Q7Z569 UNIPROT USP15 protein Q9Y4E8 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-272029 "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 ZNF304 protein Q9HCX3 UNIPROT CDKN2B protein P42772 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000391 24623306 t Luana "Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells." SIGNOR-266099 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 Ub:E2 complex SIGNOR-C497 SIGNOR RBX1 protein P62877 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-270993 CDK2 protein P24941 UNIPROT ORC2 protein Q13416 UNIPROT up-regulates phosphorylation Thr226 SAPVGKEtPSKRMKR 9606 22334659 t gcesareni "Phosphorylation at thr-116 and thr-226 of orc2 occurs by cyclin-dependent kinase during the s phase and is maintained until the m phase. Phosphorylation of orc2 at thr-116 and thr-226 dissociated the orc2-5 from chromatin." SIGNOR-196048 N-[[3-fluoro-4-[[2-(1-methyl-4-imidazolyl)-7-thieno[3,2-b]pyridinyl]oxy]anilino]-sulfanylidenemethyl]-2-phenylacetamide chemical CHEBI:91393 ChEBI FLT4 protein P35916 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194337 BMPR1A protein P36894 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" 10090 19620713 f 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-255785 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM3 protein O75382 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-271146 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 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 ARIH1 protein Q9Y4X5 UNIPROT EIF4E2 protein O60573 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000007 14623119 t miannu "Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7. Thus, by promoting the ubiquitin-mediated degradation of 4EHP, HHARI may have a role in both protein degradation and protein translation." SIGNOR-268848 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 MAPK8 protein P45983 UNIPROT SIRT1 protein Q96EB6 UNIPROT up-regulates phosphorylation Ser47 DGPGLERsPGEPGGA 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-162318 A-966492 chemical CID:16666333 PUBCHEM PARP2 protein Q9UGN5 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-203622 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 PAFAH1B1 protein P43034 UNIPROT DYNC1H1 protein Q14204 UNIPROT "up-regulates activity" binding 10090 BTO:0000938 11163259 t miannu "We demonstrate that LIS1 directly interacts with the cytoplasmic dynein heavy chain (CDHC) and NUDEL. 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-252158 IL1B protein P01584 UNIPROT IL1R1 protein P14778 UNIPROT "up-regulates activity" binding 9606 BTO:0000801 24166242 t lperfetto "Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor." SIGNOR-249511 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 RHCE protein P18577 UNIPROT "Ankyrin complex" complex SIGNOR-C383 SIGNOR "form complex" binding 9606 BTO:0000424 22465511 t lperfetto "The ankyrin associated complex brings together proteins of both the band 3 tetrameric complex (band 3, glycophorin A (GPA), protein 4.2, carbonic anhydrase II) and the Rh complex (RhAG, RhCE, RhD, CD47, ICAM-4, glycophorin B (GPB)) " SIGNOR-266022 DIABLO protein Q9NR28 UNIPROT BIRC5 protein O15392 UNIPROT down-regulates binding 9606 17546047 t gcesareni "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. mitochondrial survivin associated with smac/diablo, delaying its release." SIGNOR-155364 NFYB protein P25208 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-254819 HCFC1 protein P51610 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-267165 NAT10 protein Q9H0A0 UNIPROT TP53 protein P04637 UNIPROT "up-regulates quantity by stabilization" acetylation Lys120 FLHSGTAkSVTCTYS 9606 BTO:0002552 26882543 t miannu "NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity. " SIGNOR-272406 CDK2 protein P24941 UNIPROT CDX2 protein Q99626 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser287 EPLSPVSsLQASVPG 9606 16027724 t llicata "Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation|We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo." SIGNOR-250728 STK4 protein Q13043 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR up-regulates phosphorylation Ser209 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." SIGNOR-253000 RPS6KA3 protein P51812 UNIPROT PFKFB2 protein O60825 UNIPROT "up-regulates activity" phosphorylation Ser466 PVRMRRNsFTPLSSS 9606 2846551 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-23753 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 NTRK1 protein P04629 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 10708759 t esanto "Autophosphorylated trka binds directly to plc?, Abl, and shc." SIGNOR-75402 PPP5C protein P53041 UNIPROT MAP3K5 protein Q99683 UNIPROT "down-regulates activity" dephosphorylation Thr838 GINPCTEtFTGTLQY 9606 BTO:0000567 11689443 t lperfetto "Pp5 directly dephosphorylated an essential phospho-threonine residue within the kinase domain of ask1 and thereby inactivated ask1 activity in vitro and in vivo." SIGNOR-111301 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 PCDHA10 protein Q9Y5I2 UNIPROT PCDHGA11 protein Q9Y5H2 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-265712 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 "vitamin D" smallmolecule CHEBI:27300 ChEBI calcidiol smallmolecule CHEBI:17933 ChEBI "up-regulates quantity" "precursor of" 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-270567 UHMK1 protein Q8TAS1 UNIPROT PIMREG protein Q9BSJ6 UNIPROT up-regulates phosphorylation Ser131 GAQKGSGsPTHSLSQ 9606 23419774 t lperfetto "Cats is a substrate of kis and mapped the phosphorylation site to cats serine 131 (s131). Kis enhances the transcriptional repressor activity of cats" SIGNOR-192702 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 GATA1 protein P15976 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-254430 ATP5F1B protein P06576 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-261397 ZRANB1 protein Q9UGI0 UNIPROT TWIST1 protein Q15672 UNIPROT "down-regulates activity" deubiquitination 9606 BTO:0000007 29748601 t miannu "Trabid inhibits Twist1 activity by cleaving RNF8-mediated Twist1 K63-linked ubiquitination" SIGNOR-273502 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 pevonedistat chemical CHEBI:145535 ChEBI UBE2F protein Q969M7 UNIPROT "down-regulates quantity" "chemical inhibition" 9606 BTO:0001109 19360080 t Monia "MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme; A single dose of MLN4924 resulted in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration of compound" SIGNOR-261067 NEK6 protein Q9HC98 UNIPROT RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation Ser53 EGGQLNEsMDHGGVG -1 12023960 t miannu "Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation." SIGNOR-262952 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 PI3K complex SIGNOR-C156 SIGNOR AKT1 protein P31749 UNIPROT "up-regulates activity" 9606 BTO:0000938 9346240 f lperfetto "Growth factors can promote cell survival by activating the phosphatidylinositide-3'-OH kinase and its downstream target, the serine-threonine kinase Akt" SIGNOR-252708 SMAD3 protein P84022 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates activity" binding 10090 12524424 t gcesareni "Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters" SIGNOR-250567 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 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 GSK3B protein P49841 UNIPROT MYOCD protein Q8IZQ8 UNIPROT "down-regulates activity" phosphorylation Ser630 VLSSTFLsPQCSPQH 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-251248 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 ESR2 protein Q92731 UNIPROT SCN11A protein Q9UI33 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253475 NLK protein Q9UBE8 UNIPROT LEF1 protein Q9UJU2 UNIPROT down-regulates phosphorylation Ser166 TYSDEHFsPGSHPSH 9606 12556497 t gcesareni "Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.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-97808 PP1 proteinfamily SIGNOR-PF54 SIGNOR MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" dephosphorylation Ser370 KKTIVNDsRESCVEE 9606 BTO:0001938 23277204 t lperfetto "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-264666 EXOC4 protein Q96A65 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-270787 BTK protein Q06187 UNIPROT GTF2I protein P78347 UNIPROT up-regulates phosphorylation 9606 BTO:0000776 9012831 t gcesareni "We now describe a protein, bap-135, that is associated with btk in b cells and is a substrate for phosphorylation by btk.Taken together, these observations suggest that bap-135 may reside downstream of btk in a signaling pathway originating at the bcr." SIGNOR-46060 POLR2B protein P30876 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-266162 E2F1 protein Q01094 UNIPROT DLK1 protein P80370 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 19874716 t lperfetto "Using luciferase reporter assay, ChIP assay and EMSA, we found that the -211/-194 region of the pref-1 promoter is essential for the binding of E2F1 as well as E2F1-dependent transcriptional activation." SIGNOR-271684 CTDSP2 protein O14595 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" dephosphorylation Ser213 NLSPNPMsPAHNNLD 9606 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-248295 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 zinc(2+) chemical CHEBI:29105 ChEBI "BRCA1-C complex" complex SIGNOR-C299 SIGNOR "form complex" binding 25400280 t lperfetto "The BRCA1‚ÄìC complex consisting of BRCA1, Mre11:Rad50:Nbs1 (collectively known as the MRN complex) and CtIP plays a role in DSB end resection, a process that also involves EXO1 and DNA2" SIGNOR-269478 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 PPP2CA protein P67775 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-248642 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 ADD1 protein P35611 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-266037 INS protein P01308 UNIPROT COMT protein P21964 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000542 17612537 f "Regulation of expression" miannu "Catechol O-methyltransferase expression in granulosa cells was up-regulated by insulin, DHT, and ATRA." SIGNOR-251961 EGFR protein P00533 UNIPROT SHC1 protein P29353 UNIPROT up-regulates binding 10090 BTO:0000944 7518560 t lperfetto "Both competition experiments with synthetic phosphopeptides and dephosphorylation protection analysis demonstrated that y-1173 and y-992 are major and minor binding sites, respectively, for shc on the egfr." SIGNOR-235481 BCAR1 protein P56945 UNIPROT NAB2 protein Q15742 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-253891 FLT4 protein P35916 UNIPROT FLT4 protein P35916 UNIPROT "up-regulates activity" phosphorylation Tyr1230 RHSLAARyYNWVSFP 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-104072 PRKACA protein P17612 UNIPROT PTPN7 protein P35236 UNIPROT down-regulates phosphorylation 9606 19047375 t gcesareni "B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk" SIGNOR-182522 "Ub:E1 (UBA1 substrate)" complex SIGNOR-C495 SIGNOR UBE2U protein Q5VVX9 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-271337 GPR183 protein P32249 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-256858 SRC protein P12931 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr627 KGDKQVEyLDLDLDS 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-236302 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 WWTR1 protein Q9GZV5 UNIPROT TEAD1 protein P28347 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 tead1?_?_?4." SIGNOR-192768 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 BAK1 protein Q16611 UNIPROT DIABLO protein Q9NR28 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-118905 HPS5 protein Q9UPZ3 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 HPS7" SIGNOR-260689 "SWI/SNF complex" complex SIGNOR-C92 SIGNOR RUNX1 protein Q01196 UNIPROT "up-regulates activity" binding 9606 20506188 t miannu "Our findings indicate that RUNX1 interacts with the human SWI/SNF complex to control hematopoietic-specific gene expression." SIGNOR-261965 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr1190 DIYETDYyRKGGKGL -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-254705 PRKCB protein P05771 UNIPROT ORAI1 protein Q96D31 UNIPROT down-regulates phosphorylation Ser30 TTSGSRRsRRRSGDG 9606 20534587 t llicata "We propose that pkc suppresses soce and crac channel function by phosphorylation of orai1 at n-terminal serine residues ser-27 and ser-30." SIGNOR-166044 "A4/b1 integrin" complex SIGNOR-C162 SIGNOR DLL1 protein O00548 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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-253285 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 SMAD3 protein P84022 UNIPROT SMAD4 protein Q13485 UNIPROT "up-regulates activity" binding 9606 9843571 t gcesareni "TGF-² 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-235168 4-(2,4,5-tripyridin-4-yl-3-thiophenyl)pyridine smallmolecule CHEBI:94284 ChEBI GLI2 protein P10070 UNIPROT down-regulates "chemical inhibition" 9606 BTO:0000150;BTO:0000551 19860666 t gcesareni "Both molecules gant58 and gant61 were capable of interfering with gli1 as well as gli2-mediated transcription in a dose-dependent manner" SIGNOR-188866 TNFSF13B protein Q9Y275 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-81360 AREG protein P15514 UNIPROT ERBB2 protein P04626 UNIPROT up-regulates phosphorylation 9606 7679104 t gcesareni "Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor" SIGNOR-31199 MAPK3 protein P27361 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates phosphorylation Ser312 SYLSQMTsPSIHSTT 9606 19801668 t llicata "In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation." SIGNOR-188347 CTNNB1 protein P35222 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-256534 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 STAT3 protein P40763 UNIPROT VEGFA protein P15692 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12545153 t luana "Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells. " SIGNOR-259456 "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 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 DUSP8 protein Q13202 UNIPROT MAPK14 protein Q16539 UNIPROT down-regulates dephosphorylation 9606 23159405 t gcesareni "M3/6 (dusp8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of jnk and, to a lesser extent, p38 mapk" SIGNOR-199695 SMAD3 protein P84022 UNIPROT CEBPA protein P49715 UNIPROT "down-regulates activity" binding 10090 12524424 t gcesareni "Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPAR2 and leptin promoters" SIGNOR-241924 FOXO3 protein O43524 UNIPROT RBL2 protein Q08999 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 BTO:0000944 11884591 t gcesareni "Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression." SIGNOR-238606 GRM1 protein Q13255 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-264347 ABL1 protein P00519 UNIPROT YTHDC1 protein Q96MU7 UNIPROT down-regulates phosphorylation 9606 15175272 t lperfetto "We show that yt521-b is tyrosine phosphorylated by c-abl in the nucleus.We propose that tyrosine phosphorylation causes sequestration of YT521-B in an insoluble nuclear form, which abolishes the ability of YT521-B to change alternative splice sites." SIGNOR-125167 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 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 naltrexone chemical CHEBI:7465 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-258946 CUDC-101 chemical CID:24756910 PUBCHEM EGFR protein P00533 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-262254 HOXC11 protein O43248 UNIPROT HNF1A protein P20823 UNIPROT up-regulates 9606 9582375 f miannu "The observed stimulatory effect of hoxc11 on hnf1_ may be due to a similar stabilizing effect on hnf1_ dna binding and/or an increase in transcriptional activity of hnf1_." SIGNOR-57484 MAPK9 protein P45984 UNIPROT RXRA protein P19793 UNIPROT "down-regulates activity" phosphorylation Ser260 NMGLNPSsPNDPVTN 9606 16551633 t gcesareni "Under stress conditions, hyperphosphorylated by activated jnk on ser-56, ser-70, thr-82 and ser-260. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear rxralpha levels, via a multistep, jnk-dependent mechanism involving ser260, nuclear export, and proteasomal degradation." SIGNOR-145301 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 SET protein Q01105 UNIPROT PPP2CB protein P62714 UNIPROT down-regulates binding 9606 21806989 t miannu "Here we report that both the amino terminal fragment (i(2ntf);aa 1-175) and the carboxy terminal fragment (i(2ctf);aa 176-277) of i(2)(pp2a) inhibit pp2a by binding to its catalytic subunit pp2ac" SIGNOR-175722 RET protein P07949 UNIPROT RET protein P07949 UNIPROT up-regulates phosphorylation Tyr1062 TWIENKLyGMSDPNW 9606 14711813 t lperfetto "Mass spectrometric analysis revealed that ret tyr806, tyr809, tyr900, tyr905, tyr981, tyr1062, tyr1090, and tyr1096 were autophosphorylation sitesret short and middle isoforms contain 16 tyrosine residues in their intracellular domains, and ret long isoforms have two additional tyrosines in the c-terminal tail. Among these tyrosines, tyr905, tyr1015, tyr1062, and tyr1096 are thought to be phosphorylated to become binding sites for grb7/grb10, phospholipase c_, shc/snt(frs2)/enigma, and grb2, respectively." SIGNOR-121141 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 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 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 GTP smallmolecule CHEBI:15996 ChEBI 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-269118 alogliptin chemical CHEBI:72323 ChEBI DPP4 protein P27487 UNIPROT "down-regulates activity" "chemical inhibition" -1 22475866 t Luana "Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization." SIGNOR-258333 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H4C1 protein P62805 UNIPROT "down-regulates activity" acetylation Lys17 GLGKGGAkRHRKVLR 9606 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-263944 DYRK1A protein Q13627 UNIPROT FOXO3 protein O43524 UNIPROT "down-regulates activity" phosphorylation Ser330 RLSPIMAsTELDEVQ 9606 19188143 t lperfetto "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-106833 LCK protein P06239 UNIPROT LAX1 protein Q8IWV1 UNIPROT "up-regulates activity" phosphorylation Tyr193 SSEDSHDyVNVPTAE 9606 BTO:0000007 12359715 t miannu "Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. " SIGNOR-273525 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 PRKCQ protein Q04759 UNIPROT RASGRP3 protein Q8IV61 UNIPROT up-regulates phosphorylation Thr133 YDWMRRVtQRKKVSK 9606 BTO:0000776 15545601 t lperfetto "Activation of rasgrp3 by phosphorylation of thr-133 is required for b cell receptor-mediated ras activation. our data suggest that pkc, after being activated by diacylglycerol, phosphorylates rasgrp3, thereby contributing to its full activation." SIGNOR-130490 MAPK3 protein P27361 UNIPROT BCL2 protein P10415 UNIPROT "up-regulates quantity by stabilization" phosphorylation Thr74 ARTSPLQtPAAPGAA 9606 10669763 t gcesareni "The results of this study reveal the following novel findings: destruction of the three putative MAP kinase sites at positions 56, 74, and 87 results in ubiquitination and subsequent degradation of the protein. Progressive inactivation of these MAP kinase sites revealed that Bcl-2 stability is mainly regulated by phosphorylation at Thr74 and Ser87, with Ser87 phosphorylation playing a predominant role. TNF-Œ± or the MAP kinase-specific inhibitor PD98059 diminishes Ser87 phosphorylation of Bcl-2 in vivo, while activated ERK2 induces phosphorylation of Bcl-2 in vivo and in vitro." SIGNOR-74943 RPS6KB1 protein P23443 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser167 GGRERLAsTNDKGSM 9606 7838153 t gcesareni "Serine 167 is the major phosphorylation site on the human estrogen receptor. Phosphorylation is mediated by casein kinase ii." SIGNOR-34117 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 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 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 DCC protein P43146 UNIPROT SRC protein P12931 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-268372 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 NAB2 protein Q15742 UNIPROT EGR1 protein P18146 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-253886 SYK protein P43405 UNIPROT LAX1 protein Q8IWV1 UNIPROT "up-regulates activity" phosphorylation Tyr193 SSEDSHDyVNVPTAE 9606 BTO:0000007 12359715 t miannu "Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. " SIGNOR-273532 BMPR2 protein Q13873 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-33443 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 GATA3 protein P23771 UNIPROT PPARG protein P37231 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 15632071 f fspada "Constitutive expression of both gata-2 and gata-3 suppressed adipocyte differentiation, partially through direct binding to the peroxisome proliferator-activated receptor gamma (ppargamma) promoter and suppression of its basal activity" SIGNOR-132955 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser54 RVKALPLsPRKRLGD 9606 9889196 t lperfetto "Phosphorylation of mammalian cdc6 by cyclin a/cdk2 regulates its subcellular localization/based on our data we suggest that the phosphorylation of cdc6 by cyclin a/cdk2 is a negative regulatory event that could be implicated in preventing re-replication during s phase and g2." SIGNOR-217328 MAPK14 protein Q16539 UNIPROT AKT2 protein P31751 UNIPROT "down-regulates activity" 9606 20626350 f lperfetto "On the other hand, p38 alfa may negatively modulate akt activity, indipendently of pi3k by regulating the interaction between caveolin 1 and pp2a through a mechanism dependent on cell attachment." SIGNOR-166591 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 APEX1 protein P27695 UNIPROT CYP11B2 protein P19099 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 22652909 f miannu "We conclude that APEX1 is a novel transcriptional repressor of CYP11B2 and that differential APEX1 binding at -1651 of CYP11B2 results in altered gene expression." SIGNOR-253736 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 NRAS protein P01111 UNIPROT PI3K complex SIGNOR-C156 SIGNOR "up-regulates activity" binding 9606 21779497 t lperfetto "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-252700 MAP2K6 protein P52564 UNIPROT MAPK14 protein Q16539 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-236116 Ub:E2 complex SIGNOR-C497 SIGNOR ZSWIM2 protein Q8NEG5 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-270950 NR3C1 protein P04150 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity" "transcriptional regulation" 9606 26652733 t "inferred from family member" "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-267792 NHLH2 protein Q02577 UNIPROT HES1 protein Q14469 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 21573214 f miannu "Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter." SIGNOR-254828 PRKAA1 protein Q13131 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "up-regulates activity" phosphorylation Ser626 SLECDMEsIIRSELM 9606 BTO:0000007 17711846 t gcesareni "Phosphorylation by AMPK leads to the activtion of FOXO3 transcriptional activity without affecting FOXO3 subcellular localization." SIGNOR-252979 CREB1 protein P16220 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-267786 XRCC4 protein Q13426 UNIPROT "Lig4-Xrcc4 complex" complex SIGNOR-C354 SIGNOR "form complex" binding -1 19837014 t miannu "The DNA ligase IV-Xrcc4 complex is responsible for the ligation of broken DNA ends in the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair in mammals." SIGNOR-264532 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-270255 CDS2 protein O95674 UNIPROT "phosphatidic acid" smallmolecule CHEBI:16337 ChEBI "down-regulates quantity" "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-267021 MAML1 protein Q92585 UNIPROT CCNC protein P24863 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-130709 DAPK3 protein O43293 UNIPROT MDM2 protein Q00987 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser166 SSRRRAIsETEENSD 9606 15001356 t gcesareni "Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein." SIGNOR-123159 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide chemical CHEBI:91326 ChEBI CDK4 protein P11802 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189990 POLR2E protein P19388 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-266147 CTTNBP2NL protein Q9P2B4 UNIPROT STRN4 protein Q9NRL3 UNIPROT "up-regulates activity" binding 9606 BTO:0000938 23015759 t miannu "Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A." SIGNOR-261701 ATF3 protein P18847 UNIPROT PCLAF protein Q15004 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23593430 f gcesareni "P15(paf) is a direct transcriptional target of atf3" SIGNOR-201850 STOML2 protein Q9UJZ1 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21746876 f Giorgia "We performed real-time RT-PCR to measure the levels of PGC-1alpha mRNA and found that these were increased in SLP-2hi cells (Fig. 3h), supporting the idea that upregulation of SLP-2 expression is associated with an increase in the expression of mitochondrially targeted genes." SIGNOR-260379 ARHGEF1 protein Q92888 UNIPROT RHOA protein P61586 UNIPROT up-regulates "guanine nucleotide exchange factor" 9606 BTO:0000887;BTO:0001260 10836144 t gcesareni "Rhogefs catalyze the exchange of gdp for gtp and thereby activate rho." SIGNOR-77914 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 ABCA7 protein Q8IZY2 UNIPROT APP protein P05067 UNIPROT "down-regulates quantity" relocalization 9606 BTO:0000142 27472885 f miannu "Together these results indicate that ABCA7 mediates phagocytic clearance of amyloid-β in the brain, and reveal a mechanism by which loss of function of ABCA7 increases the susceptibility to AD." SIGNOR-265176 NR3C1 protein P04150 UNIPROT RXRA protein P19793 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 12573484 f gcesareni "Physiological concentrations of glucocorticoids increase cellular cyp2c9 (and cyp3a5) but also car, rxr and pxr levels via a gr-mediated mechanism" SIGNOR-98102 CDK2 protein P24941 UNIPROT RRN3 protein Q9NYV6 UNIPROT up-regulates phosphorylation Ser44 LENDFFNsPPRKTVR 9606 SIGNOR-C16 15004009 t miannu "Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia" SIGNOR-123231 ALK protein Q9UM73 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates phosphorylation 9606 BTO:0000785 12185581 t gcesareni "Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc." SIGNOR-91537 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 "glutamic acid" smallmolecule CHEBI:18237 ChEBI KAR proteinfamily SIGNOR-PF57 SIGNOR "up-regulates activity" "chemical activation" 9606 15919192 t 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‚Äì4); five kainate receptor genes (GluR5‚Äì7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A and NR3B); and two delta subunits." SIGNOR-264694 "BHC complex" complex SIGNOR-C353 SIGNOR SYN1 protein P17600 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000007 12032298 t miannu "We show that BHC interacts with the promoter of the synapsin gene and mediates its RE1-dependent repression. BHC is recruited to the endogenous synapsin gene." SIGNOR-264504 calcium(2+) smallmolecule CHEBI:29108 ChEBI Excitatory_synaptic_transmission phenotype SIGNOR-PH133 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-264953 HRH4 protein Q9H3N8 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-256672 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 PML protein P29590 UNIPROT KAT6A/PML complex SIGNOR-C55 SIGNOR "form complex" binding 9606 BTO:0001271 23431171 t miannu "We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression" SIGNOR-201489 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 CALM3 protein P0DP25 UNIPROT CAMKK1 protein Q8N5S9 UNIPROT up-regulates binding 9606 10770941 t miannu "The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases" SIGNOR-266344 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 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 MAP2K1 protein Q02750 UNIPROT MAPK3 protein P27361 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-258994 PRKACA protein P17612 UNIPROT SUFU protein Q9UMX1 UNIPROT up-regulates phosphorylation Ser342 LAHDRAPsRKDSLES 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-200492 TRADD protein Q15628 UNIPROT BIRC2 protein Q13490 UNIPROT "up-regulates activity" binding 9606 BTO:0000007;BTO:0001412;BTO:0000567 8943045 t amattioni "The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex." SIGNOR-45134 MAPK15 protein Q8TD08 UNIPROT JUN protein P05412 UNIPROT up-regulates phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 12169099 t gcesareni "Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation." SIGNOR-91371 G6PD protein P11413 UNIPROT NADP(3-) smallmolecule CHEBI:58349 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-268125 BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Tyr654 RNEGVATyAAAVLFR 9606 BTO:0001271 17318191 t lperfetto "Bcr-abl stabilizes beta-catenin in chronic myeloid leukemia through its tyrosine phosphorylationthe notion that y86 and y654 are located respectively within the n_ and c_terminal transcriptional domains of __catenin suggests that one or both residues might regulate the transactivating function of __catenin. In this regard, phosphorylation of y654 was reported to strengthen __catenin association with the basal transcription factor tata_binding protein (tbp)" SIGNOR-153431 SCN3A protein Q9NY46 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-253409 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 CSNK2A1 protein P68400 UNIPROT ANP32B protein Q92688 UNIPROT up-regulates phosphorylation Thr244 GEKRKREtDDEGEDD 9606 17178712 t gcesareni "Here, we are able to report that casein kinase 2 (ck2) phosphorylates april on residue threonine244 (thr(244)) and demonstrate that the ck2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes cd83 expression in activated jurkat t cells by interfering with the nucleocytoplasmic translocation of cd83 mrna" SIGNOR-151261 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNA2 protein P20248 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193537 CyclinD/CDK4 complex SIGNOR-C18 SIGNOR MEF2C protein Q06413 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-216963 DDB1 protein Q16531 UNIPROT EDVP complex SIGNOR-C530 SIGNOR "form complex" binding 9606 BTO:0000007 19287380 t miannu "We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex. " SIGNOR-271791 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR CDK2 protein P24941 UNIPROT up-regulates phosphorylation Thr160 GVPVRTYtHEVVTLW 9606 SIGNOR-C16 12359725 t lperfetto "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-244614 JAZF1 protein Q86VZ6 UNIPROT NR2C2 protein P49116 UNIPROT down-regulates binding 9606 15302918 t miannu "Tip27 interacts specifically with tak1 / tip27 functions as a tak1-selective repressor" SIGNOR-127900 PLIN3 protein O60664 UNIPROT M6PR protein P20645 UNIPROT "up-regulates activity" relocalization 9534 BTO:0004055 9590177 t lperfetto "TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi." SIGNOR-253093 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC6 protein Q99741 UNIPROT "down-regulates activity" phosphorylation Ser74 TPHLPPCsPPKQGKK 9606 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-217280 KLHL20 protein Q9Y2M5 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 20389280 t miannu "Here, we identify the BTB-Kelch protein KLHL20 as a negative regulator of DAPK. KLHL20 binds DAPK and Cullin 3 (Cul3) via its Kelch-repeat domain and BTB domain, respectively. The KLHL20-Cul3-ROC1 E3 ligase complex promotes DAPK polyubiquitination, thereby inducing the proteasomal degradation of DAPK." SIGNOR-271961 MAPK1 protein P28482 UNIPROT RPS3 protein P23396 UNIPROT unknown phosphorylation Thr42 SGVEVRVtPTRTEII 9606 15950189 t llicata "Erk phosphorylates threonine 42 residue of ribosomal protein s3." SIGNOR-136075 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 "denileukin diftitox" smallmolecule SID:125240988 ChEBI IL2RB protein P14784 UNIPROT "up-regulates activity" "chemical activation" 9606 15757436 t miannu "Denileukin diftitox (DAB389IL-2; Ontak) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. " SIGNOR-259393 MED20 protein Q9H944 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-266679 EEF1A1 protein P68104 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-269504 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 JNK proteinfamily SIGNOR-PF15 SIGNOR JUN protein P05412 UNIPROT "up-regulates activity" phosphorylation Ser63 KNSDLLTsPDVGLLK 9606 BTO:0001950 21561061 t Luana "3b Induces Phosphorylation of c-Jun (Ser-63) throughActivation of the JNK Pathway.| An enhanced phosphorylation of JNK and MEK4 was observed in cells expressing 3b ascompared to control cells expressing GFP" SIGNOR-260758 LAMA2 protein P24043 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-255984 CHN2 protein P52757 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-260500 PLRG1 protein O43660 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR "form complex" binding 9606 BTO:0000567 20176811 t miannu "In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27." SIGNOR-271969 CWC15 protein Q9P013 UNIPROT PRP19-CDC5L complex SIGNOR-C534 SIGNOR "form complex" binding 9606 BTO:0000567 20176811 t miannu "In this study, we affinity purified the human Prp19/CDC5L complex from HeLa cell lines stably expressing FLAG-AD002 or FLAG-SPF27 and determined its molecular architecture and EM structure. To learn more about the spatial organization of the human Prp19 (hPrp19)/CDC5L complex, which is comprised of hPrp19, CDC5L, PRL1, AD002, SPF27, CTNNBL1, and HSP73, we purified native hPrp19/CDC5L complexes from HeLa cells stably expressing FLAG-tagged AD002 or SPF27." SIGNOR-271970 SIRT5 protein Q9NXA8 UNIPROT NFE2L2 protein Q16236 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 31815138 f Monia "Western blot showed that Sirt5 overexpression upregulated Nrf2. Sirt5 attenuates apoptosis through Nrf2/HO-1 and Bcl-2." SIGNOR-261208 MAPK3 protein P27361 UNIPROT SP1 protein P08047 UNIPROT up-regulates phosphorylation Thr739 SEGSGTAtPSALITT 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-248070 SRC protein P12931 UNIPROT SH3PXD2A protein Q5TCZ1 UNIPROT "up-regulates activity" phosphorylation 20943948 t lperfetto " Recently, we have shown that tyrosine kinase c-Src substrate Tks4 and Tks5 proteins are novel members of the organizer superfamily" SIGNOR-264706 Gbeta proteinfamily SIGNOR-PF4 SIGNOR FGFR1 protein P11362 UNIPROT down-regulates phosphorylation 9606 23405013 t "inferred from 70% family members" lperfetto "Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling" SIGNOR-270013 OPTN protein Q96CV9 UNIPROT Cell_growth phenotype SIGNOR-PH33 SIGNOR up-regulates 10090 BTO:0005118 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-259877 TYSND1 protein Q2T9J0 UNIPROT TYSND1 protein Q2T9J0 UNIPROT "down-regulates activity" 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-261053 PRKCG protein P05129 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 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-129328 Avacopan chemical CID:49841217 PUBCHEM C5AR1 protein P21730 UNIPROT "down-regulates activity" binding 9606 31734405 t lperfetto "CCX168 (avocapan), a C5aR antagonist, has proven its safety and efficiency in phase I and phase II trials conducted in AAV patients." SIGNOR-263473 PTPN18 protein Q99952 UNIPROT ERBB2 protein P04626 UNIPROT "down-regulates quantity by destabilization" dephosphorylation Tyr1196 GAVENPEyLTPQGGA 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-262596 PDX1 protein P52945 UNIPROT Hexokinase proteinfamily SIGNOR-PF76 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000627 8866550 f "inferred from family member" 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-270264 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[(5-nitro-2-thiazolyl)thio]-1H-1,2,4-triazol-5-one chemical CHEBI:94732 ChEBI JNK proteinfamily SIGNOR-PF15 SIGNOR down-regulates "chemical inhibition" 9606 18922779 t "inferred from 70% of family members" gcesareni "Bi-78d3, dose-dependently inhibits the phosphorylation of jnk substrates both in vitro and in cell." SIGNOR-269884 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 UBR5 protein O95071 UNIPROT EDVP complex SIGNOR-C530 SIGNOR "form complex" binding 9606 BTO:0000007 19287380 t miannu "We named this E3 ligase complex containing EDD, DDB1 and VPRBP proteins as EDVP complex to distinguish it from the previously identified Cul4-Roc1-DDB1-VPRBP E3 ligase complex. " SIGNOR-271790 SCF-SKP2 complex SIGNOR-C136 SIGNOR CDKN1B protein P46527 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 BTO:0000567 phosphorylation:Thr187 NAGSVEQtPKKPGLR 10559916 t lperfetto "SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27|We conclude that the stable interaction of p27 with SKP2 is highly specific and dependent upon phosphorylation of p27 on T187." SIGNOR-267557 CDK1 protein P06493 UNIPROT TOP2A protein P11388 UNIPROT unknown phosphorylation Ser1361 SPPKTKTsPKLSNKE 9606 BTO:0000567 7635160 t llicata "We show that many of the sites phosphorylated on topoisomerase iia in vivo correspond to sites phosphorylated in vitro by both p3pdcz and mitogen-activated protein (map) kinase. we have also shown that phosphorylation of ser1353 and ser1360 yields different phosphopeptide maps depending upon whether one or both of these sites are phosphorylated." SIGNOR-30252 MAP3K11 protein Q16584 UNIPROT MAPK8 protein P45983 UNIPROT up-regulates 9606 9003778 f gcesareni "The kinase-inactive mlk-3 failed to activate sapk, demonstraiting that mlk-3 catalytic activity is necessary for the induction of the sapk pathway." SIGNOR-45791 MAPK1 protein P28482 UNIPROT MAPKAPK2 protein P49137 UNIPROT up-regulates phosphorylation Thr334 QSTKVPQtPLHTSRV 9606 8846784 t fstefani "Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation of any two of the three residues thr222, ser272 and thr334. gst-mapkap kinase-2 lacking the n-terminal domain was inactive, but activated fully when phosphorylated at thr222, ser272 and thr334 by p42 mapk or rk." SIGNOR-44347 "HIRA complex 2" complex SIGNOR-C462 SIGNOR H3-3A protein P84243 UNIPROT "up-regulates quantity by stabilization" 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-269440 CSNK2A2 protein P19784 UNIPROT SMC3 protein Q9UQE7 UNIPROT unknown phosphorylation Ser1067 GDVEGSQsQDEGEGS 9606 18442975 t gcesareni "Our data provide evidence that phosphorylation of a core cohesin subunit smc3 by atm plays an important role in dna damage response and suggest that a constitutive phosphorylation by ck2 may affect intra-s phase checkpoint by modulating smc3 phosphorylation by atm." SIGNOR-178487 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 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 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 RUNX2 protein Q13950 UNIPROT NOTCH1 protein P46531 UNIPROT down-regulates binding 9606 20740684 t "Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1-IC-RBP-Jk complex" gcesareni "Runx2 is an inhibitor of the notch1 signaling pathway during normal osteoblast differentiation. The n-terminal domain of runx2 was crucial to the binding and inhibition of the the n-terminus of the notch1 intracellular domain." SIGNOR-167627 CDK11A protein Q9UQ88 UNIPROT CyclinD3/CDK11A complex SIGNOR-C542 SIGNOR "form complex" binding -1 12082095 t lperfetto "Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3|" SIGNOR-273117 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 UFL1 protein O94874 UNIPROT H4C1 protein P62805 UNIPROT "up-regulates activity" ubiquitination Lys32 DNIQGITkPAIRRLA 9606 BTO:0000007;BTO:0001938 30886146 t lperfetto "Here we report that UFM1 specific ligase 1 (UFL1), an ufmylation E3 ligase, is important for ATM activation." SIGNOR-265072 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 CREB1 protein P16220 UNIPROT PKM protein P14618 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 16308421 f gcesareni "In fasted mammals, glucose homeostasis is maintained through induction of the camp response element-binding protein (creb) coactivator transducer of regulated creb activity 2 (torc2), which stimulates the gluconeogenic program in concert with the forkhead factor foxo1" SIGNOR-142103 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 ULK3 protein Q6PHR2 UNIPROT ULK3 protein Q6PHR2 UNIPROT "up-regulates activity" phosphorylation Ser384 RLLAALEvASAAMAK 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-260795 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 D-ribofuranose smallmolecule CHEBI:47013 ChEBI "D-ribofuranose 5-phosphate(2-)" smallmolecule CHEBI:78346 ChEBI "up-regulates quantity" "precursor of" 9606 25749547 t miannu "Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds." SIGNOR-267071 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 NCOA4 protein Q13772 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 10347167 t miannu "Identification of ara70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. / ppargamma and ara70 interact in the absence of the ppargamma ligand 15-deoxy-delta12,14-prostaglandin j2, although the addition of exogenous ligand enhances this interaction." SIGNOR-67687 "Immunoglobulin mu heavy chain" protein P0DOX6 UNIPROT BCR-Mk complex SIGNOR-C433 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-268187 AMPK complex SIGNOR-C15 SIGNOR TSC2 protein P49815 UNIPROT up-regulates phosphorylation Ser1387 QPLSKSSsSPELQTL 9606 16959574 t lperfetto "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. Phosphorylation of tsc2 by ampk is required for translation regulation and cell size control in response to energy deprivation." SIGNOR-216438 CDON/SPAG9 complex SIGNOR-C21 SIGNOR ABL1 protein P00519 UNIPROT unknown binding 9606 19470755 t lperfetto "We report that abl associates with both cdo and jlp during myoblast differentiation" SIGNOR-217019 "SWI/SNF ACTL6A-ARID1A-SMARCA2 variant" complex SIGNOR-C470 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-269828 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SMAD2 protein Q15796 UNIPROT up-regulates phosphorylation 9606 BTO:0000763;BTO:0000149 10197981 t "inferred from 70% family members" 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-270065 citrate(3-) smallmolecule CHEBI:16947 ChEBI PFK proteinfamily SIGNOR-PF79 SIGNOR "down-regulates activity" binding 9606 31751601 t miannu "Once in the cytoplasm, citrate is able to inhibit phosphofructokinase 1 (PFK1) [4], the enzyme that is in charge of the “committed” step in glycolysis and converts fructose-6-phosphate to fructose-1, 6-bisphosphate (Fig. 1). In addition, citrate can inhibit PFK2, a bifunctional enzyme that regulates the rates of glycolysis and gluconeogenesis. Thus, a high level of citrate can lead to the reduction of glycolysis by directly inhibiting PFK1 and PFK2 and indirectly inhibiting PK." SIGNOR-267579 SERPINC1 protein P01008 UNIPROT F11 protein P03951 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-264137 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 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 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 MAPK14 protein Q16539 UNIPROT MAPKAPK2 protein P49137 UNIPROT "up-regulates activity" phosphorylation Thr25 APPPQPPtPALPHPP 9606 8846784 t lperfetto "Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation" SIGNOR-44351 FLT1 protein P17948 UNIPROT FLT1 protein P17948 UNIPROT up-regulates phosphorylation Tyr1213 GSSDDVRyVNAFKFM 9606 11583921 t tpavlidou "Vegfr-1 mutated at y1213, y1242, and y1333 were constructed and expressed in pae cells, to the same level as that of pae/vegfr-1 cells. The mutated vegfr-1 y1213f expressed in pae cells was kinase inactive." SIGNOR-110850 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 SP1 protein P08047 UNIPROT SLC2A1 protein P11166 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 9148896 f 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-241485 RET protein P07949 UNIPROT GRB7 protein Q14451 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-41765 PPP3CC protein P48454 UNIPROT BAD protein Q92934 UNIPROT "up-regulates activity" dephosphorylation Ser99 PFRGRSRsAPPNLWA 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-248529 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 EIF4E protein P06730 UNIPROT Protein_synthesis phenotype SIGNOR-PH29 SIGNOR up-regulates 9606 15094766 f lperfetto "A key player in the regulation of translation is the mRNA 5' cap-binding protein eIF4E, which is the rate-limiting member of the eIF4F complex" SIGNOR-236806 PRKAR2A protein P13861 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-258752 TAOK3 protein Q9H2K8 UNIPROT STK3 protein Q13188 UNIPROT up-regulates phosphorylation 9606 23431053 t gcesareni "In addition, the thousand-and-one (tao) amino acids kinase or taok1 3 has been shown to directly phosphorylate and activate hpo or mst1/2" SIGNOR-201333 LHFPL5 protein Q8TAF8 UNIPROT "Hair cells mechanotransduction channel" complex SIGNOR-C290 SIGNOR "up-regulates activity" binding 10090 BTO:0000630 23217710 t lperfetto "Here we show that TMHS is an auxiliary subunit of the hair cells mechanotransduction channel.|TMHS belongs to the tetraspan family. It binds to PCDH15, controls the assembly of the hair cells mechanotransduction machinery, regulates the properties of their mechanotransduction channels, and is required for adaptation." SIGNOR-262574 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 BMP7 protein P18075 UNIPROT BMPR2 protein Q13873 UNIPROT up-regulates binding 9606 SIGNOR-C29 7644468 t acerquone "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-30512 SDHA protein P31040 UNIPROT "Mitochondrial respiratory chain complex II" complex SIGNOR-C278 SIGNOR "form complex" binding 30030361 t lperfetto "Complex II (EC 1.3.5.1) or succinate dehydrogenase (quinone) is shared between the TCA cycle and the ETC and has no proton pumping activity. It is composed of four nDNA-encoded subunits. The two hydrophilic catalytic subunits are SDHA/SDH1 and SDHB/SDH2. Hydrophobic subunits SDHC/SDH3 and SDHD/SDH4 constitute the cII membrane anchor, containing a haem b group and two CoQ binding sites" SIGNOR-262188 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 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 proline smallmolecule CHEBI:26271 ChEBI Pro-tRNA(Pro) smallmolecule CHEBI:29154 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-270434 PRKCA protein P17252 UNIPROT DGKZ protein Q13574 UNIPROT unknown phosphorylation Ser265 SKKKKRAsFKRKSSK 9716136 t lperfetto "Two isoforms of protein kinase C, but not others, regulate the localization of DGK-zeta. |The PSD in MARCKS is phosphorylated by PKC, which suggested that DGK-zeta may also be a substrate for PKC, and that this couldregulate its intracellular location." SIGNOR-249010 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 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 imatinib chemical CHEBI:45783 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-258120 ERBB2 protein P04626 UNIPROT SHC3 protein Q92529 UNIPROT up-regulates relocalization 9606 16729043 t gcesareni "Erbb3 is characterized by a large number of binding sites for phosphatidylinositol-3-kinase (pi3k), while erbb2 has only few interaction partners with shc as the most frequent one." SIGNOR-146855 BMPR1B protein O00238 UNIPROT SMAD1 protein Q15797 UNIPROT up-regulates phosphorylation Ser462 GSPHNPIsSVS 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-52662 "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 PRKCA protein P17252 UNIPROT PLCB1 protein Q9NQ66 UNIPROT unknown phosphorylation Ser887 HSQPAPGsVKAPAKT 10090 BTO:0005065 11278470 t lperfetto ". Two-dimensional phosphopeptide mapping and site-directed mutagenesis demonstrated that PKC promoted phosphorylation of PLC beta1 at serine 887 in the nucleus of IGF-I-treated cells. Overexpression of either a PLC beta1 mutant in which the PKC phosphorylation site Ser(887) was replaced by alanine, or a dominant-negative PKC alpha, resulted in a sustained activation of nuclear PLC following IGF-I stimulation." SIGNOR-249081 p38 proteinfamily SIGNOR-PF16 SIGNOR CDC25B protein P30305 UNIPROT "down-regulates activity" phosphorylation Ser323 QRLFRSPsMPCSVIR 9606 11333986 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 proteins phosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3" SIGNOR-107412 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 D-threo-isocitrate(3-) smallmolecule CHEBI:15562 ChEBI IDH2 protein P48735 UNIPROT "up-regulates activity" "chemical activation" 9606 32943735 t "Wild-type IDH1 and IDH2 catalyze the reaction by converting isocitrate and NADP+ into α-KG and CO2 with the concomitant generation of NADPH in the cytosol and mitochondrial matrix" SIGNOR-267370 COL1A1 protein P02452 UNIPROT DDR1 protein Q08345 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-272340 COL21A1 protein Q96P44 UNIPROT DDR1 protein Q08345 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-272341 PFKFB4 protein Q16877 UNIPROT "β-D-fructose 6-phosphate" smallmolecule CHEBI:57634 ChEBI "up-regulates quantity" "chemical modification" -1 30553771 t miannu "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-268118 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 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 NT5E protein P21589 UNIPROT adenosine smallmolecule CHEBI:16335 ChEBI "up-regulates quantity" "chemical modification" -1 31461341 t Luana "Ecto-5'-nucleotidase [cluster of differentiation 73 (CD73)] is a ubiquitously expressed glycosylphosphatidylinositol-anchored glycoprotein that converts extracellular adenosine 5'-monophosphate to adenosine." SIGNOR-269742 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 RPS6KA1 protein Q15418 UNIPROT CDC25A protein P30304 UNIPROT down-regulates phosphorylation Ser293 GSTKRRKsMSGASPK 9606 23708659 t lperfetto "Rsk promotes g2/m transition through activating phosphorylation of cdc25a and cdc25b rsk is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of t359/s363 in rsk. Together, these findings indicate that rsk promotes g2/m transition in mammalian cells through activating phosphorylation of cdc25a and cdc25b." SIGNOR-202113 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 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR 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-256436 NAE1 protein Q13564 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000938 25568892 f lperfetto "Overexpression of AppBp1 in primary neurons induces apoptosis through the neddylation pathway" SIGNOR-251579 HRH1 protein P35367 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-257251 RAB1A protein P62820 UNIPROT GOLGA2 protein Q08379 UNIPROT "up-regulates activity" relocalization 10116 11285137 t Giulio "Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi" SIGNOR-261285 TGFB1 protein P01137 UNIPROT COL4A1 protein P02462 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000764 20846954 f Regulation miannu "We used diploid human lung fibroblasts (WI38 cells) induced by TGFβ to differentiate into myofibroblast-like cells. In order to characterize this system, we first studied the expression of the myofibroblast marker genes ACTA2 (coding for smooth muscle α-actin; SMA), COL4A1 (encoding collagen type IV α1) and SM22A (coding for smooth muscle protein 22-α). As shown in Figure 1A and B, TGFβ induced the expression all three genes." SIGNOR-251922 PRKCA protein P17252 UNIPROT VIM protein P08670 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser27 TASRPSSsRSYVTTS -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-248879 FBXO44 protein Q9H4M3 UNIPROT "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR "up-regulates activity" binding -1 23086937 t miannu "The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro." SIGNOR-272038 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 CAMK2G protein Q13555 UNIPROT AMPA proteinfamily SIGNOR-PF58 SIGNOR "up-regulates activity" phosphorylation 12609872 t "inferred from family member" llicata "Direct phosphorylation of the GluR1 subunit of postsynaptic AMPA receptors by Ca(2+)/calmodulin-dependent protein kinase II (CaM-KII) is believed to be one of the major contributors to the enhanced strength of glutamatergic synapses in CA1 area of hippocampus during long-term potentiation. | Validity of the approach was confirmed by modeling, and silence analysis was applied then to the GluR1 AMPA receptor mutated at S831, the site phosphorylated by CaM-KII during long-term potentiation. Silence analysis indicates that a negative charge at S831 is a critical determinant for the enhanced channel function as a charge carrier. Silence and variance analyses, when applied to the same sets of data, were in agreement on the receptor regulation upon mutations." SIGNOR-270234 CFL2 protein Q9Y281 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-261837 ARID1B protein Q8NFD5 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-270702 AKT2 protein P31751 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-249582 PIM1 protein P11309 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser253 APRRRAVsMDNSNKY 9606 18593906 t tpavlidou "Pim-mediated phosphorylation and inactivation of forkhead transcription factors, foxo1a and foxo3a, was involved in the transcriptional repression of the p27(kip1) gene." SIGNOR-252966 UCHL3 protein P15374 UNIPROT RPS27A protein P62979 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-270828 ARID1A protein O14497 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-270729 ADGRG1 protein Q9Y653 UNIPROT GNA12 protein Q03113 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-272344 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 Oxatomide chemical CHEBI:31943 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-257791 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 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 "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 NTRK1 protein P04629 UNIPROT NTRK1 protein P04629 UNIPROT up-regulates phosphorylation Tyr680 RDIYSTDyYRVGGRT 9606 9099755 t gcesareni "In vitro studies indicate that trka autophosphorylates at tyrosines 490, 670, 674, 675, and 785" SIGNOR-47175 PEX14 protein O75381 UNIPROT PEX7 protein O00628 UNIPROT "up-regulates activity" binding -1 15798189 t miannu "The peroxisomal docking complex is a key component of the import machinery for matrix proteins. The core protein of this complex, Pex14, is thought to represent the initial docking site for the import receptors Pex5 and Pex7." SIGNOR-253028 PTPRA protein P18433 UNIPROT PTPRA protein P18433 UNIPROT "down-regulates activity" dephosphorylation Tyr798 YIDAFSDyANFK 9606 7518772 t "Transient overexpression of c-Src together with RPTP alpha in human embryonic kidney 293 cells increased phosphorylation of Tyr789, suggesting that c-Src may phosphorylate RPTP alpha in vivo. RPTP alpha had autodephosphorylation activity in vitro. When expressed in 293 cells the level of Tyr789 phosphorylation was higher in a non-functional mutant of RPTP alpha than in wild type RPTP alpha, indicating that RPTP alpha may have autodephosphorylation activity in vivo as well.|We show that RPTP alpha, but not a mutant of RPTP alpha with a Tyr-->Phe mutation at position 789, bound to GRB2 in vitro." SIGNOR-248439 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 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 AKT proteinfamily SIGNOR-PF24 SIGNOR CHUK protein O15111 UNIPROT up-regulates phosphorylation Thr23 EMRERLGtGGFGNVC 9606 SIGNOR-C14 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-244210 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 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1875 SPTSPKYsPTSPTYS 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-203568 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 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 Avasimibe chemical CID:166558 PUBCHEM SOAT1 protein P35610 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-190119 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 BCL2L2 protein Q92843 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189156 "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 MAPK14 protein Q16539 UNIPROT CDKN1A protein P38936 UNIPROT "up-regulates quantity by stabilization" phosphorylation Ser130 SGEQAEGsPGGPGDS 9606 12058028 t gcesareni "The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro." SIGNOR-89436 FGD1 protein P98174 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-260551 vadimezan chemical CHEBI:75934 ChEBI NQO1 protein P15559 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191397 Riluzole chemical CHEBI:8863 ChEBI KCNN4 protein O15554 UNIPROT "up-regulates activity" "chemical activation" 9606 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258022 PLG protein P00747 UNIPROT PLAT protein P00750 UNIPROT "up-regulates activity" cleavage Arg310 QYSQPQFrIKGGLFA 9606 BTO:0000131 1447176 t 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-263534 L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "gamma-aminobutyric acid" smallmolecule CHEBI:16865 ChEBI "up-regulates quantity" "precursor of" 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-267550 CyclinA2/CDK2 complex SIGNOR-C83 SIGNOR CDC7 protein O00311 UNIPROT "up-regulates activity" phosphorylation Thr376 QVAPRAGtPGFRAPE 10846177 t llicata "Among four possible Cdk phosphorylation sites of huCdc7, replacement of Thr-376, corresponding to the activating threonine of Cdk, with alanine (T376A mutant) dramatically reduces kinase activity, indicative of kinase activation by phosphorylation of this residue. In vitro, Cdk2-Cyclin E, Cdk2-Cyclin A, and Cdc2-Cyclin B, but not Cdk4-Cyclin D1, phosphorylates the Thr-376 residue of huCdc7, suggesting possible regulation of huCdc7 by Cdks." SIGNOR-250725 "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 BCR-Ml complex SIGNOR-C434 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-268440 JAK2 protein O60674 UNIPROT LEPR protein P48357 UNIPROT "up-regulates activity" phosphorylation Tyr1141 SKKTFASyMPQFQTC 9606 BTO:0000007 11018044 t miannu "LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2." SIGNOR-263494 RPL15 protein P61313 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-262483 PRKACA protein P17612 UNIPROT MAP2 protein P11137 UNIPROT up-regulates phosphorylation Ser1782 GAEIITQsPGRSSVA 9606 BTO:0000567;BTO:0000938 BTO:0000142 11029056 t gcesareni "Specific phosphorylation states may enhance the interaction of map2 with the actin cytoskeleton, thereby providing a regulated mechanism for map2 function within distinct cytoskeletal domains" SIGNOR-83100 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 NCS1 protein P62166 UNIPROT GRK2 protein P25098 UNIPROT "down-regulates activity" binding 9606 BTO:0000007;BTO:0000938 12351722 t miannu "Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization." SIGNOR-263965 ZFYVE9 protein O95405 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" relocalization 9606 9865696 t lperfetto "We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex." SIGNOR-232126 STAR protein P49675 UNIPROT cholesterol smallmolecule CHEBI:16113 ChEBI "up-regulates quantity" relocalization 17579211 t lperfetto "StAR transfers cholesterol from the outer to the inner mitochondrial membranes, where the enzyme complex of cholesterol side chain cleavage cytochrome P450 (P450scc) converts it to the first steroid, pregnenolone" SIGNOR-265727 SP1 protein P08047 UNIPROT SLC9A3 protein P48764 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 7227 BTO:0001677 16464174 f "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-254270 TM9SF4 protein Q92544 UNIPROT Autophagy phenotype SIGNOR-PH31 SIGNOR up-regulates 9606 29125601 f miannu "In the present study, we report a novel autophagy-related protein TM9SF4, which plays a functional role in the induction phase of autophagic process. Overexpression of TM9SF4 promoted autophagic flux in HEK293 cells." SIGNOR-266704 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 SIRT2 protein Q8IXJ6 UNIPROT PGAM1 protein P18669 UNIPROT "up-regulates activity" deacetylation Lys100 GGLTGLNkAETAAKH 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-266517 EGFR protein P00533 UNIPROT EGFR protein P00533 UNIPROT "up-regulates activity" phosphorylation Tyr1197 STAENAEyLRVAPQS 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-236471 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 AT-406 chemical CID:25022340 PUBCHEM BIRC2 protein Q13490 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-189954 ELANE protein P08246 UNIPROT F2RL1 protein P55085 UNIPROT "down-regulates activity" cleavage Val58 KGVTVETvFSVDEFS -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-263591 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser415 HKLDVSRsPPLMVKK 9606 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-249307 PRKACA protein P17612 UNIPROT MC4R protein P32245 UNIPROT "down-regulates activity" phosphorylation Ser329 LGGLCDLsSRY 9606 12639913 t miannu "Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA" SIGNOR-250016 CYSLTR1 protein Q9Y271 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-257019 CHEK2 protein O96017 UNIPROT MDM4 protein O15151 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser367 PDCRRTIsAPVVRPK 9606 18356162 t lperfetto "The chk1 and chk2 kinases have also been shown to phosphorylate ser367, leading to 14-3-3 binding (34_36, 38, 44). In both cases, the outcome differed: in chk1-mediated phosphorylation, mdmx was translocated to the cytoplasm;in chk2-mediated phosphorylation, mdmx was degraded (34_36, 38, 44). It is possible that the damage response is mediated through additional phosphorylation sites other than ser367 and that, depending on the type of damage, certain sites will be modified, leading to different outcomes." SIGNOR-178071 XL765 chemical CHEBI:71958 ChEBI PIK3CD protein O00329 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207878 Pravadoline chemical CID:56463 PUBCHEM PTGS2 protein P35354 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206322 FYN protein P06241 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 15537652 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." 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-130274 PDPK1 protein O15530 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Thr308 KDGATMKtFCGTPEY 9606 15718470 t gcesareni "Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase." SIGNOR-243203 MED15 protein Q96RN5 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-266660 "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 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-258806 ARHGAP1 protein Q07960 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-260459 CARS1 protein P49589 UNIPROT tRNA(Cys) smallmolecule CHEBI:29167 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-270469 EEF1A2 protein Q05639 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-269541 SMARCB1 protein Q12824 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-132930 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 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser437 SGIVTNGsFSSSNAE 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-249305 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 CSNK2A1 protein P68400 UNIPROT CDC34 protein P49427 UNIPROT "down-regulates activity" phosphorylation Ser203 APAPDEGsDLFYDDY 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-110383 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 "Complement C1 complex" complex SIGNOR-C309 SIGNOR 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-263436 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 COL4A5 protein P29400 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-272349 FES protein P07332 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr690 PLNSDVQyTEVQVSS 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-262867 SIK2 protein Q9H0K1 UNIPROT IRS1 protein P35568 UNIPROT "down-regulates quantity" phosphorylation Ser794 QHLRLSTsSGRLLYA 24841198 t lperfetto "SIK2 is known to attenuate insulin signaling by phosphorylating IRS-1/Ser789" SIGNOR-265745 AURKA protein O14965 UNIPROT TPX2 protein Q9ULW0 UNIPROT "up-regulates activity" phosphorylation Ser125 QRRSLRLsAQKDLEQ 9606 BTO:0000567 26240182 t lperfetto "Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells" SIGNOR-265088 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser38 EGRQPSPsPSPTERA 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124244 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 TNF protein P01375 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-254809 ATM protein Q13315 UNIPROT SIAH1 protein Q8IUQ4 UNIPROT down-regulates phosphorylation Ser19 GTSKCPPsQRVPALT 9606 18536714 t llicata "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-177945 tandutinib chemical CHEBI:90237 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-258298 RAF1 protein P04049 UNIPROT MAP3K5 protein Q99683 UNIPROT down-regulates binding 9606 11427728 t gcesareni "Raf-1 interacts with the proapoptotic, stress-activated protein kinase ask1 (apoptosis signal-regulating kinase 1) in vitro and in vivo." SIGNOR-109023 MAPK1 protein P28482 UNIPROT RPS6KB1 protein P23443 UNIPROT up-regulates phosphorylation Ser434 SFEPKIRsPRRFIGS 9606 14967450 t gcesareni "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-121984 CPE protein P16870 UNIPROT Oxytocin protein P01178-PRO_0000020495 UNIPROT "up-regulates activity" cleavage 9606 25767437 t miannu "First, OT preprohormone is produced, that will be cleaved and matured by successive enzymes. The OT gene encodes for the Pre-Pro-OT-Neurophysin I (pre-pro-hormone), which is cleaved by different enzymes to give rise to different OT intermediate forms and to the Neurophysin I, and finally to the mature amidated form that is released (Figure ​2)." SIGNOR-270338 USP22 protein Q9UPT9 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-269578 MAPK1 protein P28482 UNIPROT IL16 protein Q14005 UNIPROT up-regulates phosphorylation Ser845 SIRQRISsFETFGSS 9606 14768064 t lperfetto "The precursor form of the cytokine il-16 (proil-16) was shown to be phosphorylated on ser144 . 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-121852 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 GLI1 protein P08151 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-209617 metformin chemical CHEBI:6801 ChEBI G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity by expression" "transcriptional regulation" 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 CBX3 protein Q13185 UNIPROT H3-4 protein Q16695 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-264495 IL12A protein P29459 UNIPROT IL12RB2 protein Q99665 UNIPROT up-regulates binding 9606 11086056 t gcesareni "Il-12r beta 2 plays an essential role in mediating the biological functions of il-12 in mice." SIGNOR-84361 "nitric oxide" smallmolecule CHEBI:16480 ChEBI GUCY1A2-B3 complex SIGNOR-C138 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-243964 SSU72 protein Q9NP77 UNIPROT POLR2A protein P24928 UNIPROT "up-regulates activity" dephosphorylation Ser1735 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-248824 CDK1 protein P06493 UNIPROT RCC1 protein P18754 UNIPROT "up-regulates activity" phosphorylation Ser11 KRIAKRRsPPADAIP -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-262702 FER protein P16591 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr690 PLNSDVQyTEVQVSS 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-262865 Serum stimulus SIGNOR-ST3 SIGNOR PRKAA2 protein P54646 UNIPROT down-regulates 9606 19584320 f miannu "Ampk is activated under conditions of low energy charge and typically inhibits anabolic reactions and promotes catabolism" SIGNOR-186644 PTPN6 protein P29350 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 9534 8943354 t "Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1" SIGNOR-248466 NEK2 protein P51955 UNIPROT NEK2 protein P51955 UNIPROT down-regulates phosphorylation Ser241 RRIPYRYsDELNEII 9606 17197699 t gcesareni "Enzymatic activity, inhibited;" SIGNOR-151767 STAT6 protein P42226 UNIPROT PPARG protein P37231 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-249533 PTPN2 protein P17706 UNIPROT JAK1 protein P23458 UNIPROT "down-regulates activity" dephosphorylation Tyr1035 IETDKEYyTVKDDRD 10090 11909529 t "The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3|We have identified JAK1 and JAK3 as physiological substrates of TCPTP.| Using a site-specific antibody directed against the activation loop phosphotyrosines in JAK1 (pY1022/pY1023), we found that these sites were in fact dephosphorylated by TCPTP" SIGNOR-248396 HIC1 protein Q14526 UNIPROT VEGFA protein P15692 UNIPROT "down-regulates quantity by repression" "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-254247 GADD45A protein P24522 UNIPROT CyclinB/CDK1 complex SIGNOR-C17 SIGNOR down-regulates binding 9606 10362260 t lperfetto "Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex" SIGNOR-217508 MMP12 protein P39900 UNIPROT FGA protein P02671 UNIPROT "down-regulates quantity by destabilization" cleavage Phe540 FSPMLGEfVSETESR -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-263623 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 FASLG protein P48023 UNIPROT FAS protein P25445 UNIPROT "up-regulates activity" binding 9606 14965271 t lperfetto "Fas (CD95) is activated by its natural ligand FasL" SIGNOR-216292 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 P2RY12 protein Q9H244 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-256855 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 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 PTGES3 protein Q15185 UNIPROT HSP90AA1 protein P07900 UNIPROT "up-regulates activity" binding -1 9817749 t lperfetto "The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23, which is thought to regulate the binding and release of substrate polypeptide from Hsp90. " SIGNOR-262831 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 SRC protein P12931 UNIPROT VIL1 protein P09327 UNIPROT "up-regulates activity" phosphorylation Tyr60 KTASSLSyDIHYWIG 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-247437 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK1 protein P39086 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-264470 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 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 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 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 PRKAA1 protein Q13131 UNIPROT CPT1C protein Q8TCG5 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21892142 f gcesareni "In 2010, bungard et al., reported that ampk can target transcriptional regulation through phosphorylation of histone h2b on serine3681. Cells expressing a mutant h2b s36a blunted the induction of stress genes upregulated by ampk including p21 and cpt1c." SIGNOR-176422 ILK protein Q13418 UNIPROT NACA protein Q13765 UNIPROT up-regulates phosphorylation Ser43 PELEEQDsTQATTQQ 9606 15299025 t lperfetto "Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase." SIGNOR-127694 PCDH19 protein Q8TAB3 UNIPROT GABA-A proteinfamily SIGNOR-PF61 SIGNOR "up-regulates quantity by stabilization" binding 10116 BTO:0003102 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-267216 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 TLE1 protein Q04724 UNIPROT SIX6 protein O95475 UNIPROT "up-regulates activity" binding -1 12441302 t lperfetto "Biochemical and mutational analysis shows that the Six domain of both SIX3 and SIX6 strongly interact with the QD domain of TLE1 and AES. TLE1 over-expression induces an enlargement of the eye field and reinforcesSIX3/SIX6 capability of initiating retina formation" SIGNOR-234592 "2-oxoglutaric acid" smallmolecule CHEBI:30915 ChEBI OXGR1 protein Q96P68 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-257555 CHD2 protein O14647 UNIPROT MYOD1 protein P15172 UNIPROT "up-regulates activity" binding 29962935 t miannu "CHD2 also showed an interaction with MyoD, a master regulator of skeletal muscle differentiation, and together MyoD and CHD2 bind to myogenic gene promoters." SIGNOR-264525 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 NRG1 protein Q02297 UNIPROT ERBB3 protein P21860 UNIPROT up-regulates binding 9606 BTO:0000150 7514177 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 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3." SIGNOR-26878 "Set1-Ash2 HMT complex" complex SIGNOR-C352 SIGNOR "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" methylation 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-265349 COL4A3 protein Q01955 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-272351 DLGAP2 protein Q9P1A6 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-264590 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 ROCK1 protein Q13464 UNIPROT ARHGAP24 protein Q8N264 UNIPROT "up-regulates activity" phosphorylation Ser413 SVHKLDVsRSPPLMV 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-249306 GSK3B protein P49841 UNIPROT RCAN1 protein P53805 UNIPROT "up-regulates activity" phosphorylation Ser163 PDKQFLIsPPASPPV 10090 BTO:0000165 12063245 t 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-249359 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 IKBKB protein O14920 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates activity" phosphorylation Ser927 DSDSVCDsGVETSFR 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-104807 taurine smallmolecule CHEBI:15891 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-267793 WNK3 protein Q9BYP7 UNIPROT SLC12A4 protein Q9UP95 UNIPROT "down-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-264627 "COP9 signalosome variant 1" complex SIGNOR-C489 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-270795 PTPN12 protein Q05209 UNIPROT PTK2 protein Q05397 UNIPROT down-regulates dephosphorylation 9606 11432829 t gcesareni "This function correlated with the ability of ptp-pest to induce dephosphorylation of shc, pyk2, fak and cas, and inactivate the ras pathway." SIGNOR-109035 RNF123 protein Q5XPI4 UNIPROT CBX5 protein P45973 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-272035 MCHR1 protein Q99705 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-257302 WNK1 protein Q9H4A3 UNIPROT STK39 protein Q9UEW8 UNIPROT up-regulates phosphorylation Thr231 TRNKVRKtFVGTPCW 9606 BTO:0000007 BTO:0000671 16083423 t gcesareni "Phosphorylation by WNK1 or WNK4 markedly increased SPAK and OSR1 activity. Phosphopeptide mapping studies demonstrated that WNK1 phosphorylated kinase-inactive SPAK and OSR1 at an equivalent residue located within the T-loop of the catalytic domain (Thr233 in SPAK, Thr185 in OSR1) and a serine residue located within a C-terminal non-catalytic region (Ser373 in SPAK, Ser325 in OSR1)" SIGNOR-160846 FES protein P07332 UNIPROT FES protein P07332 UNIPROT up-regulates phosphorylation Tyr811 RPSFSTIyQELQSIR 9606 8663427 t llicata "Substitution of kinase domain tyrosine residues 713 or 811 with phenylalanine resulted in a loss of the 10- and 4-kda phosphopeptides, respectively, identifying these tyrosines as in vitro autophosphorylation sites. Cnbr cleavage analysis of fes isolated from 32po4-labeled 293t cells showed that tyr-713 and tyr-811 are also autophosphorylated in vivo. . Mutagenesis of tyr-713 reduced both autophosphorylation of tyr-811 and transphosphorylation of bcr, a recently identified fes substrate, supporting a major regulatory role for tyr-713." SIGNOR-42659 MAPK1 protein P28482 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Thr522 SSPGSPGtPGSRSRT 9606 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-249417 RBKS protein Q9H477 UNIPROT D-ribofuranose smallmolecule CHEBI:47013 ChEBI "down-regulates quantity" "chemical modification" 9606 25749547 t miannu "Human ribokinase (RK) is a member of the ribokinase family, and is the first enzyme responsible for D-ribose metabolism, since D-ribose must first be converted into D-ribose-5-phosphate to be further metabolized and incorporated into ATP or other high energy phosphorylated compounds." SIGNOR-267072 HTR6 protein P50406 UNIPROT GNAS protein Q5JWF2 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-256801 FBXO21 protein O94952 UNIPROT ABCB1 protein P08183 UNIPROT "down-regulates quantity by destabilization" binding -1 26299618 t miannu "Here we demonstrate that a ubiquitin E3-ligase, FBXO21, targets the multidrug resistance transporter, ABCB1, also known as P-glycoprotein (P-gp), for proteasomal degradation.Purified in vitro translated FLAG-tagged P-gp along with E2 (UbcH5c), E3 ligase FBXO21, Cul1, Skp1, Roc1 purified from Sf-9 insect cells were incubated in vitro." SIGNOR-272422 DDX17 protein Q92841 UNIPROT "RNA helicases p68/p72" complex SIGNOR-C34 SIGNOR "form complex" binding 9606 BTO:0000887;BTO:0001103 17011493 t lperfetto "We have found that the rna helicases p68/p72 are myod-associated proteins and that the noncoding rna sra also immunoprecipitates with myod. In vitro and in vivo experiments indicated that both p68/p72 and sra are coactivators of myod." SIGNOR-149961 PTPRG protein P23470 UNIPROT KIT protein P10721 UNIPROT "down-regulates activity" dephosphorylation Tyr730 DMKPGVSyVVPTKAD -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-254710 IKBKE protein Q14164 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" phosphorylation Ser398 VDLHISNsHPLSLTS -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-178375 SRR protein Q9GZT4 UNIPROT D-serine smallmolecule CHEBI:16523 ChEBI "up-regulates quantity" "chemical modification" 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-268270 ARF3 protein P61204 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-272150 MAPK3 protein P27361 UNIPROT CEBPA protein P49715 UNIPROT down-regulates phosphorylation Ser21 PMSSHLQsPPHAPSS 9606 BTO:0000876 14701740 t 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-120570 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 CAMK2A protein Q9UQM7 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser579 NVKSKIGsTENLKHQ 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-249314 FSCN1 protein Q16658 UNIPROT Actin_cytoskeleton_reorganization phenotype SIGNOR-PH84 SIGNOR up-regulates 10090 BTO:0000526 21706053 f miannu "Plexin-B3 interacts with the actin-binding protein fascin-1. The present finding suggests fascin-1 as a potential effector of plexin-B3 to mediate the signal of Sema5A in glioma cells.Sema5A and plexin-B3 remodel F-actin cytoskeleton and induce fascin-1 translocation in glioma cells." SIGNOR-268375 EFNA1 protein P20827 UNIPROT EPHA1 protein P21709 UNIPROT up-regulates binding 9606 9330863 t gcesareni "The eph family receptors and ligands." SIGNOR-51932 MSH6 protein P52701 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-123705 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 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 "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 DLX5 protein P56178 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates -1 19195802 f Luana "DLX5 and adjacent DLX6 are homeobox genes working in neurogenesis." SIGNOR-265797 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 CDK1 protein P06493 UNIPROT KAT5 protein Q92993 UNIPROT up-regulates phosphorylation Ser86 TKNGLPGsRPGSPER 9606 16103124 t gcesareni "Moreover, app stabilized tip60 through cdk-dependent phosphorylation" SIGNOR-139649 NPFFR1 protein Q9GZQ6 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-256851 PTPN12 protein Q05209 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1007 VLPQDKEyYKVKEPG 9606 BTO:0003892 11731619 t "PTP-PEST-Containing Lysates from EGF-Treated HC11 Cells Dephosphorylate JAK2 More Efficiently than Lysates from Control Cells|phospho-JAK2-specific rabbit polyclonal antiserum (44-426, BioSource Technologies, Inc., Camarillo, CA) which recognizes Tyr1007/1008 in the activation site" SIGNOR-248657 BCL6 protein P41182 UNIPROT CD80 protein P33681 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000776 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-253931 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 MECP2 protein P51608 UNIPROT Neurogenesis phenotype SIGNOR-PH168 SIGNOR up-regulates 10090 BTO:0000601 25420914 f Luana "Our current study highlights the phosphorylation, but not the overall expression level, of MeCP2 as a significant regulatory mechanism in regulating adult neurogenesis in the hippocampus. " SIGNOR-264967 CAMK1 protein Q14012 UNIPROT CDKN1B protein P46527 UNIPROT "up-regulates activity" phosphorylation Thr198 PGLRRRQt 10090 23707388 t Monia "We also demonstrate that i) CaMKI phosphorylates p27 at Thr157and Thr198 in human cells and at Thr170and Thr197in mouse cells to modulate its subcellular localization;|Collectively, these results suggest that CaMKI is involved in mediating G1 progression by promoting cyclin D1/cdk4 complex formation through site-specific p27 phosphorylation in human lung epithelia." SIGNOR-261194 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 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 PFAS protein O15067 UNIPROT 2-formamido-N(1)-(5-O-phosphonato-beta-D-ribosyl)acetamidine smallmolecule CHEBI:147287 ChEBI "up-regulates quantity" "chemical modification" 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-267311 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 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 PAX1 protein P15863 UNIPROT MEOX2 protein P50222 UNIPROT "up-regulates activity" binding -1 11423130 t miannu "We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family." SIGNOR-222232 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 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 PKN3 protein Q6P5Z2 UNIPROT ARHGAP18 protein Q8N392 UNIPROT "up-regulates activity" phosphorylation Thr158 RVETVSQtLRKKNKQ -1 33092266 t lperfetto "We present strong evidence that PKN3-ARHGAP18 interaction is increased upon ARHGAP18 phosphorylation and that the phosphorylation of ARHGAP18 by PKN3 enhances its GAP domain activity and contributes to negative regulation of active RhoA.|These results support our data from phosphoproteomic screen and suggest that ARHGAP18 can be phosphorylated by PKN3 on Thr154, Ser156 and Thr158." SIGNOR-264572 ZWILCH protein Q9H900 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-265014 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 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 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "up-regulates activity" phosphorylation Ser1647 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-269370 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 WARS1 protein P23381 UNIPROT tryptophan smallmolecule CHEBI:27897 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-270510 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 NPY protein P01303 UNIPROT NPY2R protein P49146 UNIPROT up-regulates binding 9606 9549761 t gcesareni "Analogs of npy and pyy have been synthesized that contain a proline residue in position 34 of the molecule, i.e., [leu31, pro34]npy (fuhlendorff et al., 1990) or [pro34]pyy (grandt et al., 1994b), and are much more potent at y1 than y2receptors." SIGNOR-56568 NEU1 protein Q99519 UNIPROT AKT proteinfamily SIGNOR-PF24 SIGNOR "down-regulates activity" 9606 BTO:0003554 32164705 f Giorgia "Taken together, these findings indicate that NEU1 overexpression reduces cell proliferation and enhances cell apoptosis through by downregulation of FN-integrin β1-mediated Akt signaling pathway." SIGNOR-260659 PPARA protein Q07869 UNIPROT ACSL1 protein P33121 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003204 17150915 f miannu "To investigate the intimate function of PPARalpha in the kidney, we analyzed the target gene expression in human metastatic renal cell carcinoma cell line, Caki-1, using small interfering RNA (siRNA) against PPARalpha and real-time RT-PCR methods. We found that some selected genes (long-chain fatty-acid-CoA ligase (FACL1), carnitine palmitoyltransferase 1A (CPT1A), adipose differentiation-related protein (ADRP) and aquaporin 3 (AQP3)) were down-regulated by PPARalpha siRNA." SIGNOR-255044 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 FFAR1 protein O14842 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-256942 TYMS protein P04818 UNIPROT dTMP(2-) smallmolecule CHEBI:63528 ChEBI "up-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-268235 Ub:E2 complex SIGNOR-C497 SIGNOR TRIML1 protein Q8N9V2 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-271200 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT "down-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 14625384 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-119233 ARHGAP35 protein Q9NRY4 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-260493 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 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 LYN protein P07948 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-268212 RBPJ protein Q06330 UNIPROT PAX7 protein P23759 UNIPROT up-regulates binding 9606 22493066 t gcesareni "Nicd regulates pax7 through interaction with rbp-j, which binds to two consensus sites upstream of the pax7 gene." SIGNOR-196948 P2RY14 protein Q15391 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-257002 NFE2L2 protein Q16236 UNIPROT TBXAS1 protein P24557 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 14565864 f lperfetto "Ecotopic expression of NF-E2 related factors showed that Nrf2, but not Nrf1, Nrf3, or Bach1, activated TXAS promoter in a dose-dependent manner." SIGNOR-268993 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 Œ≤-alanine relative to glycine, the concentration of each agonist required for half-maximal current activation (EC50) and, in mutant GlyRs where Œ≤-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 Œ±1 homomeric GlyRs recombinantly expressed in mammalian HEK 293 cells. Taurine and Œ≤-alanine act as full agonists of human Œ±1 GlyRs when expressed in this system." SIGNOR-270261 APOBEC3C protein Q9NRW3 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-261326 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 ESR2 protein Q92731 UNIPROT SCN1A protein P35498 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253472 ETS1 protein P14921 UNIPROT MUC4 protein Q99102 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001861 19757157 t lperfetto "Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level." SIGNOR-254098 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 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 ChEBI "up-regulates quantity" "precursor of" 9606 22049910 t "Glutaminase (GLS1/2) catalyzes the conversion of L-glutamine to L-glutamate and ammonia." SIGNOR-266907 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 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 FZD1 protein Q9UP38 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-253512 FBP1 protein P09467 UNIPROT "beta-D-fructofuranose 1,6-bisphosphate(4-)" smallmolecule CHEBI:32966 ChEBI "down-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-267610 PPARGC1A protein Q9UBK2 UNIPROT MSTN protein O14793 UNIPROT "down-regulates quantity by repression" "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-256151 MMP16 protein P51512 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-272361 MMP17 protein Q9ULZ9 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-272362 MMP20 protein O60882 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-272365 CSTF2 protein P33240 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-268366 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 ABL1 protein P00519 UNIPROT DGCR8 protein Q8WYQ5 UNIPROT "up-regulates activity" phosphorylation Tyr267 KRRTEEKyGGDSDHP 9606 BTO:0000007 26126715 t miannu "The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr(267)." SIGNOR-262604 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 MDH2 protein P40926 UNIPROT NAD(1-) smallmolecule CHEBI:57540 ChEBI "down-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-268100 SUFU protein Q9UMX1 UNIPROT GLIS3 protein Q8NEA6 UNIPROT down-regulates binding 9606 21543335 t fspada "These data indicate that the inhibition of glis3-mediated transactivation by sufu appears to rely on the interaction with glis3 through the ygh motif and is not related to an effect on the general transcriptional machinery" SIGNOR-173573 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 SATB2 protein Q9UPW6 UNIPROT IGHM protein P01871 UNIPROT "up-regulates quantity" "transcriptional regulation" 9606 14701874 t gianni "The SATB2 protein was shown to bind MAR sequences flanking the enhancer of the endogenous immunoglobulin μ heavy chain (IgH) gene in vivo, and this binding was found to correlate with an increase in the expression of a transfected rearranged μ wild-type gene" SIGNOR-268933 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 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 MAT2B protein Q9NZL9 UNIPROT Proliferation phenotype SIGNOR-PH4 SIGNOR up-regulates 9606 BTO:0000599 23325603 f miannu "MAT2B and GIT1 regulate cell growth and increase ERK activity.GIT1 and MAT2B (V1 and V2) require one another to regulate growth and activate ERK" SIGNOR-261246 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 "Noncanonical PRC1" complex SIGNOR-C151 SIGNOR Adipogenesis phenotype SIGNOR-PH26 SIGNOR down-regulates 10090 BTO:0000011 25533466 f miannu "We show that FBXL10/KDM2B is an anti-adipogenic factor that is up-regulated during the early phase of 3T3-L1 preadipocyte differentiation and in adipose tissue in a diet-induced model of obesity. Interestingly, 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-252248 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1721 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-203540 (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide chemical CHEBI:91449 ChEBI PI3K complex SIGNOR-C156 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-252658 H2BC11 protein P06899 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-263710 HAND2 protein P61296 UNIPROT HAND2 protein P61296 UNIPROT "up-regulates activity" binding -1 11812799 t miannu "The basic helix-loop-helix factor, HAND2, functions as a transcriptional activator by binding to E-boxes as a heterodimer" SIGNOR-223476 MMP1 protein P03956 UNIPROT COL2A1 protein P02458 UNIPROT "down-regulates quantity by destabilization" cleavage Gly774 RGDVGEKgPEGAPGK -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-272338 PPP2R1A protein P30153 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-243445 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 RXRB protein P28702 UNIPROT RARA protein P10276 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-16674 C1D protein Q13901 UNIPROT NR1D1 protein P20393 UNIPROT "up-regulates activity" binding 9606 BTO:0000567 9405624 t 2 miannu "SUN-CoR is a protein involved in transcriptional repression by nuclear hormone receptors. The C terminus of SUN-CoR interacts with TR and RevErb in vitro and associates with RevErb in cells, SUN-CoR potentiates repression by both receptors in cells, and the N terminus of SUN-CoR contains an intrinsic repression domain." SIGNOR-241272 MMP13 protein P45452 UNIPROT FGG protein P02679 UNIPROT "down-regulates quantity by destabilization" cleavage Tyr27 LSSTCVAyVATRDNC -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-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain" SIGNOR-263614 MAPK1 protein P28482 UNIPROT EP300 protein Q09472 UNIPROT up-regulates phosphorylation Ser2366 MEQGHFAsPDQNSML 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-156895 IFNA1 protein P01562 UNIPROT IFNAR2 protein P48551 UNIPROT up-regulates binding 9606 11278538 t gcesareni "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-104641 CTNNB1 protein P35222 UNIPROT α-Catenin proteinfamily SIGNOR-PF72 SIGNOR "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-265813 IRX1 protein P78414 UNIPROT FGF7 protein P21781 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-261654 MASP2 protein O00187 UNIPROT C4B protein P0C0L5 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -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-263422 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 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 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 STAT3 protein P40763 UNIPROT KRT17 protein Q04695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000667 21796151 f miannu "IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms." SIGNOR-255234 PTPN1 protein P18031 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation Tyr1008 LPQDKEYyKVKEPGE 9606 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-248405 AKT1 protein P31749 UNIPROT PEA15 protein Q15121 UNIPROT "up-regulates activity" phosphorylation Ser116 KDIIRQPsEEEIIKL 9606 BTO:0000007 12808093 t lperfetto "Protein kinase b/akt binds and phosphorylates ped/pea-15, stabilizing its antiapoptotic action." SIGNOR-102092 MACROH2A1 protein O75367 UNIPROT rRNA_transcription phenotype SIGNOR-PH145 SIGNOR down-regulates 16428466 f miannu "These data unambiguously identify mH2A as a strong transcriptional repressor and show that the repressive effect of mH2A is realized on at least two different transcription activation chromatin-dependent pathways: histone acetylation and nucleosome remodeling." SIGNOR-272930 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 BID protein P55957 UNIPROT BAX protein Q07812 UNIPROT up-regulates binding 9606 17289999 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-152929 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 CTSH protein P09668 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-256325 TNFRSF25 protein Q93038 UNIPROT TRADD protein Q15628 UNIPROT up-regulates binding 9606 14585074 t amattioni "Dr3 induces apoptosis by tradd-mediated recruitment of fadd and caspase-8" SIGNOR-100480 PF-3845 chemical CID:25154867 PUBCHEM FAAH protein O00519 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-206049 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 EP300 protein Q09472 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates acetylation Lys70 GKAVRGAkGHHHPHP 9606 12408818 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-95169 NFKB1 protein P19838 UNIPROT BMP4 protein P12644 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000018 17350185 t Luana " The effect of TNF-alpha on the Bmp4 promoter is mediated through NF-kB." SIGNOR-266086 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 GSK3B protein P49841 UNIPROT ACLY protein P53396 UNIPROT "up-regulates activity" phosphorylation Thr447 NASGSTStPAPSRTA 10653665 t "Thr 446 and Ser 450, which are phosphorylated by glycogen synthase kinase-3 (GSK-3). Phosphorylation resulted in a 6-fold increase in V(max) and the conversion of citrate dependence from sigmoidal, displaying negative cooperativity, to hyperbolic." SIGNOR-251219 MTOR protein P42345 UNIPROT mTORC1 complex SIGNOR-C3 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-205615 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 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 MAPK11 protein Q15759 UNIPROT RUNX2 protein Q13950 UNIPROT up-regulates 9606 20551513 f gcesareni "Mechanistic analysis revealed that the tak1-mkk3/6-p38 mapk axis phosphorylated runx2, promoting its association with the coactivator creb-binding protein (cbp), which is re-quired to regulate osteoblast genetic programs." SIGNOR-166167 VEGFD protein O43915 UNIPROT KDR protein P35968 UNIPROT up-regulates binding 9606 9435229 t gcesareni "Vegf-d is a ligand for both vegf receptors (vegfrs) vegfr-2 (flk1) and vegfr-3 (flt4) and can activate these receptors." SIGNOR-55163 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 ACD protein Q96AP0 UNIPROT POT1/ACD complex SIGNOR-C64 SIGNOR "form complex" 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-152318 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 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR6 protein P50406 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-257525 CAMK2G protein Q13555 UNIPROT ADCY3 protein O60266 UNIPROT "down-regulates activity" phosphorylation Ser1076 NVASRMEsTGVMGNI 9606 BTO:0000007 8798667 t llicata "Phosphorylation and inhibition of type III adenylyl cyclase by calmodulin-dependent protein kinase II in vivo. | Site-directed mutagenesis of a CaM kinase II consensus site (Ser-1076 to Ala-1076) in III-AC greatly reduced Ca2+-stimulated phosphorylation and inhibition of III-AC in vivo." SIGNOR-250691 MAPK3 protein P27361 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-264441 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 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 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 CDK5 protein Q00535 UNIPROT NES protein P48681 UNIPROT unknown phosphorylation Thr315 AENSRLQtPGGGSKT 10090 BTO:0000165 12832492 t llicata "We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. | Cdk5 activity is necessary for differentiation and the concomitant nestin reorganization in C2C12 myoblasts." SIGNOR-250670 MAPK8 protein P45983 UNIPROT JUNB protein P17275 UNIPROT "up-regulates activity" phosphorylation Thr102 SNGVITTtPTPPGQY 10090 9889198 t miannu "JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation." SIGNOR-250120 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 calcium(2+) smallmolecule CHEBI:29108 ChEBI S100A8 protein P05109 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001044 16690079 t miannu "S100 proteins comprise the largest family of calcium-binding proteins. Members of this family usually form homo- or heterodimers, which may associate to higher-order oligomers in a calcium-dependent manner. The heterodimers of S100A8 and S100A9 represent the major calcium-binding proteins in phagocytes. Both proteins regulate migration of these cells via modulation of tubulin polymerization." SIGNOR-261935 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 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 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 Quadazocine chemical CID:115077 PUBCHEM 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-258420 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 ULK2 protein Q8IYT8 UNIPROT ATG13 protein O75143 UNIPROT up-regulates phosphorylation 9606 19225151 t gcesareni "Ulks directly phosphorylates atg13." SIGNOR-184126 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser39 TTSTRTYsLGSALRP -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-250239 PSPH protein P78330 UNIPROT L-serine chemical CHEBI:17115 ChEBI "up-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-268571 PRKCB protein P05771 UNIPROT LMNB1 protein P20700 UNIPROT unknown phosphorylation Ser395 LKLSPSPsSRVTVSR -1 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-248911 MAP2K6 protein P52564 UNIPROT MAPK12 protein P53778 UNIPROT up-regulates phosphorylation Tyr185 ADSEMTGyVVTRWYR 9606 19230643 t gcesareni "Mapkk6 was shown to phosphorylate and specifically activate the p38/mpk2 sub of the mitogen-activated protein kinase superfamily . the p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms . p38mapks are activated by dual phosphorylation on a t-x-y motif in the activation loop through the action of map kinase kinases" SIGNOR-184138 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 MRAP2 protein Q96G30 UNIPROT MC3R protein P41968 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-252367 ID2 protein Q02363 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-241140 PVR protein P15151 UNIPROT TIGIT protein Q495A1 UNIPROT "up-regulates activity" binding 9606 30591568 t lperfetto "Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12)." SIGNOR-261425 AKT proteinfamily SIGNOR-PF24 SIGNOR EZR protein P15311 UNIPROT up-regulates phosphorylation Thr567 QGRDKYKtLRQIRQG 9606 15531580 t lperfetto "Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression" SIGNOR-244263 GRK5 protein P34947 UNIPROT ST13 protein P50502 UNIPROT "up-regulates activity" phosphorylation Ser346 AQNPANMsKYQSNPK 9606 BTO:0000007 21728385 t miannu "An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303-319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells.we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4." SIGNOR-262877 PRKCA protein P17252 UNIPROT PTGIR protein P43119 UNIPROT unknown phosphorylation Ser328 TPLSQLAsGRRDPRA 9606 BTO:0000007 9722557 t lperfetto "These results indicate that PKC-dependent phosphorylation is of critical importance to homologous regulation of hIP. Ser-328 is a primary site for PKC phosphorylation of hIP." SIGNOR-249011 CRTC2 protein Q53ET0 UNIPROT G6P proteinfamily SIGNOR-PF81 SIGNOR "up-regulates quantity" "transcriptional regulation" 9600 BTO:0000567 26652733 t "inferred from family member" "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-270253 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 HACD proteinfamily SIGNOR-PF86 SIGNOR "very long-chain 2,3-trans-enoyl CoA(4-)" smallmolecule CHEBI:83728 ChEBI "up-regulates quantity" "chemical modification" 9606 18554507 t miannu "Very long-chain fatty acids are produced through a four-step cycle. 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.We also established that the HACD proteins interact with ELOVL proteins. Our analyses have completed the identification of mammalian enzymes responsible for the entire VLCFA elongation cycle." SIGNOR-267918 SEC63 protein Q9UGP8 UNIPROT SEC62 protein Q99442 UNIPROT "up-regulates activity" binding 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-265273 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 "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 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 EPHA2 protein P29317 UNIPROT EPHA2 protein P29317 UNIPROT up-regulates phosphorylation Tyr735 KYLANMNyVHRDLAA 9606 18387945 t lperfetto "The binding of ephrin ligands to eph receptors induces the transphosphorylation of the cytoplasmic domains and initiates kinase activity.Taken together, these results suggest that tyr587, tyr593, tyr771, and tyr734 are likely to be autophospho-rylated in vascular endothelial cells." SIGNOR-178177 PAK1 protein Q13153 UNIPROT MAP2K1 protein Q02750 UNIPROT "up-regulates activity" phosphorylation Ser298 RTPGRPLsSYGMDSR 9606 BTO:0001955 12876277 t lperfetto "We find that adhesion to fibronectin induces pak1-dependent phosphorylation of mek1 on s298 and that this phosphorylation is necessary for efficient activation of mek1 and subsequent mapk activation." SIGNOR-236002 IRAK4 protein Q9NWZ3 UNIPROT NCF1 protein P14598 UNIPROT up-regulates phosphorylation Thr133 KLPTDNQtKKPETYL 9606 BTO:0000130 17217339 t lperfetto "Phosphorylation of the cytosolic factor p47phox is essential for activation of the nadph oxidase.We found that thr133, ser288 and thr356, targets for irak-4 phosphorylation in vitro, are also phosphorylated in endogenous p47phox after lps stimulation. We conclude that irak-4 phosphorylates p47phox and regulates nadph oxidase activation after lps stimulation." SIGNOR-152023 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 SMO protein Q99835 UNIPROT GNGT1 protein P63211 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-148601 FBXW8 protein Q8N3Y1 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0001109 phosphorylation:Thr286 EEVDLACtPTDVRDV 17205132 t miannu "We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8." SIGNOR-271624 KLHL25 protein Q9H0H3 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0002552 27664236 t miannu "Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. " SIGNOR-272334 PDPK1 protein O15530 UNIPROT SGK2 protein Q9HBY8 UNIPROT up-regulates phosphorylation 9606 15209375 t gcesareni "One of the most studiedevents controlled by ptdins(3,4,5)p3, comprises the activation of aof 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-126177 "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 TLN1 protein Q9Y490 UNIPROT ITGB4 protein P16144 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-257627 CSNK1D protein P48730 UNIPROT MAPT protein P10636 UNIPROT down-regulates phosphorylation Ser721 PVVSGDTsPRHLSNV 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-121713 WNT7B protein P56706 UNIPROT FZD1 protein Q9UP38 UNIPROT up-regulates binding 9606 BTO:0000887;BTO:0000763;BTO:0001260 15923619 t gcesareni "Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling." SIGNOR-137931 SRC protein P12931 UNIPROT GJA1 protein P17302 UNIPROT down-regulates phosphorylation Tyr265 KDCGSQKyAYFNGCS 9606 16916748 t lperfetto "The oncogenic tyrosine kinase, v-src, phosphorylates connexin43 (cx43) on y247 and y265 and inhibits cx43 gap junctional communication (gjc), the process of intercellular exchange of ions and metabolites." SIGNOR-148917 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 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 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 PAK2 protein Q13177 UNIPROT MYLK protein Q15746 UNIPROT "down-regulates activity" phosphorylation Ser1760 RAIGRLSsMAMISGL -1 10748018 t miannu "PAK2 can directly phosphorylate MLCK, inhibiting its activity and limiting the development of isometric tension. PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991." SIGNOR-250223 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 NRG2 protein O14511 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-26211 CALM1 protein P0DP23 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. We show that Ca2+/CaM-dependent modulation on KIF1A allows for binding to vesicular cargo. Our results indicate that at low calcium concentrations, the tail domain of KIF1A does not bind to vesicular cargo, whereas at high calcium concentrations, CaM binds KIF1A, allowing for subsequent DCV motility." SIGNOR-266888 EP300 protein Q09472 UNIPROT PLAGL2 protein Q9UPG8 UNIPROT up-regulates acetylation 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-140947 CD2AP protein Q9Y5K6 UNIPROT ACTB protein P60709 UNIPROT "up-regulates activity" 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-264770 RAP1GDS1 protein P52306 UNIPROT KRAS protein P01116 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-171415 MAPK3 protein P27361 UNIPROT MED1 protein Q15648 UNIPROT up-regulates phosphorylation Thr1457 HSKSPAYtPQNLDSE 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-93993 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 NEUROG3 protein Q9Y4Z2 UNIPROT NEUROG2 protein Q9H2A3 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-254633 PRKACA protein P17612 UNIPROT PDE3B protein Q13370 UNIPROT unknown phosphorylation Ser442 TPQLRRSsGTSGLLP -1 8163498 t miannu "Serine 427 is the target for cAMP-PK phosphorylation of the rat adipocyte cGI-PDE in vitro" SIGNOR-250023 AVPR1B protein P47901 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-257176 RSPO2 protein Q6UXX9 UNIPROT SDC4 protein P31431 UNIPROT up-regulates binding 9606 21397842 t "Thrombospondin domains" gcesareni "We show that rspo3 binds syndecan 4 (sdc4) and that together they activate wnt/pcp signaling." SIGNOR-172719 SIRT1 protein Q96EB6 UNIPROT 2''-O-acetyl-ADP-D-ribose(2-) smallmolecule CHEBI:83767 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-267963 ARHGEF11 protein O15085 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-260538 STAT3 protein P40763 UNIPROT CD274 protein Q9NZQ7 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 27141364 t irozzo "STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK." SIGNOR-259188 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 ACTL6A protein O96019 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-270847 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 MMP26 protein Q9NRE1 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-272370 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 DUSP3 protein P51452 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "down-regulates activity" dephosphorylation 9534 BTO:0004055 10224087 t "inferred from 70% of family members" "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.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2" SIGNOR-269928 ENY2 protein Q9NPA8 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-269577 UHRF2 protein Q96PU4 UNIPROT CCNE1 protein P24864 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9534 BTO:0000298 21952639 t miannu "We found that NIRF directly ubiquitinated cyclins D1 and E1, as evidenced by the appearance of the tail (Fig. 4B). In summary, the above findings suggest that NIRF tightly cooperates with the core cell cycle machinery and induces G1 arrest, which is accompanied by ubiquitination of cyclins D1 and E1." SIGNOR-271886 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 BCOR protein Q6W2J9 UNIPROT Differentiation phenotype SIGNOR-PH37 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-256010 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 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-257981 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 MAPK8 protein P45983 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-196038 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 FYN protein P06241 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-251162 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 TAB1 protein Q15750 UNIPROT MAPK14 protein Q16539 UNIPROT "up-regulates activity" binding 9606 11847341 t lperfetto "Here, we report an unexpected activation mechanism for p38alpha MAPK that does not involve the prototypic kinase cascade. Rather it depends on interaction of p38alpha with TAB1 [transforming growth factor-beta-activated protein kinase 1 (TAK1)-binding protein 1] leading to autophosphorylation and activation of p38alpha." SIGNOR-114843 alvocidib chemical CHEBI:47344 ChEBI CDK2 protein P24941 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-191532 FOXO3 protein O43524 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 BTO:0000007 14976264 f lperfetto "Sirt1 inhibited foxo3's ability to induce cell death." SIGNOR-217887 ROBO2 protein Q9HCK4 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-268378 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 NODAL protein Q96S42 UNIPROT LIF protein P15018 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0003879 20383200 f Regulation miannu "Nodal induced LIF and Cripto-1 expressions through Smad2 signaling pathway." SIGNOR-251941 RPS6KA1 protein Q15418 UNIPROT RPS6 protein P62753 UNIPROT up-regulates phosphorylation Ser235 IAKRRRLsSLRASTS 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-153618 C5AR2 protein Q9P296 UNIPROT CR1 protein P17927 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-263465 STAT1 protein P42224 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 19643666 t lperfetto "Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways." SIGNOR-249565 IRF4 protein Q15306 UNIPROT IL4 protein P05112 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000782 11956291 f "IRF4 synergizes with NFATc2 and the IL-4-inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production" SIGNOR-254501 MAP3K7 protein O43318 UNIPROT NFKBIA protein P25963 UNIPROT "down-regulates quantity by destabilization" 9606 BTO:0000567 9480845 f lperfetto "Overexpression of tak1 together with its activator protein, tak1 binding protein 1 (tab1), induced the nuclear translocation of nf-kappa b p50/p65 heterodimer accompanied by the degradation of i kappa b alpha and i kappa b beta, and the expression of kappa b-dependent reporter gene." SIGNOR-55716 Ub:E2 complex SIGNOR-C497 SIGNOR RNF34 protein Q969K3 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-271046 STK3 protein Q13188 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR 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-269855 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR PML protein P29590 UNIPROT up-regulates phosphorylation 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "Phosphorylation of pml by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis." SIGNOR-270153 ITGB1 protein P05556 UNIPROT "A6/b1 integrin" complex SIGNOR-C164 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-253180 SMAD1 protein Q15797 UNIPROT HAND1 protein O96004 UNIPROT "up-regulates quantity" "transcriptional regulation" 10090 22219353 t Gianni "Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation" SIGNOR-268936 "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-270420 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 SF3A1 protein Q15459 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-270668 "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 "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 DYRK2 protein Q92630 UNIPROT KATNA1 protein O75449 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser109 VPVERRPsPGPRKRQ 9606 BTO:0000007 19287380 t miannu "DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d)." SIGNOR-262847 CDK1 protein P06493 UNIPROT NCOA3 protein Q9Y6Q9 UNIPROT down-regulates phosphorylation Ser728 VVKQEQLsPKKKENN 9606 SIGNOR-C17 22163316 t gcesareni "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-195233 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 CDK2 protein P24941 UNIPROT ARID4A protein P29374 UNIPROT down-regulates phosphorylation Ser1007 QHNFSVAsPLTLSQD 9606 21148318 t lperfetto "We identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation" SIGNOR-170451 "9-cis-retinoic acid" chemical CHEBI:50648 ChEBI RARB protein P10826 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-259235 FZR1 protein Q9UM11 UNIPROT APC-c complex SIGNOR-C150 SIGNOR "up-regulates activity" binding 16896351 t lperfetto "In addition to E2 enzymes, APC/C activity is also strictly dependent on one of several co-activator proteins that associate with APC/C during specific periods of the cell cycle. The best studied of these are Cdc20 and Cdh1" SIGNOR-252015 CDK2 protein P24941 UNIPROT MCM4 protein P33991 UNIPROT "down-regulates activity" phosphorylation Thr110 PRSGVRGtPVRQRPD 9606 BTO:0000567 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-100889 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 SMARCD1 protein Q96GM5 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-269785 F2RL1 protein P55085 UNIPROT GNAS protein Q5JWF2 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-256752 MFGE8 protein Q08431 UNIPROT SOCS3 protein O14543 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 21901532 f miannu "In an attempt to clarify the direct anti-inflammatory role of MFG-E8, we revealed a distinct signaling pathway where MFG-E8 activates suppressor of cytokine signaling (SOCS) 3 gene expression via STAT3 mediated pathway, which in turn served as a negative regulator for LPS induced TLR4 signaling by targeting NF-κB p65 component, thereby attenuating the down-stream signaling for TNF-α production" SIGNOR-260653 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 eletriptan chemical CHEBI:50922 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-258339 "A4/b1 integrin" complex SIGNOR-C162 SIGNOR JAG1 protein P78504 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0004093 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-253287 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 4-[[5-amino-1-[(2,6-difluorophenyl)-oxomethyl]-1,2,4-triazol-3-yl]amino]benzenesulfonamide chemical CHEBI:94506 ChEBI CCNB1 protein P14635 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-193540 SMAD7 protein O15105 UNIPROT STRAP protein Q9Y3F4 UNIPROT up-regulates binding 9606 10757800 t gcesareni "Strap recruits smad7 to the activated type i receptor and forms a complex" SIGNOR-76771 PTPN1 protein P18031 UNIPROT STAT3 protein P40763 UNIPROT down-regulates dephosphorylation Tyr705 DPGSAAPyLKTKFIC 9606 15821101 t gcesareni "Mechanism of protein tyrosine phosphatase 1b-mediated inhibition of leptin signalling. Ptp1b plays a critical role in the down-regulation of activated-stat3 by dephosphorylating tyr705, that is the phosphorylation site of activation of stat3." SIGNOR-135211 MMP1 protein P03956 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-272377 MMP14 protein P50281 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-272382 MMP15 protein P51511 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-272383 MIPOL1 protein Q8TD10 UNIPROT RELA protein Q04206 UNIPROT "down-regulates activity" 9606 31609475 f miannu "In our results, we also showed that re-expression of MIPOL1 is associated with suppression phosphorylation of AKT and p65, a subunit of NF-ҡB. This suggests that MIPOL1 may inhibit invasion by suppression of phosphorylation of AKT and p65 to further inhibit the expression of MMP-9" SIGNOR-261136 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 ERK1/2 proteinfamily SIGNOR-PF1 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-270189 S protein P59594 UNIPROT EIF2AK3 protein Q9NZJ5 UNIPROT "up-regulates activity" 9606 16940539 f miannu "SARS-CoV S protein specifically activated PERK but did not significantly affect IRE1/XBP1 or ATF6." SIGNOR-260439 CDK1 protein P06493 UNIPROT ANAPC1 protein Q9H1A4 UNIPROT up-regulates phosphorylation Ser355 AALSRAHsPALGVHS 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-119705 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 MVD protein P53602 UNIPROT HRAS protein P01112 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-265888 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 CTNND1 protein O60716 UNIPROT RAC1 protein P63000 UNIPROT up-regulates binding 9606 22946057 t gcesareni "We demonstrate that p120-catenin participates in the stimulation of rac1 activity, binding directly to this protein. In addition we show that vav2 also binds to p120-catenin and is required for rac1 activation and for beta-catenin translocation to the nucleus.Vav2 And rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by ck1 and inhibited by tyrosine phosphorylation by src or fyn" SIGNOR-198938 UBE2D1 protein P51668 UNIPROT PEX5 protein P50542 UNIPROT "up-regulates activity" 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-253022 FGF10 protein O15520 UNIPROT FGFR2 protein P21802 UNIPROT up-regulates binding 9606 9582367 t gcesareni "Rfgf-10 bound the kgfr with high affinity comparable to that of kgf" SIGNOR-57380 RBBP4 protein Q09028 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-263837 DRAM2 protein Q6UX65 UNIPROT RAC1 protein P63000 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-259141 POMC protein P01189 UNIPROT MC4R protein P32245 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-268710 TYK2 protein P29597 UNIPROT STAT3 protein P40763 UNIPROT up-regulates phosphorylation 9606 10542297 t lperfetto "Stat3 activation requires kinase function of tyk2." SIGNOR-71781 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding 9606 25875593 t irozzo "C-Fos dimerizes with c-Jun to form the transcription activator protein-1 (AP-1) which binds to the specific recognition site." SIGNOR-256368 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR NLRP3 protein Q96P20 UNIPROT "down-regulates quantity by destabilization" polyubiquitination Lys689 GFLHNMPkEEEEEEK 9606 BTO:0000018 26037928 t miannu "LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp-73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation. " SIGNOR-272434 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 "L-glutamine zwitterion" smallmolecule CHEBI:58359 ChEBI L-glutamate(1-) smallmolecule CHEBI:29985 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-267426 KDM5B protein Q9UGL1 UNIPROT SOX2 protein P48431 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-273450 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 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 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 CHM protein P24386 UNIPROT RABGGTA protein Q92696 UNIPROT "down-regulates activity" binding 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." SIGNOR-265570 WDR62 protein O43379 UNIPROT MAPK8 protein P45983 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-271718 PPP2R5D protein Q14738 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-243439 SHMT2 protein P34897 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-268224 "HIF-1 complex" complex SIGNOR-C418 SIGNOR SLC2A3 protein P11169 UNIPROT "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-267451 PTGER4 protein P35408 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-256903 CAMK2A protein Q9UQM7 UNIPROT HRH1 protein P35367 UNIPROT down-regulates phosphorylation Ser398 WKRLRSHsRQYVSGL 9606 BTO:0000975 15107581 t "Translocation from Endosome to Lysosome" gcesareni "As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2)." SIGNOR-124344 MAPK3 protein P27361 UNIPROT CIITA protein P33076 UNIPROT down-regulates phosphorylation Ser288 PDRPGSTsPFAPSAT 9606 18245089 t gcesareni "In this study we show that the extracellular signal-regulated kinases 1 and 2 (erk1/2) interact directly with ciita, targeting serine residues in the amino terminus of the protein, including serine 288. These data suggest a model whereby erk1/2-mediated phosphorylation of ciita down-regulates ciita activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation." SIGNOR-160617 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 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 MARK1 protein Q9P0L2 UNIPROT MAP4 protein P27816 UNIPROT "down-regulates activity" phosphorylation Ser928 SRLATNTsAPDLKNV -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-250170 UBE2D2 protein P62837 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-253023 PRKD1 protein Q15139 UNIPROT SSH1 protein Q8WYL5 UNIPROT down-regulates phosphorylation Ser937 SNLTRSSsSDSIHSV 9606 BTO:0000150 19567672 t llicata "Pkd-mediated phosphorylation of serines 937 and 978 regulates ssh1l subcellular localization by binding of 14-3-3 proteins 14-3-3 proteins associate with ssh1l when phosphorylated at serines 937 and 978, thereby sequestering ssh1l in the cytoplasm and preventing translocation of the phosphatase to f-actin_rich membrane protrusions" SIGNOR-186467 Gbeta proteinfamily SIGNOR-PF4 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-270005 AGTR1 protein P30556 UNIPROT Fibrosis phenotype SIGNOR-PH90 SIGNOR up-regulates 9606 32201502 f MIANNU "Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis." SIGNOR-260234 CDK1 protein P06493 UNIPROT ERF protein P50548 UNIPROT down-regulates phosphorylation 9606 SIGNOR-C17 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-29501 SRC protein P12931 UNIPROT AFAP1 protein Q8N556 UNIPROT unknown phosphorylation Tyr451 TDPEALHyDYIDVEM 9534 BTO:0004055 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-246351 CDK4 protein P11802 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" phosphorylation Thr8 MSSILPFtPPIVKRL 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-232138 "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 CSNK1A1 protein P48729 UNIPROT EIF2B5 protein Q13144 UNIPROT unknown phosphorylation Ser469 DGEFSDDsGADQEKD 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-250788 CREBL2 protein O60519 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 BTO:0000011 21728997 f Luana "Accordingly, the results of QPCR and immunoblot analysis showed that during adipogenesis, both the mRNA (Figures 4D and 4E) and protein (Figure 4F) levels of PPARγ , as well as C/EBPα, in 3T3-L1 preadipocytes transfected with either siCREBL2-1 or siCREBL2-2 were significantly decreased compared with the control (P < 0.05), suggesting that knockdown of CREBL2 protein suppress 3T3-L1 preadipocyte differentiation via inhibition of PPARγ and C/EBPα expression." SIGNOR-261574 EPHA4 protein P54764 UNIPROT EPHA4 protein P54764 UNIPROT "up-regulates activity" phosphorylation Tyr596 LNQGVRTyVDPFTYE -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." SIGNOR-251118 RUVBL2 protein Q9Y230 UNIPROT "R2TP core co-chaperone" complex SIGNOR-C515 SIGNOR "form complex" binding 9606 29662061 t miannu " Here we use cryo-EM and biochemical studies on the human R2TP core (RUVBL1-RUVBL2-RPAP3-PIH1D1) which reveal the distinctive role of RPAP3, distinguishing metazoan R2TP from the smaller yeast equivalent. RPAP3 spans both faces of a single RUVBL ring, providing an extended scaffold that recruits clients and provides a flexible tether for HSP90. " SIGNOR-270929 DVL2 protein O14641 UNIPROT LRP6 protein O75581 UNIPROT "up-regulates activity" binding 9606 BTO:0000331 10196136 t amattioni "Dvl is required for lrp6 phosphorylation, which is essential for subsequent steps of signal transduction." SIGNOR-66362 CYSLTR1 protein Q9Y271 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-257225 PRKCB protein P05771 UNIPROT PRKCB protein P05771 UNIPROT "up-regulates activity" phosphorylation Ser661 QNEFAGFsYTNPEFV 9606 10828076 t "The effect has been demonstrated using P05771-2" llicata "We found in preliminary studies that autophosphorylation at ser660 was enhanced in response to angiotensin ii and phorbol esters|However, it was apparent that the return of the mutant GFP-S660A from the membrane to the cytoplasm was impaired, suggesting a specific role for this autophosphorylation site in the regulation of reverse translocation." SIGNOR-77583 tyrosine smallmolecule CHEBI:18186 ChEBI tyramine smallmolecule CHEBI:15760 ChEBI "up-regulates quantity" "precursor of" 9606 NBK536726 t brain lperfetto "Under specific conditions, dopamine can also be synthesized by a minor pathway, in which L-tyrosine is converted into p-tyramine (mediated by AADC), with subsequent hydroxylation to dopamine by the enzyme CYP2D6 (Cytochrome P450 2D6) which is found in the substantia nigra of human brain¬¨‚Ć" SIGNOR-264175 FOS protein P01100 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "form complex" binding -1 2467839 t irozzo "The protein products of the fos (Fos) and jun (Jun) proto-oncogenes have been shown to associate with a DNA element known as the transcription factor activator protein-1 (AP-1) binding site. Jun (previously known as the Fos-binding protein p39) and Fos form a protein complex in the nucleus. These data demonstrate a cooperative interaction between the protein products of two proto-oncogenes with a DNA element involved in transcriptional regulation." SIGNOR-256362 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 (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 ARFGAP3 protein Q9NP61 UNIPROT "down-regulates activity" "chemical inhibition" -1 26152429 t lperfetto "Here we present structure-activity relationship (SAR) studies of QS11 analogs in two assays: direct inhibition of enzymatic activity of purified ARFGAP1 protein and cellular activation of the Wnt/β-catenin pathway. The results confirm the direct inhibition of ARFGAP1 by QS11, and also suggest the presence of other potential cellular targets of QS11" SIGNOR-261980 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 MAPK1 protein P28482 UNIPROT ERF protein P50548 UNIPROT up-regulates phosphorylation Ser251 PLSPFPVsPLAGPGS 9606 10330152 t lperfetto "The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a)." SIGNOR-67528 atomoxetine chemical CHEBI:127342 ChEBI SLC6A2 protein P23975 UNIPROT "down-regulates activity" "chemical inhibition" -1 9871604 t miannu "The gamma-amino alcohol/ether unit contained in venlafaxine, 2 fluoxetine, 3 and tomoxetine 3 has been prepared by a sequence of nitrile aldol reaction and nitrile reduction. Equilibrium dissociation constants KD for binding of (_+)-2 and (_+)-3 to hSERT, hNET, and hDAT are given in Table 2." SIGNOR-259071 PRKACA protein P17612 UNIPROT CFTR protein P13569 UNIPROT up-regulates phosphorylation Ser795 TASTRKVsLAPQANL 9606 1716180 t lperfetto "Cftr, the protein associated with cystic fibrosis, is phosphorylated on serine residues in response to camp agonists. Serines 660, 737, 795, and 813 were identified as in vivo targets for phosphorylation by protein kinase a.mutagenesis of all four sites abolished the response." SIGNOR-21320 CSNK1E protein P49674 UNIPROT PER3 protein P56645 UNIPROT "down-regulates activity" phosphorylation Ser622 ILSTAMLsLGSGISQ 9534 BTO:0000298 11865049 t llicata "The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly. " SIGNOR-250815 SP3 protein Q02447 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23530031 f miannu "Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation." SIGNOR-254220 "Diisodecyl phthalate" chemical CHEBI:34709 ChEBI SLC5A5 protein Q92911 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10116 BTO:0003800 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-268742 DYRK1A protein Q13627 UNIPROT CCNL2 protein Q96S94 UNIPROT unknown phosphorylation Ser330 LDGTSGFsPAPKLVE 9534 BTO:0000298 14623875 t llicata "DYRK1A interacted with cyclin L2 in pull-down assays, and overexpression of DYRK1A stimulated phosphorylation of cyclin L2 in COS-7 cells. | Three phosphoserines were identified in the slower migrating bands (Fig. 9; Ser-330, Ser-338, and Ser-369). All of these serine residues are located N-terminal of proline residues, consistent with our previous classification of DYRK1A as a “proline-directed” kinase." SIGNOR-251087 RAF1 protein P04049 UNIPROT MAP2K2 protein P36507 UNIPROT up-regulates phosphorylation Ser222 VSGQLIDsMANSFVG 9606 8157000 t gcesareni "To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1." SIGNOR-262292 PIK3AP1 protein Q6ZUJ8 UNIPROT PIK3CG protein P48736 UNIPROT up-regulates binding 9606 BTO:0000801 22187458 t gcesareni "This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Therefore, bcap is an essential activator of the pi3k pathway downstream of tlr signaling, providing a brake to limit potentially pathogenic excessive tlr responses." SIGNOR-191670 CNR1 protein P21554 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-257211 NR3C1 protein P04150 UNIPROT NFKB1 protein P19838 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 8639160 t gcesareni "We have described how the receptor uses several means to achieve repression of the genes regulated by AP-1 and NF-KB proteins" SIGNOR-251680 SOX2/POU5F1 complex SIGNOR-C73 SIGNOR OTX2 protein P32243 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-269240 SPI1 protein P17947 UNIPROT JUN protein P05412 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 17041602 f miannu "Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets." SIGNOR-256065 PRTN3 protein P24158 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-263596 PTAFR protein P25105 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-257061 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 Calcineurin complex SIGNOR-C155 SIGNOR NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser280 RSPSPQPsSHVAPQD 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-252336 VX-765 chemical CID:53245642 PUBCHEM CASP1 protein P29466 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-207770 TP53 protein P04637 UNIPROT BIRC5 protein O15392 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 11965534 f acerquone "Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53." SIGNOR-117328 EGR1 protein P18146 UNIPROT LHB protein P01229 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 19106114 f miannu "EGR1 bound to two binding sites on the LHB promoter and this binding was increased by GNRH1. Mutation of either site or knockdown of endogenous EGR1 decreased basal and/or GNRH1-regulated promoter activity." SIGNOR-254919 SMARCC2 protein Q8TAQ2 UNIPROT "Brain-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C486 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-270754 RPE protein Q96AT9 UNIPROT "D-xylulose 5-phosphate(2-)" smallmolecule CHEBI:57737 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-267068 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 CDK4 protein P11802 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-232142 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 MEN1 protein O00255 UNIPROT TERT protein O14746 UNIPROT down-regulates 9606 12837246 f miannu "The tumor suppressor menin, is a direct repressor of htert" SIGNOR-102874 Gbeta proteinfamily SIGNOR-PF4 SIGNOR SP3 protein Q02447 UNIPROT up-regulates phosphorylation 9606 17685427 t "inferred from 70% family members" gcesareni "Here, we show that sp3, which, as sp1, belongs to the gc-rich binding transcription factor family, is also phosphorylated by erk in vitro on serine 73." SIGNOR-270053 JAK2 protein O60674 UNIPROT MYC protein P01106 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 12370803 f irozzo "In this study, we show that Jak2 is involved in c-Myc induction by inducing c-MYC mRNA and protecting c-Myc protein from 26S proteasome-dependent degradation. These results indicate that c-Myc is a downstream target of activated Jak2 in Bcr-Abl positive cells. " SIGNOR-255811 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 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 ADGRG1 protein Q9Y653 UNIPROT ADGRG1 protein Q9Y653 UNIPROT "up-regulates activity" cleavage 24949629 t "Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation." SIGNOR-253980 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 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 Gbeta proteinfamily SIGNOR-PF4 SIGNOR ARRB1 protein P49407 UNIPROT down-regulates phosphorylation 9606 10347142 t "inferred from 70% family members" 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-270094 CEBPB protein P17676 UNIPROT SLC5A8 protein Q8N695 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 20082847 t "Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription." SIGNOR-254054 bufexamac chemical CHEBI:31317 ChEBI HDAC10 protein Q969S8 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-257891 "glutamic acid" smallmolecule CHEBI:18237 ChEBI NMDA proteinfamily SIGNOR-PF56 SIGNOR "up-regulates activity" "chemical activation" 9606 24564659 t 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-264692 SGK1 protein O00141 UNIPROT MAP3K3 protein Q99759 UNIPROT "down-regulates activity" phosphorylation Ser337 DPRGRLRsADSENAL 9534 BTO:0001538 12392720 t miannu "It was shown that the recombinant MEKK3 protein and fluorescein-labeled MEKK3 peptides (FITC-(159)epRsRhlSVi(168) and FITC-(330)dpRgRlpSAd(339)) are phosphorylated by SGK1 in vitro. It was also observed that the intrinsic kinase activity of MEKK3 on Ser(189) of MKK3 (equivalent to Ser(207) of MKK6) decreased along with phosphorylation of Ser(166) and Ser(337) in MEKK3 in vitro and in vivo. Therefore, it is suggested that SGK1 inhibits MEKK3-MKK3/6 signal transduction by phosphorylation of MEKK3." SIGNOR-250005 JAK2 protein O60674 UNIPROT JAK2 protein O60674 UNIPROT up-regulates phosphorylation Tyr966 QICKGMEyLGTKRYI 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-236290 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 VRK2 protein Q86Y07 UNIPROT BANF1 protein O75531 UNIPROT down-regulates phosphorylation Thr3 tSQKHRDF 9606 16495336 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-144803 EIF3E protein P60228 UNIPROT MCM7 protein P33993 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0002181 17310990 t irozzo "Our data show that INT6 interacts with a C-terminal domain of MCM7. Collectively, our observations suggest that INT6 restrains the increased degradation of MCM7 occurring during DNA replication by protecting its polyubiquitylated derivatives from the proteasome activity." SIGNOR-259154 PIAS1 protein O75925 UNIPROT STAT1 protein P42224 UNIPROT down-regulates binding 9606 BTO:0000887;BTO:0001103 23663276 t milica "Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna." SIGNOR-202039 CDC42 protein P60953 UNIPROT NFATC1 protein O95644 UNIPROT "up-regulates activity" 9606 18976935 f 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-253370 GRIA2 protein P42262 UNIPROT Synaptic_plasticity phenotype SIGNOR-PH158 SIGNOR up-regulates -1 32527803 f 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 naïve ones." SIGNOR-265796 RPS6KB1 protein P23443 UNIPROT HSPB1 protein P04792 UNIPROT down-regulates phosphorylation Ser15 FSLLRGPsWDPFRDW 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-186951 DAB2IP protein Q5VWQ8 UNIPROT ZEB1 protein P37275 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 27858941 f miannu "Through inhibition of PI3K–AKT signaling, DAB2IP also represses ZEB1, another CSC determinant." SIGNOR-254772 TGFBR1 protein P36897 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-227525 LCK protein P06239 UNIPROT IL2RB protein P14784 UNIPROT unknown phosphorylation Tyr381 EIEACQVyFTYDPYS -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-251375 PTPN6 protein P29350 UNIPROT CSF2RB protein P32927 UNIPROT down-regulates dephosphorylation Tyr628 PPPGSLEyLCLPAGG 9606 9162089 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-48561 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 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 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 PPM1D protein O15297 UNIPROT CHEK2 protein O96017 UNIPROT "up-regulates activity" dephosphorylation Thr68 SSLETVStQELYSIP -1 16311512 t "an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C." SIGNOR-248318 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 DYRK1A protein Q13627 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-252905 ARAP2 protein Q8WZ64 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-260455 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 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM43B protein A6NCK2 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-271266 DHPS protein P49366 UNIPROT EIF5A protein P63241 UNIPROT "up-regulates activity" "post translational modification" -1 32142284 t miannu "Deoxyhypusine synthase (DHPS) utilizes spermidine and NAD as cofactors to incorporate a hypusine modification into the eukaryotic translation initiation factor 5A (eIF5A). Hypusine is essential for eIF5A activation, which, in turn, plays a key role in regulating protein translation of selected mRNA that are associated with the synthesis of oncoproteins, thereby enhancing tumor cell proliferation." SIGNOR-266374 PAK2 protein Q13177 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser66 GVYATRSsAVRLRSS -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-250241 JAK2 protein O60674 UNIPROT STAT5B protein P51692 UNIPROT up-regulates phosphorylation 9606 9575217 t gcesareni "Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein" SIGNOR-56894 AKT3 protein Q9Y243 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR down-regulates phosphorylation Ser315 DFRSRTNsNASTVSG 9606 BTO:0000150;BTO:0001130;BTO:0001271;BTO:0000527 19188143 t gcesareni "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-252878 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 DNM1L protein O00429 UNIPROT Mitochondrial_fission phenotype SIGNOR-PH143 SIGNOR up-regulates 10090 BTO:0002295 31063459 f lperfetto "Mitochondrial fission is governed primarily by the cytoplasmic dynamin-related protein 1 (Drp1). Drp1 is a conserved dynamin GTPase superfamily protein that is translocated from its cytoplasmic pool to the outer mitochondrial membrane, where Drp1 then assembles into constrictive ring-like multimeric structures, ultimately driving mitochondrial fragmentation through a GTP-dependent mechanism|We have also previously reported that ROCK1-mediated Drp1S600 phosphorylation resulted in enhanced mitochondrial fission in podocytes" SIGNOR-262553 GSK1059615 chemical CHEBI:71955 ChEBI PIK3CA protein P42336 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-192771 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000142 22363216 t gcesareni "Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid." SIGNOR-196267 PRKCA protein P17252 UNIPROT GFAP protein P14136 UNIPROT "down-regulates activity" phosphorylation Ser38 LGPGTRLsLARMPPP -1 2155236 t lperfetto "Glial fibrillary acidic protein (GFAP), the intermediate filament component of astroglial cells, can serve as an excellent substrate for both cAMP-dependent protein kinase and protein kinase C, in vitro. GFAP phosphorylated by each protein kinase does not polymerize, and the filaments that do polymerize tend to depolymerize after phosphorylation. Dephosphorylation of phospho-GFAP by phosphatase led to a recovery of the polymerization competence of GFAP. Most of the phosphorylation sites for cAMP-dependent protein kinase and protein kinase C on GFAP are the same, Ser-8, Ser-13, and Ser-34. cAMP-dependent protein kinase has one additional phosphorylation site, Thr-7." SIGNOR-248862 LMTK2 protein Q8IWU2 UNIPROT PPP1CA protein P62136 UNIPROT "down-regulates activity" phosphorylation Thr320 NPGGRPItPPRNSAK 9606 12393858 t gcesareni "Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity." SIGNOR-94631 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 NME1 protein P15531 UNIPROT FZD1 protein Q9UP38 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-255162 SRC protein P12931 UNIPROT CDH2 protein P19022 UNIPROT down-regulates phosphorylation Tyr860 DSLLVFDyEGSGSTA 9606 BTO:0000848 16371504 t lperfetto "Src-mediated phosphorylation of the n-cadherin cytoplasmic domain results in a significant reduction in beta-catenin bindingbeta-catenin dissociates from n-cadherin and redistributes to the nucleus of transmigrating melanoma cells to activate gene transcription.Because there were only four tyrosine residues (y852, y860, y884, and y886) in this peptide, all of them were phosphorylated." SIGNOR-143238 PRKAG2 protein Q9UGJ0 UNIPROT AMPK complex SIGNOR-C15 SIGNOR "form complex" 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-139176 PPM1D protein O15297 UNIPROT MDM2 protein Q00987 UNIPROT up-regulates dephosphorylation Ser395 SQESEDYsQPSTSSS 9606 17936559 t gcesareni "Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation." SIGNOR-158328 RNMT protein O43148 UNIPROT mRNA_capping phenotype SIGNOR-PH178 SIGNOR up-regulates 9606 BTO:0000567 26942677 f lperfetto "The creation of translation-competent mRNA is dependent on RNA polymerase II transcripts being modified by addition of the 7-methylguanosine (m7G) cap. The factors that mediate splicing, nuclear export, and translation initiation are recruited to the transcript via the cap. The cap structure is formed by several activities and completed by RNMT (RNA guanine-7 methyltransferase), which catalyzes N7 methylation of the cap guanosine." SIGNOR-265503 LRRK2 protein Q5S007 UNIPROT ARFGAP1 protein Q8N6T3 UNIPROT down-regulates phosphorylation 9606 22423108 t gcesareni "Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid." SIGNOR-196732 CDK9 protein P50750 UNIPROT POLR2A protein P24928 UNIPROT up-regulates phosphorylation Ser1616 TPQSPSYsPTSPSYS 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-203508 TUT7 protein Q5VYS8 UNIPROT mRNA_polyadenylation phenotype SIGNOR-PH200 SIGNOR down-regulates 25480299 f lperfetto "Uridylation occurs pervasively on mRNAs, yet its mechanism and significance remain unknown. By applying TAIL-seq, we identify TUT4 and TUT7 (TUT4/7), also known as ZCCHC11 and ZCCHC6, respectively, as mRNA uridylation enzymes. Uridylation readily occurs on deadenylated mRNAs in cells. Consistently, purified TUT4/7 selectively recognize and uridylate RNAs with short A-tails (less than ∼ 25 nt) in vitro. PABPC1 antagonizes uridylation of polyadenylated mRNAs, contributing to the specificity for short A-tails." SIGNOR-268345 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 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 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 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 EAF1 protein Q96JC9 UNIPROT ELL protein P55199 UNIPROT up-regulates binding 9606 16006523 t miannu "Positive regulation of ell elongation activity depends on stable binding of eaf1 to the ell n terminus" SIGNOR-138516 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 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 COPS3 protein Q9UNS2 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-270764 PTH protein P01270 UNIPROT PTH2R protein P49190 UNIPROT up-regulates binding 9606 BTO:0000142;BTO:0000671 11861531 t gcesareni "Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor)" SIGNOR-115104 CYBB protein P04839 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 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-264723 "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-270412 SNTB1 protein Q13884 UNIPROT MAPK12 protein P53778 UNIPROT down-regulates binding 10090 BTO:0002314 BTO:0001103 29681515 t apalma "Basal localization of the p38g/p-Carm1 complex in muscle stem cells occurs via binding to the dystrophin-glycoprotein complex (DGC) through b1-syntrophin. In dystrophin-deficient muscle stem cells undergoing asymmetric division, p38g/b1-syntrophin interactions are abrogated, resulting in enhanced Carm1 phosphorylation" SIGNOR-255901 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 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 MAPK8 protein P45983 UNIPROT KRT8 protein P05787 UNIPROT up-regulates phosphorylation Ser74 TVNQSLLsPLVLEVD 9606 11788583 t lperfetto "Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. 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-114083 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 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 CDK1 protein P06493 UNIPROT CSNK2A1 protein P68400 UNIPROT up-regulates phosphorylation Ser370 PLGPLAGsPVIAAAN 9606 7592773 t lperfetto "Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition" SIGNOR-29521 KDM4B protein O94953 UNIPROT "Histone H3" proteinfamily SIGNOR-PF69 SIGNOR "down-regulates activity" demethylation 9606 30759871 t 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. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways." SIGNOR-265359 FPR2 protein P25090 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-256888 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 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 NOX3 protein Q9HBY0 UNIPROT superoxide smallmolecule CHEBI:18421 ChEBI "up-regulates quantity" "chemical modification" 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-264722 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 domperidone chemical CHEBI:31515 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-258380 "SAGA complex" complex SIGNOR-C465 SIGNOR H3-2 protein Q5TEC6 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-269641 CIITA protein P33076 UNIPROT HLA-DRB5 protein Q30154 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0002417 10886240 f "These results indicate that impaired up-regulation of HLA-DR in response to IFN-gamma results from insufficient induction of CIITA, but not from the signal from IFN-gamma receptor to the nucleus. The abnormal regulation of HLA-DR expression caused by impaired induction of CIITA may affect CD4+ T cell development in thymoma." SIGNOR-254013 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 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 FGFR1 protein P11362 UNIPROT ACAT1 protein P24752 UNIPROT "up-regulates activity" phosphorylation Tyr407 HALKQGEyGLASICN 9606 BTO:0002552 27867011 t lperfetto "Treatment with the FGFR1 inhibitor TKI258 in FGFR1-expressing H1299 cells led to decreased Y407 phosphorylation of ACAT1 in the mitochondrial fraction, where both ACAT1 and a fraction of FGFR1 were detected|Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity," SIGNOR-264423 KDM4C protein Q9H3R0 UNIPROT H3C1 protein P68431 UNIPROT "down-regulates activity" demethylation Lys10 RTKQTARkSTGGKAP 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-263865 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 BCL11A protein Q9H165 UNIPROT HBG1 protein P69891 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 20712774 f Regulation miannu "BCL11A maintains silencing of gamma-globin expression in adult erythroid cells and functions as a direct transcriptional regulator of the fetal to adult hemoglobin switch in humans. we found that BCL11A plays a central role in the evolutionarily divergent globin gene switches of mammals. As a factor critical for gamma-globin gene silencing, BCL11A should be considered as a therapeutic target to increase HbF in a directed manner in beta-thalassemia patients." SIGNOR-251774 RB1 protein P06400 UNIPROT G1/S_transition phenotype SIGNOR-PH50 SIGNOR down-regulates 9606 21524151 f lperfetto "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-245483 HES1 protein Q14469 UNIPROT MYOD1 protein P15172 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000165 BTO:0000887 10066785 f lperfetto "Notch signaling up-regulated hes1 mrna expression within 1 h and subsequently reduced expression of myod mrna." SIGNOR-235596 DZIP3 protein Q86Y13 UNIPROT H2AC12 protein Q96KK5 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-271760 AGTR1 protein P30556 UNIPROT Inflammation phenotype SIGNOR-PH12 SIGNOR up-regulates 9606 32201502 f MIANNU "Ang II binding to AT1 receptors has been implicated in inflammatory responses. Activation of this Ang II–AT1 receptor-dependent pathway is widely accepted to lead to organ damage and fibrosis." SIGNOR-260233 "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 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 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 AKT1 protein P31749 UNIPROT TBC1D4 protein O60343 UNIPROT unknown phosphorylation Thr642 QFRRRAHtFSHPPSS 9606 16880201 t llicata "14-3-3 proteins interact with as160 in an insulin- and akt-dependent manner via an akt phosphorylation site, thr-642." SIGNOR-252494 Gbeta proteinfamily SIGNOR-PF4 SIGNOR BCL2 protein P10415 UNIPROT up-regulates phosphorylation 9606 10669763 t "inferred from 70% family members" gcesareni "Erk1 and erk2 directly phosphorylate bcl2 exclusively at ser-70 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 molecular association." SIGNOR-270064 "MSL acetyltransferase" complex SIGNOR-C344 SIGNOR H2BC14 protein Q99879 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-271994 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide chemical CHEBI:95082 ChEBI BRD2 protein P25440 UNIPROT "down-regulates activity" "chemical inhibition" -1 24015967 t Gianni "This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation" SIGNOR-262202 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 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-258176 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 PAK1 protein Q13153 UNIPROT STMN1 protein P16949 UNIPROT down-regulates phosphorylation Ser16 KELEKRAsGQAFELI 9606 14645234 t gcesareni "Pak1 phosphorylates op18/stathmin specifically at serine 16 and inactivates its catastrophe promoting activity in biochemical and time lapse microscopy microtubule assembly assays. Furthermore, phosphorylation of either serine 16 or 63 is sufficient to inhibit op18/stathmin in vitro." SIGNOR-119483 EPAS1 protein Q99814 UNIPROT HBA1 protein P69905 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-251792 MPO protein P05164 UNIPROT APOA1 protein P02647 UNIPROT "down-regulates activity" oxidation 9606 20043647 t miannu "When apolipoprotein A-I (apoA-I), the major HDL protein, was oxidized by MPO, its ability to promote cellular cholesterol efflux by ABCA1 was impaired. Moreover, oxidized apoA-I was unable to activate lecithin:cholesterol acyltransferase (LCAT), which rapidly converts free cholesterol to cholesteryl ester, a critical step in HDL maturation" SIGNOR-252102 CD79B protein P40259 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-268189 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 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 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 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 domperidone chemical CHEBI:31515 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-258720 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 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 11085989 f miannu "We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation." SIGNOR-263499 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 CBLC protein Q9ULV8 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-272605 CTNND2 protein Q9UQB3 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-252131 GATA4 protein P43694 UNIPROT HAMP protein P81172 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 21609320 f miannu "Co-transfection of a GATA-4 expression vector with a hepcidin promoter reporter construct enhanced hepcidin promoter transcriptional activity." SIGNOR-254196 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 WAPL protein Q7Z5K2 UNIPROT "Cohesin complex" complex SIGNOR-C304 SIGNOR "down-regulates activity" 9606 BTO:0000567 17113138 t lperfetto "We show that human Wapl interacts with cohesin throughout the cell cycle via cohesin's Scc1 and SA1/SA2 subunits and that Wapl forms a subcomplex with Pds5A|These results indicate that Wapl is required for the release of cohesin from both interphase chromatin and mitotic chromosomes, perhaps by facilitating opening of the cohesin ring or by modulating direct interactions between cohesin and DNA." SIGNOR-265265 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 GDNF protein P39905 UNIPROT NRN1 protein Q9NPD7 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-252183 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 MAPK14 protein Q16539 UNIPROT SMAD3 protein P84022 UNIPROT "up-regulates activity" phosphorylation Ser208 DAGSPNLsPNPMSPA 9606 BTO:0001939 15520018 t miannu "Smad3 was phosphorylated at both Ser203 and Ser207 in untreated MCF10CA1h cells and the p38 and ROCK inhibitors each down-regulated phosphorylation at these sites. we demonstrate that phosphorylation at Ser203 and Ser207 residues is required for the full transactivation potential of Smad3, and that these residues are targets of the p38 and Rho/ROCK pathways." SIGNOR-250112 phosphatidylcholine chemical CHEBI:64482 ChEBI Inner_mitochondrial_membrane complex SIGNOR-C411 SIGNOR "form complex" binding 9606 25627476 t lperfetto "The lipid composition of the IMM varies from that of the OMM. PC and PE are still the most abundant phospholipids in the IMM, comprising about 75 % of total lipids.|One of the biggest differences between OMM and IMM lipid composition is the greater concentration of CL that is found in the IMM. Here, CL makes up about 15–20 % of the total phospholipid mass" SIGNOR-267003 RPL26L1 protein Q9UNX3 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-262496 zolmitriptan chemical CHEBI:10124 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-258341 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 GSK3A protein P49840 UNIPROT CAMKK2 protein Q96RR4 UNIPROT down-regulates phosphorylation Ser137 PVSSPQSsPRLPRRP 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-198130 CSNK1G2 protein P78368 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser418 LTQMGSPsIRCSSVS 9606 18794808 t lpetrilli "Cki?2 Directly phosphorylates smad3 at ser418, leading to the increased ubiquitination and proteasomal degradation of activated smad3 following tgf-? Treatment." SIGNOR-181069 RPS6KA5 protein O75582 UNIPROT H3-3A protein P84243 UNIPROT "up-regulates activity" phosphorylation Ser11 TKQTARKsTGGKAPR 9606 18508628 t "Ser 11 phosphorylation of H3 is either activatory and inhibitory as promotes DNA condensation (activatory) and induce transcription (inhibitory)." gcesareni "In addition to ser10, msk was also found to phosphorylate a second site on h3, ser28 (75). It should be noted that while both ser10 and ser28 in h3 are extensively phosphorylated during mitosis, this is independent of msks and is catalysed by aurora kinases. In contrast, msks only phosphorylate a small proportion of the total cellular histone h3 in response to mitogens or stress. The spatial distribution of ser10 and ser28 phosphorylation is very tightly regulated in cells. In vitro, msk1 will phosphorylate one histone h3 molecule on both ser10 and ser28. Surprisingly it has been shown that in cells msk phosphorylates either ser10 or ser28 but not both on individual nucleosomes." SIGNOR-178704 serotonin(1+) smallmolecule CHEBI:350546 ChEBI HTR7 protein P34969 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-257526 RPS6KA5 protein O75582 UNIPROT EIF4EBP1 protein Q13541 UNIPROT "down-regulates activity" phosphorylation Ser65 FLMECRNsPVTKTPP 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-262993 GSK3B protein P49841 UNIPROT MAPT protein P10636 UNIPROT "down-regulates activity" phosphorylation Ser512 PPKSGDRsGYSSPGS 9606 BTO:0000590 9771888 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-249353 LPAR5 protein Q9H1C0 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-256861 PKA proteinfamily SIGNOR-PF17 SIGNOR SMN1 protein Q16637 UNIPROT "up-regulates quantity by stabilization" phosphorylation 9606 BTO:0000007 19103745 t lperfetto "PKA increases SMN complex formation and SMN stability.|As expected, SMN was phosphorylated by PKA (Fig. ​(Fig.6D).6D)." SIGNOR-253114 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 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 ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR RPS6KB1 protein P23443 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000176 14967450 t "inferred from 70% family members" lperfetto "Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase" SIGNOR-270198 MAPK8 protein P45983 UNIPROT EIF4ENIF1 protein Q9NRA8 UNIPROT up-regulates phosphorylation Ser587 YLRPRIPsPIGFTPG 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-198996 ATM protein Q13315 UNIPROT RBBP8 protein Q99708 UNIPROT down-regulates phosphorylation Ser664 IDPGADLsQYKMDVT 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-79872 KPNA2 protein P52292 UNIPROT IRF3 protein Q14653 UNIPROT "up-regulates activity" relocalization 9606 32979938 t miannu "The results from Figure 1C suggest that ORF6 inhibits IFN-β production through IRF3 or a component downstream of IRF3. Thus, we examined the effect of ORF6 on IRF3 nuclear translocation. Upon poly(I:C) treatment, IRF3 translocated to the cell nucleus in the absence of ORF6, whereas the expression of ORF6 blocked its nuclear translocation (Figure 2D). Karyopherin α 1–6 (KPNA1–6) are importing factors for nuclear translocation of cargos, including IRF3, IRF7, and STAT1 (Chook and Blobel, 2001). Co-immunoprecipitation showed that ORF6 selectively interacted with KPNA2, but not the other KPNAs (Figure 2E), suggesting that ORF6 inhibits IFN-β production by binding to KPNA2 to block IRF3 nuclear translocation (Figure 2F)." SIGNOR-262514 PRKCA protein P17252 UNIPROT SNAP23 protein O00161 UNIPROT unknown phosphorylation Ser161 ENLTQVGsILGNLKD 9606 12930825 t lperfetto "Ion trap mass spectrometry revealed that platelet SNAP-23 was phosphorylated at Ser23/Thr24 and Ser161, after cell activation by thrombin; these sites were also identified in PKC-phosphorylated r-SNAP-23. SNAP-23 mutants that mimic phosphorylation at Ser23/Thr24 inhibited syntaxin 4 interactions, whereas a phosphorylation mutant of Ser161 had only minor effects. | Because mutants that mimic SNAP-23 phosphorylation affect syntaxin 4 interactions, we hypothesize that SNAP-23 phosphorylation may be important for modulating SNARE-complex interactions during membrane trafficking and fusion." SIGNOR-249227 ROCK1 protein Q13464 UNIPROT VIM protein P08670 UNIPROT "down-regulates activity" phosphorylation Ser72 SSAVRLRsSVPGVRL 9534 BTO:0000298 9565595 t lperfetto "We found that vimentin, the most widely expressed intermediate filament protein, served as an excellent substrate for Rho-associated kinase (Rho-kinase) and that vimentin phosphorylated by Rho-kinase lost its ability to form filaments in vitro. Two amino-terminal sites on vimentin, Ser38 and Ser71, were identified as the major phosphorylation sites for Rho-kinase, and Ser71 was the most favored and unique phosphorylation site for Rho-kinase in vitro. " SIGNOR-248998 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 MRTFA protein Q969V6 UNIPROT KLF4 protein O43474 UNIPROT down-regulates 9606 21673106 f "miR-143 and miR-145 target KLF4" gcesareni "This result suggests that mrtf-a, but not myocd, is essential for bmp4-dependent induction ofmir-143/145gene transcription. Of the mirnas identified to target klf4, only mir-143 and mir-145 were induced at least 1.5-fold by both bmp4 and tgf- , suggesting that they may be critical for bmp4- and tgf- -mediated reduction of klf4." SIGNOR-174261 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 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 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 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 EGFR protein P00533 UNIPROT PLCG1 protein P19174 UNIPROT up-regulates phosphorylation Tyr1253 EGSFESRyQQPFEDF 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-20976 "Av/b1 integrin" complex SIGNOR-C175 SIGNOR TERT protein O14746 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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-253274 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 ABL1 protein P00519 UNIPROT WASF3 protein Q9UPY6 UNIPROT "up-regulates activity" phosphorylation Tyr151 KKDGLKFyTDPSYFF 9606 BTO:0000815 17623672 t "WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3." SIGNOR-262299 HSP90AB1 protein P08238 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-252415 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 OGA protein O60502 UNIPROT PFKP protein Q01813 UNIPROT "up-regulates activity" deglycosylation Ser540 VMVPATVsNNVPGSD 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-267606 CYP17A1 protein P05093 UNIPROT androst-4-ene-3,17-dione smallmolecule CHEBI:16422 ChEBI "up-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-268654 MAPK14 protein Q16539 UNIPROT PIAS2 protein O75928 UNIPROT "up-regulates activity" phosphorylation Ser113 STSVTPHsPSSPVGS 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-262948 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 AKT1 protein P31749 UNIPROT mTORC1 complex SIGNOR-C3 SIGNOR up-regulates phosphorylation 9606 BTO:0001103 15829723 t apalma "Once phosphorylated, Akt can act on a broad spectrum of substrates that can influence cell survival and proliferation and protein synthesis (65). Phosphorylation of mTOR by Akt leads to mTOR activation (40, 52) and the subsequent activation of p70S6K" SIGNOR-255844 TXK protein P42681 UNIPROT LCP2 protein Q13094 UNIPROT up-regulates phosphorylation Tyr145 PVEDDADyEPPPSND 9606 BTO:0000782 10660534 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-74848 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 ESCRT-III complex SIGNOR-C379 SIGNOR Membrane_fusion phenotype SIGNOR-PH122 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-265536 TUBA1B protein P68363 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-269727 ZMYND8 protein Q9ULU4 UNIPROT EGFR protein P00533 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-262040 WNK1 protein Q9H4A3 UNIPROT SLC12A6 protein Q9UHW9 UNIPROT down-regulates phosphorylation Thr1048 YQEKVHMtWTKDKYM 9606 BTO:0000938 BTO:0000142 19665974 t gcesareni "We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases." SIGNOR-187560 GSK3B protein P49841 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-249344 GSK3B protein P49841 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-249348 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 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 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 DTX1 protein Q86Y01 UNIPROT ASCL1 protein P50553 UNIPROT down-regulates binding 9606 11564735 t gcesareni "Through its binding to p300, dtx1 inhibited transcriptional activation by the neural-specific helix-loop-helix-type transcription factor mash1" SIGNOR-110626 RXRA protein P19793 UNIPROT RAR proteinfamily SIGNOR-PF45 SIGNOR up-regulates binding 9606 1310351 t "inferred from 70% of 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-269850 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 ATR protein Q13535 UNIPROT PRKDC protein P78527 UNIPROT up-regulates phosphorylation Thr2609 LTPMFVEtQASQGTL 9606 16908529 t gcesareni "Finally, in vitro atr-mediated phosphorylation at the t2609 cluster was further confirmed by western blot analysis using phosphospecific antibodies against t2647 (fig. ?(Fig.7e),7e), suggesting that dna-pkcs could be the direct target of atr kinase." SIGNOR-148722 TEAD proteinfamily SIGNOR-PF22 SIGNOR YAP1 protein P46937 UNIPROT "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-230719 F2RL1 protein P55085 UNIPROT WWOX protein Q9NZC7 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-254854 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 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 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 STK4 protein Q13043 UNIPROT Mob1 proteinfamily SIGNOR-PF42 SIGNOR up-regulates phosphorylation 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-269856 PRKAA1 protein Q13131 UNIPROT CFTR protein P13569 UNIPROT "down-regulates activity" phosphorylation Ser737 EPLERRLsLVPDSEQ 9606 19095655 t Luana "AMPK phosphorylates CFTR¬†in vitro¬†at two essential serines (Ser737and Ser768) in the R domain, formerly identified as ""inhibitory"" PKA sites.|Interestingly two of these sites, namely Ser737 and Ser768, have been identified as “inhibitory” R domain sites, i.e. when mutated to alanines they augment the open probability of CFTR relative to wild type|Our present results suggest that it might be AMPK rather than PKA that is phosphorylating Ser737 and Ser768 under baseline conditions" SIGNOR-259858 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 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 NME1 protein P15531 UNIPROT NETO2 protein Q8NC67 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 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-255166 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 MSX2 protein P35548 UNIPROT DLX5 protein P56178 UNIPROT "down-regulates activity" binding 10090 BTO:0000947 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-240990 AKT proteinfamily SIGNOR-PF24 SIGNOR MTOR protein P42345 UNIPROT unknown phosphorylation Ser2448 RSRTRTDsYSAGQSV 9606 10910062 t lperfetto "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. These results demonstrate that mTOR is a direct target of the PI3K-AKT signaling pathway in mitogen-stimulated cells, and that the identified AKT phosphorylation sites are nested within a repressor domain that negatively regulates the catalytic activity of mTOR.¬†" SIGNOR-244311 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 CDK2 protein P24941 UNIPROT CCP110 protein O43303 UNIPROT "down-regulates activity" phosphorylation Thr566 NTRQQMDtPMVSCGN -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-265959 COP1 protein Q8NHY2 UNIPROT CEBPB protein P17676 UNIPROT "down-regulates quantity by destabilization" ubiquitination 10090 BTO:0000078 32795415 t Gianni "We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures." SIGNOR-261924 DOK1 protein Q99704 UNIPROT "A6/b4 integrin" complex SIGNOR-C174 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-257690 AKT proteinfamily SIGNOR-PF24 SIGNOR HJURP protein Q8NCD3 UNIPROT "up-regulates activity" phosphorylation Ser486 GLETRRLsLPSSKAK -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-262623 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 PRKCB protein P05771 UNIPROT CHAT protein P28329 UNIPROT up-regulates phosphorylation Ser594 HKAAVPAsEKLLLLK 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-129292 Phenelzine chemical CHEBI:8060 ChEBI MAOA protein P21397 UNIPROT "down-regulates activity" "chemical inhibition" -1 18426226 t Luana "Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine." SIGNOR-257777 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 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 CDK2 protein P24941 UNIPROT SMAD3 protein P84022 UNIPROT down-regulates phosphorylation Ser213 NLSPNPMsPAHNNLD 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-126732 WWTR1 protein Q9GZV5 UNIPROT SMAD3 protein P84022 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-232098 ESR2 protein Q92731 UNIPROT SCN9A protein Q15858 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 10090 BTO:0000938 BTO:0001264 22169964 f miannu "17β-Estradiol regulates the gene expression of voltage-gated sodium channels. . In this study, we investigate the mRNA expressions of Nav channel subtypes mediated differentially by the ERs in the DRGs of wild-type (WT) and estrogen receptor knockout (αERKO and βERKO) mice. In the present study, by means of quantitative real-time PCR, we found that the expressions of Nav1.1, Nav1.7, Nav1.8, and Nav1.9 subtypes were elevated in αERKO and βERKO mice" SIGNOR-253473 ARID1A protein O14497 UNIPROT "Brain-specific SWI/SNF SMARCA4 variant" complex SIGNOR-C486 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-270751 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 CARD9 protein Q9H257 UNIPROT BCL10 protein O95999 UNIPROT "up-regulates quantity by stabilization" binding 9606 BTO:0000007 11053425 t "To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB." SIGNOR-257602 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 CDK2 protein P24941 UNIPROT EZH2 protein Q15910 UNIPROT "up-regulates activity" phosphorylation Thr416 EANSRCQtPIKMKPN 9606 BTO:0000007 23241245 t "Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1." SIGNOR-255656 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 ESR1 protein P03372 UNIPROT F12 protein P00748 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000599 9794469 f miannu "Transcription of the FXII gene is stimulated by estrogens through specific interaction of the estrogen receptor alpha (ER alpha) with an estrogen response element present on FXII promoter." SIGNOR-254072 SLBP protein Q14493 UNIPROT H2BC3 protein P33778 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-265385 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-265809 "prostaglandin E2(1-)" smallmolecule CHEBI:606564 ChEBI PTGER1 protein P34995 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-257569 NFIX protein Q14938 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-268906 SOCS1 protein O15524 UNIPROT STAT1 protein P42224 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 16628196 f miannu "SOCS1, which is another inducible gene, not only blocks STAT1 activation but also inhibits STAT1-dependent TLR3, IRF-7, and MIP-1α." SIGNOR-255229 7-[4-[4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one chemical CID:56597938 PUBCHEM DRD2 protein P14416 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0002181 22025698 t Luana "Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D2R ligands. " SIGNOR-258320 CDK1 protein P06493 UNIPROT NUCKS1 protein Q9H1E3 UNIPROT "down-regulates activity" phosphorylation Ser181 LKATVTPsPVKGKGK -1 12413487 t miannu "putative phosphorylation site for Cdk1 is present in the DNA-binding domain peptide. This site, corresponding to Ser 181 in the NUCKS primary structure, is phosphorylated in vitro by Cdk1 with a Km of approximately 35 μM [7]. Phosphorylation of Ser 181 in the synthetic, DNA-binding domain peptide reduces its affinity for DNA-by 100%." SIGNOR-261959 CSNK1A1 protein P48729 UNIPROT MDM4 protein O15151 UNIPROT up-regulates phosphorylation Ser289 DDLEDSKsLSDDTDV 9606 23028042 t lperfetto "Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding." SIGNOR-199015 TTK protein P33981 UNIPROT TTK protein P33981 UNIPROT up-regulates phosphorylation Thr676 NQMQPDTtSVVKDSQ 9606 19120698 t llicata "Autophosphorylation appears to be a priming event for kinase activation. We identified mps1 autophosphorylation sites in the activation and the p+1 loops. Whereas activation loop autophosphorylation enhances kinase activity" SIGNOR-183026 PAXIP1 protein Q6ZW49 UNIPROT PAX2 protein Q02962 UNIPROT "up-regulates activity" binding 10090 BTO:0000944 10908331 t miannu "PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. The degree of interaction with the Pax2 C-terminal polypeptides correlates with their transcription transactivation potential and we have therefore designated this factor PTIP for Pax transactivation-domain interacting protein." SIGNOR-236965 AKT proteinfamily SIGNOR-PF24 SIGNOR CDKN1C protein P49918 UNIPROT down-regulates phosphorylation Thr310 GVGSVEQtPRKRLR 9606 BTO:0000150 23421998 t lperfetto "Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination" SIGNOR-201046 Goserelin chemical CHEBI:5523 ChEBI GNRHR protein P30968 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0001033 22416801 t miannu "The efficacy of degarelix compared with a GnRH agonist (goserelin, plus flare protection with bicalutamide) was evaluated in a 12‐week trial in men with lower urinary tract symptoms secondary to prostate cancer." SIGNOR-259161 F2R protein P25116 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-257403 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 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 enzalutamide chemical CHEBI:68534 ChEBI AR protein P10275 UNIPROT down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194325 trametinib chemical CHEBI:75998 ChEBI MEK1/2 proteinfamily SIGNOR-PF25 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-262312 mTORC2 complex SIGNOR-C2 SIGNOR AKT proteinfamily SIGNOR-PF24 SIGNOR "up-regulates activity" phosphorylation Ser477 PQFSYSAsGTA 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-252451 RPL39 protein P62891 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-262490 HMGB2 protein P26583 UNIPROT POU2F1 protein P14859 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-240151 RAP1GDS1 protein P52306 UNIPROT RAC1 protein P63000 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-171418 "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 "GABA-A (a6-b3-d) receptor" complex SIGNOR-C329 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-268609 PPP1CC protein P36873 UNIPROT TP53 protein P04637 UNIPROT "down-regulates activity" dephosphorylation Ser15 PSVEPPLsQETFSDL 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-248499 GSK3B protein P49841 UNIPROT JUN protein P05412 UNIPROT "down-regulates activity" phosphorylation Ser243 PGETPPLsPIDMESQ 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-235892 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 GSK3B protein P49841 UNIPROT ARHGAP31 protein Q2M1Z3 UNIPROT "up-regulates activity" phosphorylation Thr789 PPAPPPPtPLEESTP 10090 BTO:0000944 17158447 t miannu "We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation." SIGNOR-262879 GDNF protein P39905 UNIPROT PTK2 protein Q05397 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-252184 ATF1 protein P18846 UNIPROT IL10 protein P22301 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 10540320 f mianu "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 MAPKAPK2 protein P49137 UNIPROT ZFP36 protein P26651 UNIPROT "down-regulates activity" phosphorylation Ser113 TELCRTFsESGRCRY -1 14688255 t miannu "We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated." SIGNOR-250156 P2RY4 protein P51582 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-257122 CDK2 protein P24941 UNIPROT SF3B1 protein O75533 UNIPROT up-regulates phosphorylation Thr244 GRAKGSEtPGATPGS 9606 SIGNOR-C16 12105215 t gcesareni "To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313" SIGNOR-90434 DNMT3A protein Q9Y6K1 UNIPROT HOXA9 protein P31269 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24280869 f miannu "HOXA9 is significantly upregulated in both categories of DNMT3A modifications and this has been associated with poor prognosis in AML before (Figure 3d). In fact, almost the entire HOXA and HOXB cluster were significantly upregulated in AML samples with either epimutation or mutation in DNMT3A." SIGNOR-256128 MAPK3 protein P27361 UNIPROT CTTN protein Q14247 UNIPROT up-regulates phosphorylation Ser418 TEERLPSsPVYEDAA 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-169686 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 CFL1 protein P23528 UNIPROT Axonal_growth_cone_formation phenotype SIGNOR-PH199 SIGNOR down-regulates 9606 16226035 f 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-268382 GEMIN6 protein Q8WXD5 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-253120 MAPK1 protein P28482 UNIPROT PML protein P29590 UNIPROT up-regulates phosphorylation Ser530 DGPPSPRsPVIGSEV 9606 BTO:0001271 15093545 t "The effect has been demonstrated using P29590-4" gcesareni "We conclude that phosphorylation by map kinase cascades potentiates the antiproliferative functions of pml and helps mediate the proapoptotic effects of as(2)o(3)." SIGNOR-124056 SUZ12 protein Q15022 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23836662 f miannu "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-254150 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 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 SRC protein P12931 UNIPROT SRC protein P12931 UNIPROT up-regulates phosphorylation Tyr216 KLDSGGFyITSRTQF 9606 BTO:0000150 12753909 t lperfetto "This study establishes that her2/hrg signaling selectively upregulates tyr phosphorylation of c-src at tyr-215 located within the sh2 domain, increases c-src kinase activity" SIGNOR-236246 "AIIB/b3 integrin" complex SIGNOR-C173 SIGNOR PTPN1 protein P18031 UNIPROT "up-regulates activity" binding 16115959 t lperfetto "N this study, we demonstrate an essential role for protein-tyrosine phosphatase (PTP)-1B in this process. In resting platelets, c-Src forms a complex with alphaIIbbeta3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain c-Src autoinhibition. Fibrinogen binding to alphaIIbbeta3 triggers PTP-1B recruitment to the alphaIIbbeta3-c-Src-Csk complex in a manner that is dependent on c-Src and specific tyrosine (tyrosine 152 and 153) and proline (proline 309 and 310) residues in PTP-1B. Studies of PTP-1B-deficient mouse platelets indicate that PTP-1B is required for fibrinogen-dependent Csk dissociation from alphaIIbbeta3, dephosphorylation of c-Src tyrosine 529, and c-Src activation." SIGNOR-261800 cabozantinib chemical CHEBI:72317 ChEBI FLT3 protein P36888 UNIPROT "down-regulates activity" "chemical inhibition" 9606 BTO:0000184 26536165 t miannu "Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3." SIGNOR-262242 SH3BP1 protein Q9Y3L3 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-260514 LCK protein P06239 UNIPROT LAT protein O43561 UNIPROT up-regulates phosphorylation Tyr220 SLDGSREyVNVSQEL 9606 BTO:0000782 16938345 t gcesareni "Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation." SIGNOR-149186 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 bromocriptine chemical CHEBI:3181 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-258723 DNA_damage stimulus SIGNOR-ST1 SIGNOR MLH1/PMS2 complex SIGNOR-C59 SIGNOR up-regulates -1 10542278 f miannu "HMLH1 and hPMS2 function in postreplicative mismatch repair in the form of a heterodimer referred to as hMutLα. Tumors or cell lines lacking this factor display mutator phenotypes and microsatellite instability, and mutations in the hMLH1 andhPMS2 genes predispose to hereditary non-polyposis colon cancer. Recombinant hMutLα and hMutLβ, expressed in the baculovirus system, were tested for their activity in an in vitro mismatch repair assay." SIGNOR-259062 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 CREB1 protein P16220 UNIPROT PPARGC1A protein Q9UBK2 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 11557984 t "CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo" SIGNOR-256150 GAS6 protein Q14393 UNIPROT TYRO3 protein Q06418 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-34414 HIC1 protein Q14526 UNIPROT E2F1 protein Q01094 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000452 19486893 f miannu "HIC1 is also implicated in growth control since it recruits BRG1, one of the two alternative ATPases (BRM or BRG1) of SWI/SNF chromatin-remodeling complexes to repress transcription of E2F1 in quiescent fibroblasts." SIGNOR-254239 AP1 complex SIGNOR-C154 SIGNOR CCL2 protein P13500 UNIPROT "up-regulates activity" "transcriptional regulation" 9606 21561061 t Luana "3b Potentiates AP-1-Dependent MCP-1 Promoter Activity" SIGNOR-260764 CDK2 protein P24941 UNIPROT ESR1 protein P03372 UNIPROT up-regulates phosphorylation Ser118 LHPPPQLsPFLQPHG 9606 SIGNOR-C83 10428798 t gcesareni "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-69718 PI3K complex SIGNOR-C156 SIGNOR BTK protein Q06187 UNIPROT "up-regulates activity" phosphorylation 10090 BTO:0000899 10201980 t lperfetto "Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation" SIGNOR-252709 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 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 GDP smallmolecule CHEBI:17552 ChEBI GNAS protein Q5JWF2 UNIPROT down-regulates "chemical inhibition" 9606 17095603 t gcesareni "Galfa subunits cycle between inactive (GDP-bound) and active (GTP-bound) states, and the lifetime of the active state is limited by GTP hydrolysis." SIGNOR-253072 E2F5 protein Q15329 UNIPROT CBP/p300 complex SIGNOR-C6 SIGNOR "up-regulates activity" binding 9606 BTO:0001938 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. These results indicate that phosphorylation of E2F-5 at the CDK site at position 251 by cyclin E–Cdk2 augments transcription by enhancing the interaction of E2F-5 with p300/CBP co-activator proteins." SIGNOR-262733 SMURF proteinfamily SIGNOR-PF29 SIGNOR SMAD5 protein Q99717 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-270213 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 F10 protein P00742 UNIPROT "Factor Va-Xa" complex SIGNOR-C318 SIGNOR "form complex" binding -1 2026608 t lperfetto "The binding of factor Xa to factor Va in the presence of Ca2+ ions and phospholipid is fundamental for the activation of prothrombin to thrombin. |Regardless of which protein was labeled, a factor Xa-Va complex (s20,w = 9.8) was formed. The interaction is specific and reversible. I" SIGNOR-263557 CSNK1G1 protein Q9HCP0 UNIPROT FOXO proteinfamily SIGNOR-PF27 SIGNOR "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-252901 cetuximab antibody DB00002 DRUGBANK EGFR protein P00533 UNIPROT "down-regulates activity" binding 9606 BTO:0001615 16336752 t miannu "Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment." SIGNOR-259890 ERK1/2 proteinfamily SIGNOR-PF1 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-270176 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 N protein P59595 UNIPROT AP1 complex SIGNOR-C154 SIGNOR "up-regulates activity" 9606 14623261 t Luana "Taken together, we have shown that the coronavirus N protein can activate AP-1 signal transduction pathway." SIGNOR-260725 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 TLN1 protein Q9Y490 UNIPROT "A3/b1 integrin" complex SIGNOR-C161 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-257610 MRPL51 protein Q4U2R6 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-262337 MRPL54 protein Q6P161 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-262336 MRPL14 protein Q6P1L8 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-262379 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 MAP2K6 protein P52564 UNIPROT PAK6 protein Q9NQU5 UNIPROT up-regulates phosphorylation Tyr566 KSLVGTPyWMAPEVI 9606 15550393 t llicata "Moreover, pak6 was directly activated by mkk6, and mutation of tyrosine 566 in a consensus mkk6 site (threonine-proline-tyrosine, tpy) in the activation loop of the pak6 kinase domain prevented activation by mkk6." SIGNOR-130975 "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 NEK2 protein P51955 UNIPROT PP1 proteinfamily SIGNOR-PF54 SIGNOR down-regulates phosphorylation 9606 10880350 t lperfetto "Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity. / threonine-307 and -318 appear to be equally well phosphorylated by nek2" SIGNOR-264655 TMLHE protein Q9NVH6 UNIPROT 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine smallmolecule CHEBI:15786 ChEBI "up-regulates quantity" "chemical modification" 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-269684 EZH2 protein Q15910 UNIPROT HOXB13 protein Q92826 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001033 22808286 f miannu "EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex." SIGNOR-254144 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 AMPK complex SIGNOR-C15 SIGNOR HDAC4 protein P56524 UNIPROT down-regulates phosphorylation 9606 BTO:0000938 BTO:0000887 21565617 t lperfetto "We show here that in liver, class iia hdacs (hdac4, 5, and 7) are phosphorylated and excluded from the nucleus by ampk family kinases." SIGNOR-216658 SMURF1 protein Q9HCE7 UNIPROT FKBP3 protein Q00688 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-272694 AIMP1 protein Q12904 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 ​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-270359 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 PBX1 protein P40424 UNIPROT CDKN2A protein P42771 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 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-267239 PRKCZ protein Q05513 UNIPROT PRKCZ protein Q05513 UNIPROT up-regulates phosphorylation Thr560 TSEPVQLtPDDEDAI 9606 11141077 t gcesareni "Our findings suggest that insulin, via pip(3), provokes increases in pkc-zeta enzyme activity through (a) pdk-1-dependent t410 loop phosphorylation, (b) t560 autophosphorylation" SIGNOR-85505 RBM15 protein Q96T37 UNIPROT RBM15/NXF1 complex SIGNOR-C67 SIGNOR "form complex" binding 9606 17001072 t miannu "Rbm15 binds to nxf1 and the two proteins cooperate in stimulating rte-mediated mrna export and expression." SIGNOR-149883 AHCTF1 protein Q8WYP5 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-262086 CDK2 protein P24941 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. We propose that under physiological conditions, phosphorylation of Smad3 by CDK inhibits its transcriptional activity, contributing to a decreased level of p15 and an increased level of c-Myc, thus facilitating cell cycle progression from G1 to S phase." SIGNOR-250750 PRKCQ protein Q04759 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-249283 PDPK1 protein O15530 UNIPROT OXTR protein P30559 UNIPROT "up-regulates activity" phosphorylation 9606 BTO:0000007 35104164 t lperfetto "We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1).|In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop." SIGNOR-268577 MAP2K2 protein P36507 UNIPROT PPARG protein P37231 UNIPROT up-regulates binding 9606 18596912 t gcesareni "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-179393 KAT2A protein Q92830 UNIPROT SLC44A2 protein Q8IWA5 UNIPROT "up-regulates quantity" 9606 BTO:0003065 21367571 f lperfetto "Among these, SLC44A2 (a putative choline transporter) was strikingly upregulated by ethanol (three fold), and GCN5 silencing downregulated it" SIGNOR-260408 PPP3CB protein P16298 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser180 GSSASFIsDTFSPYT 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-248370 "Neurokinin A" smallmolecule CHEBI:80311 ChEBI TACR2 protein P21452 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-257587 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 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 PRKD1 protein Q15139 UNIPROT CTTN protein Q14247 UNIPROT down-regulates phosphorylation Ser298 EKLAKHEsQQDYSKG 9606 20363754 t lperfetto "Pkd phosphorylates cortactin in vitro and in vivo at serine 298 thereby generating a 14-3-3 binding motif. In vitro, a phosphorylation-deficient cortactin-s298a protein accelerated vca-arp-cortactin-mediated synergistic actin polymerization and showed reduced f-actin binding" SIGNOR-164756 PRKCD protein Q05655 UNIPROT BDKRB2 protein P30411 UNIPROT "down-regulates activity" phosphorylation Ser373 SMGTLRTsISVERQI 9606 BTO:0000007 11517230 t lperfetto "In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation." SIGNOR-249108 T_cell_activation phenotype SIGNOR-PH73 SIGNOR IFNG protein P01579 UNIPROT "up-regulates quantity" 9606 BTO:0002417 32454942 f miannu "interferon gamma- (IFNγ-) and interleukin-17- (IL-17-) secreting CD4+ T cells are believed to be the pathogenic initiators of MS [22], and in MS patients, the increased production of either IFNγ or IL-17 is associated with pathology" SIGNOR-263818 cyproheptadine chemical CHEBI:4046 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-258869 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 EP300 protein Q09472 UNIPROT EP300 protein Q09472 UNIPROT "up-regulates activity" acetylation 9606 BTO:0003292 28045112 t lperfetto "Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3|Importantly, Brd3 promotes the recruitment of IRF3/p300 complex to the promoter of Ifnb1, and increases the acetylation of histone3/histone4 within the Ifnb1 promoter, leading to the enhancement of type I interferon production." SIGNOR-262045 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 CYTH2 protein Q99418 UNIPROT ARF6 protein P62330 UNIPROT "up-regulates activity" "guanine nucleotide exchange factor" 10116 BTO:0003102 14565977 t miannu "Effects of ARNO upon Axonogenesis Are Mediated by Downstream Activation of ARF6. ARNO/ARF6 signaling pathways that could modulate actin reorganization in the axonal growth cone. ARNO stimulates GTP exchange on ARF6, thereby increasing the amount of active ARF6." SIGNOR-264910 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 WNT5B protein Q9H1J7 UNIPROT PPARG protein P37231 UNIPROT up-regulates 9606 19577541 f fspada "Wnt5b additionally appears to be a potent enhancer of adipogenic capacity by stimulation of ppargamma" SIGNOR-186625 RPS6KA3 protein P51812 UNIPROT NFATC4 protein Q14934 UNIPROT up-regulates phosphorylation Ser289 PALSRRGsLGEEGSE 10090 17213202 t lperfetto "The results indicated that rsk2 phosphorylated two additional sites at ser289 (peptide 2) and ser344 (peptide 3)rsk2 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-234473 "Cullin 1-RBX1-Skp1" complex SIGNOR-C529 SIGNOR SQSTM1 protein Q13501 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0000007 25721664 t miannu "F-box protein Fbxo3 targets Smurf1 ubiquitin ligase for ubiquitination and degradation. Here we show that another F-box protein Fbxo3, belonging to the FBXO type protein family, also interacts with and targets Smurf1 for poly-ubiquitination and proteasomal degradation. The SCF complex is composed of F-box protein, Skp1, Cullin1 (Cul1) and ROC1. Fbxo3, whose substrates are few, forms SCF Fbxo3 ubiquitin ligase and regulates the degradations of Fbxl2, p62, HIPK2 and p300 through the ubiquitin-proteasome pathway." SIGNOR-272446 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 KLHL15 protein Q96M94 UNIPROT "Cullin 3-RBX1-Skp1" complex SIGNOR-C526 SIGNOR "up-regulates activity" binding 9606 BTO:0000007 23135275 t miannu "Here, we report that KLHL15-Cul3 specifically targets B'β to promote turnover of the PP2A subunit by ubiquitylation and proteasomal degradation. We mapped KLHL15 residues critical for homodimerization as well as interaction with Cul3 and B'β." SIGNOR-272018 PPP1CB protein P62140 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-248568 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 RAD21 protein O60216 UNIPROT RUNX1 protein Q01196 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 24321385 t miannu "We observed that depletion of RAD21 (but not CTCF) enhanced RUNX1 transcription in human HL-60 myelocytic leukemia cells" SIGNOR-259973 EREG protein O14944 UNIPROT EGFR protein P00533 UNIPROT up-regulates binding 9606 BTO:0000150 9419975 t "Epiregulin may be a mediator of localized cell proliferation" gcesareni "Chemical cross-linking experiments showed that [125i]epiregulin directly bound to each of egfr and erbb-4 but not to erbb-2 and erbb-3. 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-54351 WNT1 protein P04628 UNIPROT MYF5 protein P13349 UNIPROT "up-regulates activity" 10090 BTO:0000887;BTO:0001103 9753670 f gcesareni "Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5" SIGNOR-60285 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 PPP1CC protein P36873 UNIPROT CDK9 protein P50750 UNIPROT up-regulates dephosphorylation Thr186 NSQPNRYtNRVVTLW 9606 21533037 t amattioni "Pp1 is an activator of cdk9. Pp1 dephosphorylates cdk9 thr186." SIGNOR-173454 COLGALT1 protein Q8NBJ5 UNIPROT ADIPOQ protein Q15848 UNIPROT "up-regulates activity" palmitoylation 9606 BTO:0000007 28428430 t "We conclude that GLT25D1 regulates HMW adiponectin secretion and lipid accumulation, consistent with changes in mice after high-fat feeding. These results suggest a novel function of GLT25D1 leading to decreased HMW adiponectin secretion in early obesity." SIGNOR-261149 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 MELK protein Q14680 UNIPROT MELK protein Q14680 UNIPROT up-regulates phosphorylation Ser431 ENVYTPKsAVKNEEY 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-141010 YY1 protein P25490 UNIPROT NOTCH proteinfamily SIGNOR-PF30 SIGNOR "down-regulates activity" binding 9606 BTO:0000664 12913000 t "Taken together, these results indicate that transcription factor YY1 may modulate Notch signaling via association with the high molecular weight Notch complex [..] both YY1 and N1IC were present in a large complex of the nucleus to suppress the luciferase reporter activity transactivated by Notch signaling." SIGNOR-254305 LRRK2 protein Q5S007 UNIPROT SH3GL2 protein Q99962 UNIPROT down-regulates phosphorylation Ser75 LSMINTMsKIRGQEK 9606 22998870 t gcesareni "We show that lrrk2 affects synaptic endocytosis by phosphorylating endophilin-a1 at s75." SIGNOR-192072 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 PIGS protein Q96S52 UNIPROT GPAA1 protein O43292 UNIPROT "up-regulates activity" binding 10090 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-261361 MAPK14 protein Q16539 UNIPROT STAT4 protein Q14765 UNIPROT up-regulates phosphorylation Ser721 PSDLLPMsPSVYAVL 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-154787 H2AX protein P16104 UNIPROT NBN protein O60934 UNIPROT up-regulates binding 9606 15635255 t esanto "Nbs1 physically interacts with ?-H2ax to form nuclear foci at dna damage sites. The inhibition of this interaction by introduction of anti-?-H2ax antibody into cells abolishes nbs1 foci formation in response to dna damage." SIGNOR-133020 EDNRB protein P24530 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-257428 CDK1 protein P06493 UNIPROT LMNA protein P02545 UNIPROT up-regulates phosphorylation Ser22 QASSTPLsPTRITRL 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-181310 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 NGEF protein Q8N5V2 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-260562 TTL protein Q8NG68 UNIPROT TUBA8 protein Q9NY65 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-176930 GLI2 protein P10070 UNIPROT IFITM5 protein A6NNB3 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 23530031 f miannu "Regulation of the bone-restricted IFITM-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril transcription is activated by Sp1, Sp3, OSX, and GLI2 and by CpG demethylation." SIGNOR-254217 CDR2 protein Q01850 UNIPROT CENPE protein Q02224 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-252020 RACK1 protein P63244 UNIPROT PTK7 protein Q13308 UNIPROT up-regulates binding 9606 21350015 t gcesareni "Here, we identify rack1 as a novel interaction partner of ptk7. Mechanistically, rack1 is necessary for the ptk7-mediated membrane localization of dishevelled (dsh). Rack1 facilitates the ptk7-dsh interaction by recruiting pkcdelta1, a known effector of dsh membrane translocation." SIGNOR-172322 MAP3K3 protein Q99759 UNIPROT WDR62 protein O43379 UNIPROT "up-regulates quantity by stabilization" binding 30566428 t lperfetto "Specifically, we demonstrate that MEKK3 interacts with WDR62 to stabilize WDR62 and regulates JNK activity in a synergic way. On the other hand, JNK activity also regulates the phosphorylation of WDR62 at T1053 in a feedback loop which facilities the recruitment of FBW7 degradation of WDR62" SIGNOR-271714 RPS6KA3 protein P51812 UNIPROT H3C1 protein P68431 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-138475 ARHGAP23 protein Q9P227 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-260479 VEPH1 protein Q14D04 UNIPROT LATS1/2 proteinfamily SIGNOR-PF43 SIGNOR "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-269858 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 PPP3CA protein Q08209 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-248676 "Neuronal AP-3" complex SIGNOR-C445 SIGNOR Melanosome_assembly phenotype SIGNOR-PH180 SIGNOR up-regulates 9606 22203680 f miannu "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-268522 CDK1 protein P06493 UNIPROT 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-271839 PAC-1 chemical CID:6851947 PUBCHEM CASP3 protein P42574 UNIPROT up-regulates "chemical activation" 9606 Other t Selleck gcesareni SIGNOR-198535 AKT2 protein P31751 UNIPROT PCBP1 protein Q15365 UNIPROT "down-regulates activity" phosphorylation Ser43 VKRIREEsGARINIS 10090 BTO:0004183 20154680 t miannu "We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs." SIGNOR-262625 FYN protein P06241 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-268213 CHUK protein O15111 UNIPROT NCOR2 protein Q9Y618 UNIPROT down-regulates phosphorylation Ser2407 AKVSGRPsSRKAKSP 9606 SIGNOR-C14 15494311 t "Translocation from Nucleus to Cytoplasm" gcesareni "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-129956 SIAH1 protein Q8IUQ4 UNIPROT NOTCH1 protein P46531 UNIPROT up-regulates relocalization 9606 20940030 t gcesareni "The overexpression of siah1 causes the re-localization of notch from the cell surface to the cytoplasm and to the nucleus, which is indicative of notch activation" SIGNOR-168460 PTPRC protein P08575 UNIPROT JAK2 protein O60674 UNIPROT "down-regulates activity" dephosphorylation 9606 24252238 t miannu "Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates." SIGNOR-255679 AKT proteinfamily SIGNOR-PF24 SIGNOR CREB1 protein P16220 UNIPROT "up-regulates activity" phosphorylation Ser119 EILSRRPsYRKILND 9606 BTO:0000007 9829964 t gcesareni "When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner." SIGNOR-247992 AKT proteinfamily SIGNOR-PF24 SIGNOR 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-244255 MAPK3 protein P27361 UNIPROT MBP protein P02686 UNIPROT down-regulates phosphorylation Thr232 KNIVTPRtPPPSQGK 9606 BTO:0000142 16401070 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-143481 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-269196 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 LCK protein P06239 UNIPROT VAV1 protein P15498 UNIPROT unknown phosphorylation Tyr174 EAEGDEIyEDLMRSE -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-251391 RPTOR protein Q8N122 UNIPROT mTORC1 complex SIGNOR-C3 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-205627 PTPN11 protein Q06124 UNIPROT ERK1/2 proteinfamily SIGNOR-PF1 SIGNOR "up-regulates activity" 9606 11085989 f miannu "We show here that leptin can activate ERK signaling in thehypothalamus and that this stimulation is likely to occur viatwo pathways, both involving SHP-2.We have shown above that SHP-2 is a positive mediator of ERK activation by ObRb and that this requires both the phosphatase activity and tyrosine phosphorylation of SHP-2. Furthermore,Tyr-985 is required for maximal ERK phosphorylation." SIGNOR-263500 EZH2 protein Q15910 UNIPROT SNAI2 protein O43623 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 23836662 f miannu "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-254146 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 TGFBR2 protein P37173 UNIPROT TGFBR2 protein P37173 UNIPROT "down-regulates activity" phosphorylation Ser416 SVDDLANsGQVGTAR 9606 9155023 t lperfetto "Tbetarii kinase is regulated intricately by autophosphorylation on at least three serine residues. Phosphorylation of ser416 inhibits receptor function." SIGNOR-48412 SGK2 protein Q9HBY8 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-249130 MDM2 protein Q00987 UNIPROT EID1 protein Q9Y6B2 UNIPROT "down-regulates quantity by destabilization" polyubiquitination 9606 BTO:0001938 11073989 t miannu "Degradation of EID-1 occurs via ubiquitin-dependent proteolysis and correlates with MDM2 binding. These results are consistent with a model wherein destruction of EID-1 is linked to its ability to interact with MDM2 via either p300 or pRB." SIGNOR-272582 TOP2B protein Q02880 UNIPROT CDH13 protein P55290 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-242302 SRP54 protein P61011 UNIPROT SRPRA protein P08240 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-261163 Ub:E2 complex SIGNOR-C497 SIGNOR TRIM38 protein O00635 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-271141 PPP1CA protein P62136 UNIPROT Gbeta proteinfamily SIGNOR-PF4 SIGNOR down-regulates dephosphorylation 9606 12840032 t "inferred from 70% of family members" fstefani "P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3). the dual specificity phosphatases that specifically dephosphorylate and inactivate the p-erk1/2 are called mapk phosphatases" SIGNOR-269906 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 SKI protein P12755 UNIPROT SMAD3/SMAD4 complex SIGNOR-C9 SIGNOR "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-253301 SOX4 protein Q06945 UNIPROT CTNNB1 protein P35222 UNIPROT "up-regulates activity" binding 9606 BTO:0000038 17875931 t irozzo "We have demonstrated that Sox17 and Sox4 can directly interact with β-catenin and TCF/LEF proteins.Sox4 enhances β-catenin/TCF activity and the proliferation of SW480 cells.In contrast, Sox4 may function to stabilize β-catenin protein." SIGNOR-256138 Riluzole chemical CHEBI:8863 ChEBI KCNN2 protein Q9H2S1 UNIPROT "up-regulates activity" "chemical activation" 9606 BTO:0000007 18955585 t Luana "Here, we used the neuroprotectant riluzole as a template for the design of KCa2/3 channel activators that are potent enough for in vivo studies. Of a library of 41 benzothiazoles, we identified 2 compounds, anthra[2,1-d]thiazol-2-ylamine (SKA-20) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), which are 10 to 20 times more potent than riluzole and activate KCa2.1 with EC50 values of 430 nM and 2.9 μM, KCa2.2 with an EC50 value of 1.9 μM, KCa2.3 with EC50 values of 1.2 and 2.9 μM, and KCa3.1 with EC50 values of 115 and 260 nM. " SIGNOR-258020 PTPRG protein P23470 UNIPROT PXN protein P49023 UNIPROT "up-regulates activity" dephosphorylation Tyr118 VGEEEHVySFPNKQK -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-254721 (S)-N-Hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide chemical CID:6918848 PUBCHEM HDAC6 protein Q9UBN7 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-262253 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 VCP protein P55072 UNIPROT NPLOC4 protein Q8TAT6 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-252423 PPP2CA protein P67775 UNIPROT DDHD1 protein Q8NEL9 UNIPROT unknown dephosphorylation Ser727 TIPSPVTsPVLSRRH -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-262976 PAK4 protein O96013 UNIPROT CTNNB1 protein P35222 UNIPROT up-regulates phosphorylation Ser675 QDYKKRLsVELTSSL 9606 22173096 t lperfetto "Pak4 interacts with and phosphorylates _-catenin on ser675, which promotes the tcf/lef transcriptional activity and stabilizes _-catenin through inhibition of its degradation." SIGNOR-191557 EEF2K protein O00418 UNIPROT EEF2 protein P13639 UNIPROT down-regulates phosphorylation Thr59 GETRFTDtRKDEQER 9606 2261989 t gcesareni "Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58." SIGNOR-22928 ELAVL3 protein Q14576 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-266864 MAPK3 protein P27361 UNIPROT HSPB8 protein Q9UJY1 UNIPROT up-regulates phosphorylation Ser27 PFRDSPLsSRLLDDG 9606 22721717 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-197932 S100A8 protein P05109 UNIPROT Tubulin proteinfamily SIGNOR-PF46 SIGNOR "up-regulates quantity by stabilization" binding 9606 BTO:0000876 16690079 t miannu "Calcium-induced complexes of S100A8 and S100A9 have been shown to colocalize with microtubules (MTs) during activation of monocytes. Functional analyses demonstrated that the complexes are involved in cytoskeletal organization and that they directly bind to tubulin and promote tubulin polymerization in a calcium-dependent manner" SIGNOR-261937 Ub:E2 complex SIGNOR-C497 SIGNOR RNF212 protein Q495C1 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-271160 PPM1A protein P35813 UNIPROT SMAD3 protein P84022 UNIPROT "down-regulates activity" dephosphorylation 9606 16751101 t lperfetto "Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads." SIGNOR-232110 MIB2 protein Q96AX9 UNIPROT JAG2 protein Q9Y219 UNIPROT up-regulates ubiquitination 9606 15920166 t gcesareni "Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2." SIGNOR-137922 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 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 HMGA1 protein P17096 UNIPROT POU3F1 protein Q03052 UNIPROT "up-regulates activity" binding 9606 BTO:0002127 7791781 t 2 miannu "Direct contacts were identified between the POU domain of Tst-1/Oct-6 and a short stretch of 10 amino acids in the central portion of HMG-I/Y. In the presence of HMG-I/Y, Tst-1/Oct-6 exhibited an increased affinity for this AT-rich element." SIGNOR-240155 UCHL5 protein Q9Y5K5 UNIPROT SMAD7 protein O15105 UNIPROT up-regulates binding 9606 16027725 t gcesareni "Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases." SIGNOR-138879 ID2 protein Q02363 UNIPROT TCF4 protein P15884 UNIPROT "down-regulates activity" binding 10090 BTO:0004058 SIGNOR-C129 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-241376 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 CDK2 protein P24941 UNIPROT PGR protein P06401 UNIPROT down-regulates phosphorylation Ser294 APMAPGRsPLATTVM 9606 BTO:0000150 10655479 t miannu "Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26s proteasome" SIGNOR-74708 MRGPRX2 protein Q96LB1 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-257327 MRPL35 protein Q9NZE8 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-262362 DMXL2 protein Q8TDJ6 UNIPROT MADD protein Q8WXG6 UNIPROT "up-regulates quantity" binding 10116 BTO:0000142 11809763 t miannu "We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles." SIGNOR-265581 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 AURKB protein Q96GD4 UNIPROT RASSF1 protein Q9NS23 UNIPROT down-regulates phosphorylation Ser207 TSVRRRTsFYLPKDA 9606 19276349 t llicata "Here, we show that aurora a and b associate with and phosphorylate rassf1a on serine 203 aurora a regulates prometaphase progression by inhibiting the ability of rassf1a to suppress apc-cdc20 activity." SIGNOR-184561 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 CHEK2 protein O96017 UNIPROT E2F1 protein Q01094 UNIPROT "up-regulates activity" phosphorylation Ser364 PLLSRMGsLRAPVDE 9606 12717439 t Manara "Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. | These results suggest that the Ser 364 site is phosphorylated by Chk2 and that anti-P-Ser 364 recognises the phosphorylated site in E2F-1." SIGNOR-260822 PTPN2 protein P17706 UNIPROT MET protein P08581 UNIPROT "down-regulates activity" dephosphorylation Tyr1234 RDMYDKEyYSVHNKT 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-248387 HES1 protein Q14469 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 16682003 t gcesareni "Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression." SIGNOR-146684 SLC2A4 protein P14672 UNIPROT glucose chemical CHEBI:17234 ChEBI "up-regulates quantity" relocalization 9606 17403369 t "Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step. The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis" SIGNOR-267288 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 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 GAST protein P01350 UNIPROT SLC4A2 protein P04920 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000269 22228178 f "Gastrin inhibited proliferation of colon cancer cells by suppressing expression of EGR1 and AE2 and by blocking ERK phosphorylation." SIGNOR-254251 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 NR1H4 protein Q96RI1 UNIPROT ABCB4 protein P21439 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0000575 14527955 f miannu "Here we show that the MDR3 gene is trans-activated by the farnesoid X receptor (FXR) via a direct binding of FXR/retinoid X receptor alpha heterodimers to a highly conserved inverted repeat element (a FXR response element) at the distal promoter (-1970 to -1958)." SIGNOR-254833 ABI1 protein Q8IZP0 UNIPROT ABL1 protein P00519 UNIPROT up-regulates binding 9606 9010225 t gcesareni "Our results are in agreement with previous report showing that abi-1, the putative mouse homologue of e3b1, is a abl binding protein" SIGNOR-45994 MAP3K20 protein Q9NYL2 UNIPROT MAP3K20 protein Q9NYL2 UNIPROT up-regulates phosphorylation Ser165 HNHTTHMsLVGTFPW 9606 15342622 t gcesareni "Ionizing radiation induces mrk autophosphorylation and activation. Within the mrk kinase loop between the dfg (subdomain vii) and ape (subdomain viii) residues, there are three conserved threonine/serine residues (thr161, thr162, and ser165) that are important for activation." SIGNOR-128573 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 RalGAP1 complex SIGNOR-C468 SIGNOR RALA protein P11233 UNIPROT "down-regulates activity" "guanine nucleotide exchange factor" 10090 BTO:0000011 21148297 t miannu "Here we report the identification and characterization of a Ral GAP complex (RGC) that mediates the activation of RalA downstream of the PI 3-kinase/Akt pathway. The complex is composed of an RGC1 regulatory subunit and an RGC2 catalytic subunit (previously identified as AS250) that directly stimulates the guanosine triphosphate hydrolysis of RalA." SIGNOR-269795 MAPK1 protein P28482 UNIPROT PPARA protein Q07869 UNIPROT "up-regulates activity" phosphorylation Ser12 ESPLCPLsPLEAGDL 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-249433 MAP3K4 protein Q9Y6R4 UNIPROT MAP3K4 protein Q9Y6R4 UNIPROT "up-regulates activity" phosphorylation Thr1494 KLKNNAQtMPGEVNS 9606 17242196 t lperfetto "Gadd45 binding also induced mtk1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of mtk1 at thr-1493 in the kinase activation loop." SIGNOR-152408 ABL1 protein P00519 UNIPROT ROBO1 protein Q9Y6N7 UNIPROT down-regulates phosphorylation Tyr1073 PSGQPTPyATTQLIQ 9606 10892742 t gcesareni "Abl functions to antagonize robo signaling both abl and ena can directly bind to robo's cytoplasmic domain." SIGNOR-78993 CSNK2A2 protein P19784 UNIPROT PPP1R8 protein Q12972 UNIPROT "up-regulates activity" phosphorylation Thr161 LGLPEEEtELDNLTE -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-251024 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 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 afimoxifene chemical CHEBI:44616 ChEBI ESR1 protein P03372 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-258594 MMP11 protein P24347 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-272356 CSNK2A1 protein P68400 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-250930 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 CAMK2G protein Q13555 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-85102 LPAR6 protein P43657 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-257286 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 "glutamic acid" smallmolecule CHEBI:18237 ChEBI GRIK3 protein Q13003 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-264472 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 NMI protein Q13287 UNIPROT SOX10 protein P56693 UNIPROT "down-regulates activity" binding 9606 16214168 t miannu "We identify an association of Sox10 with the N-myc interactor Nmi. Nmi modulated the transcriptional activity of Sox10 in reporter gene assays. Nmi effects varied between different Sox10 target gene promoters, indicating that Nmi function in vivo may be promoter-specific." SIGNOR-225602 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 MYC protein P01106 UNIPROT CCNA2 protein P20248 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 9606 BTO:0001271 12835716 f gcesareni "These results suggest that e2f1 and cyclin a2 may be induced by c-myc to mediate the onset of mammary cancer, whereas overexpression of cyclins d1 and e may occur later to facilitate tumor progression." SIGNOR-102728 MAPK8IP1 protein Q9UQF2 UNIPROT RBPJ protein Q06330 UNIPROT down-regulates binding 9606 20508646 t "Interferes with binding to Noth1-ICD." gcesareni "Here, we show that jip1 suppresses notch1 activity. Jip1 was found to physically associate with either intracellular domain of notch1 or rbp-jk and interfere with the interaction between them." SIGNOR-165713 CSK protein P41240 UNIPROT PECAM1 protein P16284 UNIPROT "up-regulates activity" phosphorylation Tyr713 KKDTETVySEVRKAV 9534 BTO:0001538 9624175 t miannu "We demonstrated that phosphorylation of PECAM-1 by Src or Csk family kinases was sufficient to trigger its association with SHP-2. Moreover, it was able to promote binding of PECAM-1 to SHP-1, a SHP-2-related protein-tyrosine phosphatase expressed in hemopoietic cells. Taken together, these findings indicated that the Src and Csk families of kinases are strong candidates for mediating tyrosine phosphorylation of PECAM-1 and triggering its association with SH2 domain-containing phosphatases under physiological circumstances." SIGNOR-262741 RIPK1 protein Q13546 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR "up-regulates activity" binding 10090 BTO:0000452 10795740 t gcesareni "We found that TNF-R1-mediated IKK activation requires both RIP and TRAF2 proteins. Although TRAF2 or RIP can be independently recruited to the TNF-R1 complex, neither one of them alone is capable of transducing the TNF signal that leads to IKK activation" SIGNOR-245026 DAPK1 protein P53355 UNIPROT STX1A protein Q16623 UNIPROT "down-regulates activity" phosphorylation Ser188 IIMDSSIsKQALSEI 9606 BTO:0000007;BTO:0000356 12730201 t llicata "Syntaxin-1A phosphorylation by DAP kinase or its S188D mutant, which mimics a state of complete phosphorylation, significantly decreases syntaxin binding to Munc18-1, a syntaxin-binding protein that regulates SNARE complex formation and is required for synaptic vesicle docking." SIGNOR-251083 CSNK1A1 protein P48729 UNIPROT CREB1 protein P16220 UNIPROT up-regulates phosphorylation Ser100 ESEDSQEsVDSVTDS 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-64258 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 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 calcium(2+) smallmolecule CHEBI:29108 ChEBI CAMK2G protein Q13555 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-198816 serotonin smallmolecule CHEBI:28790 ChEBI HTR4 protein Q13639 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-264294 REST protein Q13127 UNIPROT CARTPT protein Q16568 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000567 18485095 f miannu "When expression of NRSF was down-regulated in HeLa cells using a RNA interfering technique, the transcriptional activity of the CART promoter or a NRSE reporter was significantly increased. Taken together, our data suggested that CART gene expression in neuroendocrine cells is strictly controlled by NRSF, via a mechanism dependent upon the CART NRSE." SIGNOR-255073 GSK3B protein P49841 UNIPROT CEBPA protein P49715 UNIPROT "up-regulates activity" phosphorylation Thr230 GHPTPPPtPVPSPHP 10090 BTO:0000944 10567568 t "Glycogen synthase kinase 3 (GSK3) phosphorylates T222 and T226, causing a conformational change in C/EBPα. GSK3-mediated phosphorylation does not, in itself, dramatically alter the activity of C/EBPα in our assays. phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes." SIGNOR-251232 MAPK1 protein P28482 UNIPROT ARRB1 protein P49407 UNIPROT down-regulates phosphorylation Ser412 EEEDGTGsPQLNNR 9606 15456867 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-129585 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 UNC5 proteinfamily SIGNOR-PF98 SIGNOR 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-268168 AR protein P10275 UNIPROT CRH protein P06850 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0000931 16446741 t lperfetto "A direct androgenic involvement in the expression of human corticotropin-releasing hormone|A potential androgen-responsive element (ARE) in the human CRH promoter was subsequently analyzed with bandshifts and cotransfections in neuroblastoma cells. In the presence of testosterone, recombinant human AR bound specifically to the CRH-ARE." SIGNOR-268723 KLHL12 protein Q53G59 UNIPROT DVL1 protein O14640 UNIPROT "down-regulates quantity by destabilization" binding 9606 BTO:0000007 16547521 t miannu " KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation." SIGNOR-271558 NDC80 protein O14777 UNIPROT "Ndc80 complex" complex SIGNOR-C361 SIGNOR "form complex" binding 27881301 t lperfetto "Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. |NDC80C contains the NDC80, NUF2, SPC24, and SPC25 subunits" SIGNOR-265188 MAP3K5 protein Q99683 UNIPROT ZNF622 protein Q969S3 UNIPROT up-regulates phosphorylation Ser314 WCNEKGKsFYSTEAV 9606 21771788 t gcesareni "Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis." SIGNOR-175113 MAPK8IP1 protein Q9UQF2 UNIPROT MAPK8 protein P45983 UNIPROT down-regulates binding 9606 15141161 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-124727 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 OXTR protein P30559 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-257065 MVD protein P53602 UNIPROT RAC1 protein P63000 UNIPROT "up-regulates activity" lipidation 10090 25378391 t miannu "Akt modulated the pathway by phosphorylating mevalonate diphosphate decarboxylase (MDD) at Ser96. These data suggest that Akt regulates Rac1 activity by directly phosphorylating MDD at Ser96, which augments Rac1 geranylgeranylation." SIGNOR-265892 P2RY12 protein Q9H244 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-257107 CDK9 protein P50750 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-161569 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 HDAC7 protein Q8WUI4 UNIPROT PLAG1 protein Q6DJT9 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-140950 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 PARD6A protein Q9NPB6 UNIPROT RAC1 protein P63000 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-199530 "bisphenol A" chemical CHEBI:33216 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-268735 PRKACA protein P17612 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser491 SSTPQRSCsAAGLHRPR 10116 BTO:0002135 17023420 t "These agents also enhanced phosphorylation of alpha-Ser(485/491) by the cAMP-dependent protein kinase. AMPK alpha-Ser(485/491) phosphorylation was necessary but not sufficient for inhibition of AMPK activity in response to forskolin/isobutylmethylxanthine." SIGNOR-256112 panobinostat chemical CHEBI:85990 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-257750 WNT5B protein Q9H1J7 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-131882 AKT proteinfamily SIGNOR-PF24 SIGNOR PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation -1 16340011 t gcesareni "It is proposed that the effect of insulin to antagonize AMP-activated protein kinase activation involves a hierarchical mechanism whereby Ser 485/Ser 491 phosphorylation by protein kinase B reduces subsequent phosphorylation of Thr 172 by LKB1 and the resulting activation of AMP-activated protein kinase." SIGNOR-252740 PRKCA protein P17252 UNIPROT SNAP25 protein P60880 UNIPROT unknown phosphorylation Thr138 GGFIRRVtNDARENE 9606 12459461 t lperfetto "This study establishes that SNAP-25 is differentially phosphorylated by protein kinase C and protein kinase A in neuroendocrine PC12 cells. Using phosphopeptide mapping and site-directed mutagenesis we identified both Thr138 and Ser187 as the targets of SNAP-25 phosphorylation by protein kinase C" SIGNOR-249179 CSNK2A1 protein P68400 UNIPROT DDHD1 protein Q8NEL9 UNIPROT "down-regulates activity" phosphorylation Ser104 GSSLRYYsEGESGGG -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-262974 "GABA-A (a6-b1-g2) receptor" complex SIGNOR-C334 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-263780 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 INSR protein P06213 UNIPROT GAB1 protein Q13480 UNIPROT "up-regulates activity" phosphorylation Tyr659 VADERVDyVVVDQQK 10090 BTO:0000944 10978177 t "HGab-1 was phosphorylated by IR at eight tyrosine residues (Y242, Y285, Y373, Y447, Y472, Y619, Y657, and Y689). t Gab-1 is the major binding partner of PI-3 kinase in 3T3L1 cells when stimulated with insulin" SIGNOR-251317 "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 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 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 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 FLT3 protein P36888 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr350 EPPDHQYyNDFPGKE 9606 10482988 t miannu "Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313." SIGNOR-251147 TFIIH complex SIGNOR-C457 SIGNOR POLR2A protein P24928 UNIPROT "down-regulates quantity by destabilization" phosphorylation Ser1738 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-269340 PRKCB protein P05771 UNIPROT MARCKS protein P29966 UNIPROT unknown phosphorylation Ser170 SFKLSGFsFKKNKKE -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-248929 CDK2 protein P24941 UNIPROT RBL2 protein Q08999 UNIPROT down-regulates phosphorylation Ser1112 LLEDGSEsPAKRICP 9606 BTO:0001938 11157749 t gcesareni "When expressed in u2os cells, the phosphorylation-deficient mutant p130(delta)(cdk4), in which the cdk4 specific sites were mutated to alanine residues, imposed a more sustained g1 arrest than a constitutively active prb(delta)(cdk), known to repress all cellular e2f activity" SIGNOR-104656 "Caspase 3 complex" complex SIGNOR-C221 SIGNOR STK4 protein Q13043 UNIPROT "up-regulates activity" cleavage Asp326 NSEEDEMdSGTMVRA 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-256444 AMPK complex SIGNOR-C15 SIGNOR MLXIPL protein Q9NP71 UNIPROT down-regulates phosphorylation Ser556 LLRSPGsPQETVPE 10116 11724780 t lperfetto "These results strongly suggested that the fatty acid inhibition of glucose-induced l-PK transcription resulted from AMPK phosphorylation of ChREBP at Ser568, which inactivated the DNA binding activity." SIGNOR-216526 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 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 MASP2 protein O00187 UNIPROT C4A protein P0C0L4 UNIPROT "up-regulates activity" cleavage Arg679 EKTTRKKrNVNFQKA -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-263431 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 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-263017 "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 RIPK1 protein Q13546 UNIPROT IKBKG protein Q9Y6K9 UNIPROT "up-regulates activity" binding 9606 SIGNOR-C14 16603398 t lperfetto "Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation." SIGNOR-145858 PPP1R14A protein Q96A00 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-265742 NTNG1 protein Q9Y2I2 UNIPROT LRRC4C protein Q9HCJ2 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-264047 SYK protein P43405 UNIPROT SYK protein P43405 UNIPROT "up-regulates activity" phosphorylation Tyr352 TEVYESPyADPEEIR 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-246613 PTPRG protein P23470 UNIPROT INSR protein P06213 UNIPROT "up-regulates activity" dephosphorylation Tyr999 YASSNPEyLSASDVF -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-254703 TNFSF13B protein Q9Y275 UNIPROT TNFRSF13C protein Q96RJ3 UNIPROT "up-regulates activity" binding 9606 BTO:0000782 15851487 t lperfetto "Baff specifically binds baff receptor" SIGNOR-135713 SMAD6 protein O43541 UNIPROT SMAD1/4 complex SIGNOR-C85 SIGNOR down-regulates binding 9606 12857866 t lperfetto "Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4" SIGNOR-217706 FES protein P07332 UNIPROT BCR protein P11274 UNIPROT "down-regulates activity" phosphorylation Tyr246 SCGVDGDyEDAELNP 9606 BTO:0000007 8955135 t "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 32Pi-labeled cells. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. " SIGNOR-251137 ITK protein Q08881 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-112471 HDAC1 protein Q13547 UNIPROT SERPINB5 protein P36952 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0001570 18247378 t miannu "We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1." SIGNOR-268494 CSNK1A1 protein P48729 UNIPROT GLI2 protein P10070 UNIPROT down-regulates phosphorylation 9606 16611981 t gcesareni "Gli2 can also be phosphorylated directly by ck-1 at the non-optimal sites" SIGNOR-146112 AKT1 protein P31749 UNIPROT 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-195549 pyruvate smallmolecule CHEBI:15361 ChEBI (S)-lactate smallmolecule CHEBI:16651 ChEBI "up-regulates quantity" "precursor of" 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-267655 CSNK2A1 protein P68400 UNIPROT JUN protein P05412 UNIPROT down-regulates phosphorylation Ser249 LSPIDMEsQERIKAE 9606 1516134 t lperfetto "Casein kinase ii is a negative regulator of c-jun dna binding and ap-1 activitywe show that two of these sites, thr-231 and ser-249, are phosphorylated by casein kinase ii (ckii)." SIGNOR-19603 FAM13B protein Q9NYF5 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-260504 DDIT3 protein P35638 UNIPROT ASNS protein P08243 UNIPROT "down-regulates quantity by repression" "transcriptional regulation" 9606 BTO:0002181 18940792 f miannu "C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene." SIGNOR-253837 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 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 PRMT1 protein Q99873 UNIPROT CNBP protein P62633 UNIPROT down-regulates methylation Arg25 ECPTGGGrGRGMRSR 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-204958 AKT proteinfamily SIGNOR-PF24 SIGNOR GSK3B protein P49841 UNIPROT down-regulates phosphorylation 28712664 t "AKT phosphorylates and inhibits GSK3 in addition to many other substrates including TSC2, FOXO proteins, TBC1D4." SIGNOR-255488 RHOH protein Q15669 UNIPROT ZAP70 protein P43403 UNIPROT "up-regulates activity" binding 9606 BTO:0000661 17028588 t irozzo "These findings suggest that RhoH is a critical regulator of thymocyte development and TCR signaling by mediating recruitment and activation of Zap70." SIGNOR-259084 PPP3CC protein P48454 UNIPROT NFATC2 protein Q13469 UNIPROT "up-regulates activity" dephosphorylation Ser172 LCLSPASsGSSASFI 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-248511 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 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 MAP3K14 protein Q99558 UNIPROT IKK-complex complex SIGNOR-C14 SIGNOR up-regulates phosphorylation 9606 9520446 t lperfetto "Nf-kappab-inducing kinase activates ikk-alpha by phosphorylation of ser-176.Nik preferentially phosphorylates ikk-alpha over ikk-beta, leading to the activation of ikk-alpha kinase activity; the accumulated nik phosphorylates ikkalfa." SIGNOR-217433 SRGAP2 protein O75044 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-260516 (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 MYH9 protein P35579 UNIPROT "RNA Polymerase II" complex SIGNOR-C391 SIGNOR "up-regulates activity" binding 9606 BTO:0004953 32685004 t miannu "Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo." SIGNOR-269285 STAG2 protein Q8N3U4 UNIPROT CD69 protein Q07108 UNIPROT up-regulates 9606 14660624 f miannu "Stag2 is able to enhance the activity of the tumor necrosis factor alpha, the cd69, and the human immunodeficiency virus long terminal repeat promoters in a nf-kappab-dependent manner." SIGNOR-119985 TRAF7 protein Q6Q0C0 UNIPROT Apoptosis phenotype SIGNOR-PH2 SIGNOR up-regulates 9606 15001576 f miannu "Overexpression of traf7 induced caspase-dependent apoptosis." SIGNOR-123218 HACE1 protein Q8IYU2 UNIPROT CCND1 protein P24385 UNIPROT "down-regulates quantity by destabilization" ubiquitination 9606 17694067 t miannu "Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1." SIGNOR-271405 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 NFIA protein Q12857 UNIPROT MYOG protein P15173 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 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-263983 MAX protein P61244 UNIPROT MYC protein P01106 UNIPROT up-regulates binding 9606 8425218 t esanto "In vivo transactivation assays suggest that myc-max and mad-max complexes have opposing functions in transcription and that max plays a central role in this network of transcription factors" SIGNOR-39137 PTPRF protein P10586 UNIPROT INSR protein P06213 UNIPROT down-regulates dephosphorylation Tyr1189 RDIYETDyYRKGGKG 9606 10734133 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-76009 STAT3 protein P40763 UNIPROT CEBPD protein P49716 UNIPROT "up-regulates quantity by expression" "transcriptional regulation" 10090 25787076 f miannu "P-Stat3 stimulates C/EBPδ expression and activity, which increases myostatin and MAFbx/Atrogin-1 and MuRF-1. Both pathways result in protein losses in muscle." SIGNOR-255334 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 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 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 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 PTGS2 protein P35354 UNIPROT "prostaglandin F2alpha" smallmolecule CHEBI:15553 ChEBI up-regulates "chemical modification" 9606 20219869 t apalma "NSAIDs are strong inhibitors of cycloxygenases (COX), and thereby impair the metabolism of arachidonic acid that is necessary for the synthesis of prostaglandins" SIGNOR-255359 PRKAA2 protein P54646 UNIPROT ULK1 protein O75385 UNIPROT up-regulates phosphorylation Ser556 GLGCRLHsAPNLSDL 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-186637 acetylcholine smallmolecule CHEBI:15355 ChEBI CHRM4 protein P08173 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-257471 PRKAA1 protein Q13131 UNIPROT PRKAA1 protein Q13131 UNIPROT "down-regulates activity" phosphorylation Ser486 DDEITEAKsGTATPQRS -1 17023420 t "We show that AMPK α-Ser485/491 can be a site for autophosphorylation, which may play a role in limiting AMPK activation in response to energy depletion or other regulators" SIGNOR-256114 LCK protein P06239 UNIPROT SHC1 protein P29353 UNIPROT "up-regulates activity" phosphorylation Tyr427 ELFDDPSyVNVQNLD 9606 BTO:0000782 9710204 t "We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins" SIGNOR-251388 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 PHLPP2 protein Q6ZVD8 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-248732 metformin chemical CHEBI:6801 ChEBI PRKAA1 protein Q13131 UNIPROT "up-regulates activity" 10116 11602624 f gcesareni "Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin€™s inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation" SIGNOR-241952 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 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 "N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester" chemical CHEBI:94187 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-257971 Ub:E2 complex SIGNOR-C497 SIGNOR UBE3B protein Q7Z3V4 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-271281 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 PKA proteinfamily SIGNOR-PF17 SIGNOR CDK18 protein Q07002 UNIPROT "up-regulates activity" phosphorylation Ser14 KNFKRRFsLSVPRTE 28361970 t lperfetto "We previously revealed that PCTK3 is activated by two pathways: interaction with cytoplasmic cyclin A and phosphorylation at Ser-12 by protein kinase A (PKA)12. Activated PCTK3 phosphorylates retinoblastoma protein (Rb) in vitro. " SIGNOR-264559 PRKCD protein Q05655 UNIPROT MEP1B protein Q16820 UNIPROT "down-regulates quantity" phosphorylation Ser687 KKYRERMsSNRPNLT 9534 BTO:0001538 12941954 t miannu "These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate." SIGNOR-263171 PCDHA2 protein Q9Y5H9 UNIPROT PCDHGA5 protein Q9Y5G8 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-265695 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 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 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 "perfluorohexanesulfonic acid" chemical CHEBI:132448 ChEBI AR protein P10275 UNIPROT "down-regulates activity" "chemical inhibition" -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-268766 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 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-261726 SERPINC1 protein P01008 UNIPROT F12 protein P00748 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-264139 GDNF protein P39905 UNIPROT RET protein P07949 UNIPROT up-regulates binding 9606 BTO:0000938 BTO:0000142 9182803 t gcesareni "A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling" SIGNOR-49094 ACP1 protein P24666 UNIPROT AKT3 protein Q9Y243 UNIPROT "down-regulates activity" dephosphorylation Ser472 RPHFPQFsYSASGRE 10090 17353188 t "Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3" SIGNOR-248457 MAPK3 protein P27361 UNIPROT SOS1 protein Q07889 UNIPROT down-regulates phosphorylation Ser1178 IMSKHLDsPPAIPPR 9606 8816480 t gcesareni "In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1" SIGNOR-43947 "EBV gH:gL:gp42" complex SIGNOR-C403 SIGNOR HLA-DRA protein P01903 UNIPROT "up-regulates activity" binding 9606 BTO:0000776 11864610 t scontino "The EBV gp42 glycoprotein binds MHC class II molecules, playing a critical role in infection of B lymphocytes. The gp42 binds HLA-DR1 using a surface site" SIGNOR-266628 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 nilotinib chemical CHEBI:52172 ChEBI BCR-ABL "fusion protein" SIGNOR-FP6 SIGNOR down-regulates "chemical inhibition" 9606 Other t Selleck gcesareni SIGNOR-194640 DDX3X protein O00571 UNIPROT SP1 protein P08047 UNIPROT "up-regulates activity" binding 9606 33627125 t miannu "DDX3X enhances transcription by interacting with transcription factors to promote their binding to the promoter of the target gene. The best characterized mechanism is its cooperation with the transcription factor SP1. The downstream genes of DDX3X-SP1-mediated transactivation include P21, KRAS, and MDM2" SIGNOR-269195 NCOA2 protein Q15596 UNIPROT AR protein P10275 UNIPROT "up-regulates activity" binding 9606 24239470 t miannu "The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis" SIGNOR-251531 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 GMIP protein Q9P107 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-260507 ARHGAP20 protein Q9P2F6 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-260474 PLEKHG1 protein Q9ULL1 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-260563 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 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 CNTFR protein P26992 UNIPROT STAT3 protein P40763 UNIPROT up-regulates 9606 10582086 f gcesareni